Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:20][CH2:19][CH2:18]2)[C:13]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:35])[CH3:37])[N:29]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC2)C(=O)O)cc1Cl
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
In a flask (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclobutyl-propionic acid (85 mg, 0.27 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylformamide (two drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 140 μL, 0.28 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 42 mg, 0.27 mmol), 2,6-lutidine (63 μL, 0.54 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1.5 h. After this time, the reaction was quenched with a small amount of methanol and diluted with ethyl acetate (20 mL). This was then washed with a 1 N aqueous hydrochloric acid solution (10 mL) and a saturated aqueous brine solution (10 mL). It was then dried over sodium sulfate, filtered and concentrated with silica gel (2 g) in vacuo and then purified on Biotage Flash chromatography system (40S column, silica gel, 100% ethyl acetate/hexanes to 10% methanol/ethyl acetate) to afford (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclobutyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (80 mg, 66%) as a white foam: ES-HRMS m/e calcd for C21H28N3O4SCl (M+H)+ 454.1562, observed 454.1557; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.49-2.21 (m, 9H, CH and 4×CH2), 3.33 (s, 3H, SO2CH3), 3.79 (m, 1H, ArCHCO), 3.87 (s, 2H, NCH2), 4.65 (s, 1H, OH), 6.44 (d, J=2.2 Hz, 1H, Ar), 7.51 (d, J=2.2 Hz, 1H, Ar), 7.57 (dd, Jm=1.5 Hz, Jo=8.2 Hz, 1H, Ar), 7.67 (d, Jm=1.5 Hz, 1H, Ar), 8.00 (d, Jo=8.2 Hz, 1H, Ar), 10.76 (s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:24][NH:25][C@H:26]([CH2:35][C:36]#[N:37])[C:27]([NH:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:28])=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:5]2=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C1COCC1>[Cl:1][C:2]1[C:3]2[CH2:24][N:25]([C@H:26]([CH2:35][C:36]#[N:37])[C:27]([NH:29][CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)=[O:28])[C:11](=[O:13])[C:10]3=[CH:9][N:8]([S:14]([C:17]4[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=4)(=[O:16])=[O:15])[C:5]([C:4]=23)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(CN[C@H](CC#N)C(=O)NC4CCCC4)c(Cl)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1ccc(S(=O)(=O)n2cc3c4c(c(Cl)cnc42)CN([C@H](CC#N)C(=O)NC2CCCC2)C3=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (R)-5-chloro-4-((3-cyano-1-(cyclopentylamino)-1-oxopropan-2-ylamino)methyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, THF (5 mL), HATU (28.6 mg, 0.075 mmol) and 4-methylmorpholine (19.01 mg, 0.188 mmol) was stirred at room temperature for 2 h. The product was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-90%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound. [M+H] calc'd for C25H24ClN5O4S, 526; found, 526.2.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][C:4](=[O:12])[NH:3][C:2]1=[O:13].CC(C)([O-])C.[K+].Br[CH2:21][CH2:22][CH2:23][Cl:24]>CN(C)C=O>[CH2:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:1][C:2](=[O:13])[N:3]([CH2:21][CH2:22][CH2:23][Cl:24])[C:4]1=[O:12]
Reactant: ClCCCBr
Reactant: O=C1Cc2ccccc2CC(=O)N1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1Cc2ccccc2CC(=O)N1CCCCl

Procedure:
Here, 1,3,4,5-tetrahydro-2H-3-benzazepin-2,4-dione (3.5 g, 0.020 mol) is suspended in dimethylformamide (30 ml) and potassium tert. butoxide (2.5 g) is added with stirring. After 10 minutes the resulting solution is added dropwise, while cooling with ice, to 1-bromo-3-chloro-propane (3.5 ml) in dimethylformamide (20 ml). After one hour it is poured onto ice water. After a short time the greasy precipitate crystallizes. The precipitate is suction filtered, dissolved in acetone, reprecipitated with water, suction filtered and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[N:25]1.C(Cl)(=O)C(Cl)=O.O1CCCC1>CN(C)C=O.CN1CCCC1=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:33]([C:26]5[C:27]6[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=6)[NH:24][N:25]=5)=[O:34])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1n[nH]c2ccccc12
Yield: 67.9 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.484 mmol), 1H-indazole-3-carboxylic acid (94 mg, 0.581 mmol), oxalyl chloride (84 μL, 0.969 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (5 mL) and N-methylpyrrolidone (5 mL) as starting materials and in the same manner as in Example 412, the title compound (149 mg, 68%) was obtained as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:17])=[C:4]([NH:9]C(=O)OC(C)(C)C)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl.[OH-].[Na+]>C(O)(C)C.O>[Br:1][C:2]1[C:3]([F:17])=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[NH2:9]
Reactant: Cc1cc(Br)c(F)c(NC(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(N)c(F)c(Br)c1
Temperature: 60 °C
Yield: 89.8 %

