Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:19][CH2:20][N:21]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:22][CH2:23]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(N2CCN(Cc3nc4cccnc4s3)CC2)nc1

Procedure:
The product from Example 38A (150 mg, 0.81 mmol), 1-(2-pyridinyl)piperazine (160 mg, 0.98 mmol), and DIEA (280 μL, 1.6 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.80 (m, 4H) 3.55 (m, 4H) 4.04 (s, 2H) 6.63 (m, 1H) 6.81 (m, 1H) 7.53 (m, 2H) 8.11 (m, 1H) 8.33 (dd, J=8.14, 1.70 Hz, 1H) 8.59 (dd, J=4.58, 1.53 Hz, 1H); (ESI) m/z 312 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[CH:15][CH2:16][OH:17])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[H-].[Na+].S(OC)(O[CH3:26])(=O)=O>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[CH:15][CH2:16][O:17][CH3:26])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: OCC=C1c2ccccc2CCc2cc(Cl)ccc21
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Product: COCC=C1c2ccccc2CCc2cc(Cl)ccc21
Reaction time: 0.25 h
Yield: 82 %

Procedure:
Treat 2-(2-chloro-10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidene)-ethanol (1 equivalent) with sodium hydride (2 equivalents) in a suitable dry solvent at 0° C. and stir for 15 minutes. Add dimethyl sulfate dropwise (2 equivalents) and stir at 0° C. for one hour. Quench with aqueous citric acid solution and partition between water and ethyl acetate. Dry and evaporate the organic layer. Purify the residue by silica gel chromatography to give the title compound in 82% yield
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH:7]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:8](=[O:12])[N:9]([CH3:11])[CH2:10][C:4]=2[CH:3]=1.[C:20]([NH:27][CH2:28][CH2:29][C:30](O)=[O:31])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[C:23]([O:22][C:20]([NH:27][CH2:28][CH2:29][C:30]([NH:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH:7]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:8](=[O:12])[N:9]([CH3:11])[CH2:10][C:4]=2[CH:3]=1)=[O:31])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)CC1Cc2ccc(N)cc2CN(C)C1=O
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Product: COC(=O)CC1Cc2ccc(NC(=O)CCNC(=O)OC(C)(C)C)cc2CN(C)C1=O
Yield: 87 %

Procedure:
Methyl (±)-8-amino-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate was coupled with Boc-β-alanine according to the procedure of Example 5(b). Purification by chromatography on silica gel gave the title compound (87%) as a light yellow foam: 1H NMR (CDCl3) δ8.20 (br s, 1H), 7.48 (s, 1H), 7.20 (d, J=8.3 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 5.27 (d, J=16.6 Hz, 1H), 3.92 (m, 3H), 3.80 (d, J=16.6 Hz, 1H), 3.70 (s, 3H), 3.01 (s, 3H), 2.90 (m, 5H), 2.48 (dd, J=16.8, 5.5 Hz, 1H), 1.48 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])O)[OH:4]>O>[CH2:11]1[O:12][CH:5]([CH:3]([OH:4])[CH2:2][OH:1])[C@@H:7]([OH:8])[CH:9]1[OH:10]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Solvent: O
Product: OCC(O)C1OCC(O)[C@@H]1O
Temperature: 190 °C

Procedure:
To 680.0 grams of meadowfoam acid is added to the sorbitol intermediate. Next add 0.1% stannous oxylate based upon the total weight of the batch after all ingredients have been charged, under agitation. The temperature of the mass is raised to 180-200° C. and water is stripped off as formed. The acid value and hydroxyl value drop to vanishingly small values, and the saponification value increases to theoretical.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[C:31]([F:33])[C:30]([NH2:34])=[CH:29][C:28]=3[C:35]([F:38])([F:37])[F:36])=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C(Cl)Cl.CC(N(C)C)=O.[F:49][C:50]1[CH:55]=[CH:54][C:53]([C:56](Cl)=[O:57])=[CH:52][N:51]=1>>[CH3:1][O:2][C:3](=[O:39])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[C:31]([F:33])[C:30]([NH:34][C:56]([C:53]4[CH:52]=[N:51][C:50]([F:49])=[CH:55][CH:54]=4)=[O:57])=[CH:29][C:28]=3[C:35]([F:37])([F:38])[F:36])=[CH:25][CH:26]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3cc(F)c(N)cc3C(F)(F)F)cc2)c[nH]1)C(C)C
Reactant: O=C(Cl)c1ccc(F)nc1
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3cc(F)c(NC(=O)c4ccc(F)nc4)cc3C(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.9 %

Procedure:
To a solution of ((S)-1-{(S)-2-[4-(4′-amino-5′-fluoro-2′-trifluoromethyl-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (128 mg, 0.234 mmol; Preparation 39) in DCM (3 mL, 47 mmol) and DMA (0.3 mL, 3 mmol) was added 2-fluoropyridine-5-carbonyl chloride (37 mg, 0.234 mmol), and the resulting solution was stirred at RT overnight. The reaction mixture was concentrated by rotary evaporation to give the monoHCl salt of the title intermediate as a brownish oil (163 mg), which was used without further purification. (m/z): [M+H]+ calcd for C33H31F5N6O4 671.23 found 671.7.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+]([O-])=O)[C:3]=1[CH:13]=[CH:14][N:15]1CCCC1>CC(O)=O.O.C([O-])([O-])=O.[Na+].[Na+].[Fe]>[Br:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:13]=[CH:14][NH:15]2
Reactant: CCc1ccc([N+](=O)[O-])c(C=CN2CCCC2)c1Br
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCc1ccc2[nH]ccc2c1Br
Yield: 12 %

Procedure:
A solution of crude 1-[2-(2-bromo-3-ethyl-6-nitro-phenyl)-vinyl]-pyrrolidine from Step 3 in 80 mL of AcOH was added in one portion to a refluxing suspension of iron (13 g) in 50 mL of AcOH. The resultant mixture was refluxed for 2 hrs. After cooling, the mixture was diluted with water and neutralized with Na2CO3, and extracted 3 times with EtOAc. The combined organic phases were concentrated and purified by silica gel column chromatography and preparative HPLC to yield the title compound (1.5 g, 12% from 6-ethyl-2-methyl-3-nitro-phenylamine).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH:15]=[CH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2]>C(OCC)(=O)C.CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(C=CC(=O)OC(C)(C)C)ccc2[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1cc2cc(CCC(=O)OC(C)(C)C)ccc2[nH]1
Yield: 100.8 %

Procedure:
A solution of 5-(2-tert-butoxycarbonyl-vinyl)-1H-indole-2-carboxylic acid ethyl ester (1.6 g, 5 mmol) in ethyl acetate (40 mL) and methanol (80 mL) was hydrogenated over 5% palladium on carbon (0.2 g) at room temperature for overnight. The catalyst was filtered off and the filtrate was concentrated to give 1.6 g (99%) of 5-(2-tert-butoxycarbonyl-ethyl)-1H-indole-2-carboxylic acid ethyl ester as a white solid. The solid was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([C:9](=[O:11])[CH3:10])[CH:4]=1
Reactant: ClCCCCCCBr
Reactant: CC(=O)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)c1cc(OCCCCCCCl)ccc1O
Reaction time: 8 h
Yield: 83.2 %