Procedure:
To a solution of tert-butyl 3-bromo-2-fluoro-5-methylphenylcarbamate (985 mg, 3.24 mmol) in isopropyl alcohol (10 mL) was added concentrated aqueous HCl (˜12 M, 2.6 mL, 32.4 mmol) and the reaction mixture was warmed to 60° C. for 2 hours, allowed to cool to room temperature, and then concentrated in vacuo to afford a white solid. The solid was dissolved in water and the resulting aqueous solution was neutralized with aqueous 1.0 M NaOH solution, and extracted with Et2O. The organic phase was washed with brine, dried (MgSO4) and concentrated to afford 3-bromo-2-fluoro-5-methylaniline (594 mg, 2.91 mmol, 90%) which was carried forward without further purification: 1H NMR (300 MHz, CDCl3) δ 2.21 (s, 3H) 3.71 (br s, 2H) 6.51 (d, J=7.9 Hz, 1H) 6.70 (d, J=4.7 Hz, 1H).
Reaction SMILES: [C:1]1(=[O:14])[O:13][C@@H:6]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].N1C=CN=C1.CN(C=O)C.[C:25]([Si:29](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:28])([CH3:27])[CH3:26]>C(OCC)(=O)C.O>[Si:29]([O:12][CH2:11][C@@H:9]([OH:10])[C@@H:7]([OH:8])[C@@H:6]1[O:13][C:1](=[O:14])[C@H:2]([OH:3])[C@@H:4]1[OH:5])([C:25]([CH3:28])([CH3:27])[CH3:26])([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1O[C@@H]([C@H](O)[C@H](O)CO)[C@@H](O)[C@H]1O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OC[C@@H](O)[C@@H](O)[C@@H]1OC(=O)[C@H](O)[C@@H]1O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 22 h
Yield: 55 %

Procedure:
D-glycero-D-gulo-Heptono-1,4-lactone (6) (10 g, 48.08 mmol) and imidazole (4.98 g, 1.5 equiv) were added to dry DMF (25 ml) and the mixture stirred at 0° C. under nitrogen. tert-Butylchlorodiphenylsilane (13.74 ml, 1.1 equiv) was added slowly, after which the reaction mixture was allowed to warm up to room temperature over three hours. After 22 hours, t.l.c. (eluant ethyl acetate) indicated that the mixture contained the desired monosilyl derivative (Rf 0.65) and a smaller amount of another carbohydrate derivative (Rf 0.9). The crude reaction mixture was shaken with water (50 ml), causing a white precipitate to form. Ethyl acetate (90 ml) was added and the layers separated after shaking. The aqueous layer was back-extracted with more ethyl acetate (25 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (4×25 ml) and dried (magnesium sulphate). Evaporation of the solvent followed by dry column chromatography (eluant hexane ethyl: acetate, 2:1, increasing the eluant polarity with each fraction), yielding 7-O-tert-butyldiphenylsilyl-D-glycero-D-gulo-heptono-1,4-lactone (7) (11.02 g, 55%) as a white solid, m.p. 54°-57° C. (Found: C, 61.58; H, 6.86%. C23H30O7Si requires: C, 61.87; H, 6.77%); [α]d20 -10.56° (c, 0.99 in CHCl3); vmax (CHCl3) 3410 (broad, OH) and 1790 cm-1 (γ-lactone); and 2,7-di-O-tert-butyldiphenylsilyl-D-glycero-D-gulo-heptono-1,4-lactone (8) (5.94 g, 18%) as a colorless, viscous oil [α]D20 -4.08° (c, 1.20 in CHCl3); vmax (CHCl3) 3440 (broad, OH) and 1790 cm-1 (γ-lactone).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCCCCc1ccccc1
Reactant: OCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCc1ccccc1OCCCCCc1ccccc1
Yield: 85.9 %

Procedure:
A solution of 10 g (80.56 mmol) of 2-hydroxybenzyl alcohol in 200 ml of dry acetonitrile is mixed with 27.45 g (120.83 mmol) of (5-bromopentyl)benzene from Example 26A and 12.25 g (88.61 mmol) of anhydrous potassium carbonate and heated under reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The resulting organic phase is concentrated. The crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 18.7 g (81% yield) of a colorless solid are obtained.
Reaction SMILES: [C:1](=[NH:25])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=2)=[C:8]([F:24])[CH:7]=1)[NH2:2].[OH:26]/[CH:27]=[C:28](/[CH2:33][C:34]1[CH:35]=[N:36][C:37]([O:40][CH3:41])=[N:38][CH:39]=1)\[C:29](OC)=O.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:29]=[C:28]([CH2:33][C:34]4[CH:35]=[N:36][C:37]([O:40][CH3:41])=[N:38][CH:39]=4)[C:27](=[O:26])[N:25]=3)=[CH:7][C:8]=2[F:24])=[CH:14][C:15]=1[C:20]([F:23])([F:21])[F:22]
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Reactant: COC(=O)/C(=C\O)Cc1cnc(OC)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)c(F)c3)nc2=O)cn1
Temperature: 160 °C
Yield: 14.5 %

Procedure:
A mixture of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-3-fluorophenyl)ethyl imidocarbamate (200 mg, 0.380 mmol), methyl (2Z)-3-hydroxy-2-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-propenoate (170 mg, 0.759 mmol) and K2CO3 (115 mg, 0.835 mmol) in NMP (5 mL) was heated with a microwave condition at 160° C. for 1.5 h. Purification via reverse phase flash chromatography afforded the title compound (32 mg, 0.055 mmol, 14.54% yield). LCMS: rt=3.53 min, [M+H]=551
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]CC2C=CC(OC)=CC=2)=[C:4]([O:18][CH3:19])[CH:3]=1.[F:20][C:21]([F:31])([F:30])[C:22](=O)[CH2:23][C:24]([O:26]CC)=O.OS(O)(=O)=O>C1C=CC=CC=1>[NH2:8][C:5]1[CH:6]=[C:7]2[C:2](=[CH:3][C:4]=1[O:18][CH3:19])[NH:1][C:24](=[O:26])[CH:23]=[C:22]2[C:21]([F:20])([F:30])[F:31]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: COc1ccc(CNc2ccc(N)cc2OC)cc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: COc1cc2[nH]c(=O)cc(C(F)(F)F)c2cc1N

Procedure:
This compound was prepared according to General Method 11 (EXAMPLE 22) from (4-amino-2-methoxyphenyl)-(4-methoxybenzyl)amine (1.23 g, 4.76 mmol) and ethyl 4,4,4-trifluoroacetoacetate (1.05 g, 5.71 mmol) in 60 mL benzene followed by treatment with 10 mL concentrated H2SO4 to afford 0.734 (60%) of 6-amino-7-methoxy-4-(trifluoromethyl)-1H-quinolin-2-one, a yellow solid, after rinsing with MeOH:ether:hexanes. Data for 6-amino-7-methoxy-4-(trifluoromethyl)-1H-quinolin-2-one: Rf 0.28 (19:1 CH2Cl2:MeOH); 1H NMR (500 MHz, CDCl3) δ 12.2 (v broad s, 1H), 7.06 (broad s, 1H), 6.93 (s, 1H), 6.79 (s, 1H), 4.01 (s, 3H), 3.94 (broad s, 2H).
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[F:11][C:12]1[C:17]([F:18])=[CH:16][C:15]([NH2:19])=[C:14]([NH2:20])[CH:13]=1>>[F:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:16][C:17]=1[F:18])[NH:19][C:1](=[O:8])[C:2](=[O:4])[NH:20]2
Reactant: Nc1cc(F)c(F)cc1N
Reactant: CCOC(=O)C(=O)OCC
Product: O=c1[nH]c2cc(F)c(F)cc2[nH]c1=O
Temperature: 25 °C

Procedure:
The title compound (Sarges, R. et al., J. Med. Chem. 33:2240 (1990)) was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (1.11 g, 7.63 mmol and 4,5-difluoro-1,2-diaminobenzene (110 mg, 0.763 mmol) was heated to reflux under N2 for 2 h. The reaction was allowed to cool to room temperature and the solid collected by vacuum filtration and rinsed with hexanes and air dried. This gray brown solid was recrystallized from 20 ml of EtOH and the brown-white crystals collected by vacuum filtration and the crystals further dried under vacuum (0.5 torr, 25° C.) to yield 45.3 mg (30.0%) mp>360° C. (lit.>310° C.). 1H NMR (d6 -acetone) δ7.19 (t, 2H, ArH, JH-F =9.3), 10.9 (br s, 2H, NH).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]=[C:14]1[S:18][CH2:17][C:16]2([CH2:22][CH2:21][CH2:20][CH2:19]2)[NH:15]1)([CH3:3])[CH3:2].[CH2:23](Br)[CH:24]([CH3:26])[CH3:25]>>[CH2:23]([N:15]1[C:16]2([CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:17][S:18][C:14]1=[N:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)CBr
Reactant: CC(C)c1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Product: CC(C)CN1C(=Nc2ccc([N+](=O)[O-])cc2C(C)C)SCC12CCCC2

Procedure:
2-Isoropylaniline was converted to 2-isopropylacetanilide according to Method A2a, Step 1. The acetanilide was converted to 2-isopropyl-4-nitroacetanilide according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 2-isopropyl-4-nitroaniline. The aniline was converted to 2-isopropyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-isopropyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(2-isopropyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(2-isopropyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C1(P([C:25]2[CH:30]=[CH:29]C=CC=2)C2C=CC=CC=2)C=CC=CC=1.[H-].[Na+].O.[C:34](#N)C>>[CH3:34][CH:30]([CH3:29])[CH:25]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CCCCCBr
Reactant: CC#N
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCCCC=CC(C)C
Yield: 62 %

Procedure:
223.12 g (1 mol) of ethyl 6-bromohexanoate and 275.4 g (1.05 mol) of triphenyl phosphine were refluxed for 36 hours in 1.5 l of acetonitrile. After the reaction was terminated, 500 ml of acetonitrile was distilled off, then the reaction mixture was dried. Into the dried mixture, 72.11 g (1 mol) of isobutyl aldehyde was added and stirred. Controlling the reaction temperature in the range of 25°-35° C., 40 g (1 mol) of oily (60%) sodium hydride was carefully added. Then, the reaction mixture was stirred over night at room temperature. After the reaction was ended, 500 g of water was added into the reaction mixture, the oil layer was then separated and the water layer was extracted twice with 300 ml of hexane. The organic layers were combined and washed with 300 ml of water, solvent was removed in vacuum under reduced pressure, and then distilled under 2 mm Hg to obtain 122.8 g of ethyl 8-methyl-6-nonenoate (Yield: 62% based upon the starting material).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:41]=O)[C:8]([O:39][CH3:40])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:38])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]([C@@H:32]3[CH2:36][CH2:35][CH2:34][N:33]3[CH3:37])=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.ClCCl.C(O)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH2:41][N:47]2[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]2)[C:8]([O:39][CH3:40])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:38])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:25][CH2:26][N:27]([C:30]([C@@H:32]3[CH2:36][CH2:35][CH2:34][N:33]3[CH3:37])=[O:31])[CH2:28][CH2:29]2)=[O:13])[CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CN1CCNCC1
Reactant: COc1c(C=O)cc(C(C)(C)C)cc1NC(=O)c1cc2cccc(CN3CCN(C(=O)[C@@H]4CCCN4C)CC3)c2n1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1c(CN2CCN(C)CC2)cc(C(C)(C)C)cc1NC(=O)c1cc2cccc(CN3CCN(C(=O)[C@@H]4CCCN4C)CC3)c2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
160 mg of (S)-1-methyl-7-[4-(1-methyl-pyrrolidine-2-carbonyl)-piperazin-1-ylmethyl]-1H-indole-2-carboxylic acid-(5-tert-butyl-3-formyl-2-methoxy-phenyl)-amide are dissolved in 2 ml of 1,2-dichloroethane, combined successively with 40 μl acetic acid and 45 μl of 1-methylpiperazine and stirred for 1 hour at ambient temperature. Then 70 mg of sodium triacetoxyborohydride are added and the mixture is stirred for 5 hours. Then it is divided between dichloromethane and saturated aqueous sodium hydrogen carbonate solution and the organic phase is washed with saturated aqueous sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is purified by preparative HPLC (method 7).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]([C:11]#[N:12])=[CH:9][C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])=[N:7][CH:6]=1>N1C=CC=CC=1>[F:20][C:14]1[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:13]=1[C:8]1[CH:9]=[C:10]2[C:11]([NH2:12])=[N:3][NH:2][C:5]2=[CH:6][N:7]=1
Reactant: N#Cc1cc(-c2cccc(F)c2F)ncc1Cl
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: Nc1n[nH]c2cnc(-c3cccc(F)c3F)cc12

Procedure:
Hydrazine hydrate (0.52 ml, 10.7 mmol) was added to a stirred solution of 5-chloro-2-(2,3-difluorophenyl)isonicotinonitrile (1.22 g, 4.9 mmol) in pyridine (12.5 mL). The reaction mixture was stirred at reflux for 2 hours, allowed to cool and concentrated. Purification by column chromatography using a gradient of 5–10% methanol in dichloromethane as eluent afforded the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][CH3:12])=S.O1CCCC1>[Hg]=O.C(#N)C>[CH3:12][NH:11][C:9]1[NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: CNC(=S)Nc1ccncc1N
Agent: O=[Hg]
Solvent: CC#N
Solvent: C1CCOC1
Product: CNc1nc2ccncc2[nH]1

Procedure:
A mixture of 7.3 parts of N-(3-amino-4-pyridinyl)-N'- methylthiourea, 15 parts of mercury (II)oxide, 90 parts of tetrahydrofuran and 80 parts of acetonitrile was stirred and refluxed for 20 hours. The reaction mixture was filtered hot over Hyflo and the filter-cake was washed with 240 parts of boiling ethanol. The filtrate was evaporated in vacuo and the residue was boiled in acetonitrile. The product was filtered off and dried, yielding 5 parts of N-methyl-3H-imidazo[4,5-c]pyridin-2-amine; mp. 255.7° C. (intermediate 96).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[CH2:22]([NH:29][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(N(C)c2nc(NCc3ccccc3)nc3ccccc23)cc1
Temperature: 25 °C
Yield: 13.4 %

Procedure:
A solution of (2-chloro-quinazolin-4-yl)-(4-methoxyphenyl)-methylamine (150 mg, 0.5 mmol), benzyl amine (110 uL, 1.0 mmol) and triethyl amine (100 uL) in 5 mL of THF in a seal tube was heated overnight at 80° C. After cooling to room temperature the reaction mixture was diluted with 25 mL of ethyl acetate, washed with saturated NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by column chromatography (35% ethyl acetate/hexane) to give the title compound (25 mg, 0.067 mmol, 13%). 1H NMR (CDCl3): 7.24-7.46 (m, 7H), 7.10 (m, 2H), 6.84-6.92 (m, 3H), 6.68 (ddd, J=8.1. 6.9, 1.5, 1H), 4.78 (d, J=6.5, 2H), 3.83 (s, 3H), 3.46 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][Mg]Cl.[C:12]1(=[O:18])[CH2:17][CH2:16][CH2:15][CH:14]=[CH:13]1.C[Si](Cl)(C)C.Cl>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH:14]1[CH2:15][CH2:16][CH2:17][C:12](=[O:18])[CH2:13]1
Reactant: COc1cccc(C[Mg]Cl)c1
Reactant: O=C1C=CCCC1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(CC2CCCC(=O)C2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
To a solution of 3-methoxybenzylmagnesium chloride (19.8 mole) in tetrahydrofuran (20 ml) was added a mixture of 2-cyclohexen-1-one (1.9 g) and trimethylsilyl chloride (5.8 ml) in tetrahydrofuran (30 ml) at -78° C. under N2. The mixture was stirred for 1 hour at 0° C. The reaction mixture was poured into a mixture of ethyl acetate and 1N-hydrochloric acid and the organic layer was washed with saturated sodium bicarbonate aqueous solution and brine. The combined organic extracts were concentrated and the residue was purified by column chromatography on silica gel to give 3-(3-methoxybenzyl)cyclohexanone (2.12 g).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][NH:17][CH2:16][CH2:15][N:14]2[C:19]2[CH:27]=[CH:26]C(C(O)=O)=[CH:21][CH:20]=2)=[CH:9][CH:8]=1>ClCCl.CN(C=O)C>[N:7]1[CH:8]=[CH:9][C:10]([CH:13]2[CH2:18][NH:17][CH2:16][CH2:15][N:14]2[C:19]2[CH:27]=[CH:26][C:1]([C:2]([Cl:4])=[O:3])=[CH:21][CH:20]=2)=[CH:11][CH:12]=1
Reactant: O=C(O)c1ccc(N2CCNCC2c2ccncc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(N2CCNCC2c2ccncc2)cc1
Reaction time: 2 h

Procedure:
Oxalyl chloride (0.5 ml) was added to a stirred suspension of 4-((4-pyridyl)piperazin-1-yl)benzoic acid in dichloromethane (15 ml), followed by DMF (1 drop). The mixture was stirred for 2 hours and evaporated to dryness to give 4-[(4-pyridyl)piperazin-1-yl]benzoyl chloride which was used immediately.