Procedure:
A mixture of 2',5'-dihydroxyacetophenone (150 g), 1-bromo-6-chlorohexane (186 g), and potassium carbonate (186 g) in 2500 mL of 2-butanone was refluxed for 16 hours. The solvent was removed in vacuo and the residue was stirred with 1000 mL of methylene chloride. After filtration, the filtrate was washed with 10% KOH (250 mL), water (250 mL), and brine (250 mL). The solution was dried over magnesium sulfate and the solvent was removed to give an oil which solidified overnight to give 210 g of 5'-(6-chlorohexoxy)-2'-hydroxyacetophenone as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.C([Li])CCC.CN(C)[CH:18]=[O:19]>O1CCCC1>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([CH:18]=[O:19])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: CN(C)C=O
Reactant: Brc1ccc2[nH]ncc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromoindazole (5 g, 25.38 mmol) in tetrahydrofuran (100 mL) cooled at −50° C. under argon was added dropwise a solution of 1.6 M n-butyllithium in hexanes (40 mL, 63.44 mmol). Dimethylformamide (3.9 mL, 50.75 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 15 minutes. The mixture was then quenched with water, extracted with ethyl acetate, preabsorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 10-30% ethyl acetate in hexanes to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.03 (s, 1H) 8.45 (s, 1H) 8.35 (s, 1H) 7.85 (dd, J=8.70, 1.37 Hz, 1H) 7.69 (d, J=8.54 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[N:4][C:5](F)=[CH:6][CH:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1[C:3]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[N:4][C:5]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(F)c(-c2n[nH]c3ncccc23)n1
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(F)c(-c3n[nH]c4ncccc34)n2)CC1
Temperature: 140 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
A mixture of 3-(3,6-difluoropyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine (100 mg, 0.430 mmol) and 1-methylpiperazine (100 uL, 0.901 mmol) and DIPEA (75 uL, 0.434 mmol) in NMP (1 ml) was allowed to stir at 140° C. overnight. The reaction mixture was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100 A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a white solid (35 mg, 15% Yield).
Reaction SMILES: [OH-].[K+:2].[C:3]([O:10]C)(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6]>CO>[C:5]([O:7][CH3:8])(=[O:6])[CH2:4][C:3]([O-:10])=[O:9].[K+:2]
Reactant: COC(=O)CC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)CC(=O)[O-]
Yield: 76 %

Procedure:
11.6 g of KOH (1.8 mol) are dissolved in 500 g of methanol, and the solution is added to 264.2 g of dimethyl malonate (2 mol) in the course of 2 h at room temperature. The KPG agitator is operated during this at 50 rpm. This mixes the reaction suspension inadequately, broad edge zones remain virtually unmixed. The reaction suspension is then filtered and the filtration residue is washed with methanol and dried in vacuo. 214.2 g of KMM are is obtained, equivalent to a yield of 76% of theory having a DKM content of <0.2% by weight.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.[H-].[Na+]>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1cccc(O)c1
Reactant: FC(F)(F)c1ccc(-c2ccnc(Cl)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(Oc2cc(-c3ccc(C(F)(F)F)cc3)ccn2)c1

Procedure:
This material was prepared according to the method described in Example 2 (d) using 2-chloro-4-(4-trifluoromethyl-phenyl)-pyridine (Example 410 (c), 129 mg, 0.5 mmol), 3-methoxyphenol (66 uL, 0.6 mmol), and sodium hydride (24 mg, 0.6 mmol) in DMF (1 mL). Purification on a Biotage 40S column (8:1 hexanes:EtOAc), provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 346 (M+1). Mp: 77.5-79.6° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:36])[C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:36])[C:28]3[CH:29]=[C:30]([F:35])[CH:31]=[C:32]([F:34])[CH:33]=3)[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: [N-]=[N+]=NCCNC(=O)c1cc(F)cc(F)c1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)c3cc(F)cc(F)c3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.123 g, 0.442 mmol) was reacted with N-(2-azidoethyl)-3,5-difluorobenzamide (0.100 g, 0.442 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(3,5-difluorobenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 8.25 (s, 1H), δ 7.39 (m, 3H), δ 6.88 (t, 1H), δ 6.43 (s, 1H), δ 6.38 (bs, 2H), δ 4.55 (s, 2H), δ 3.93 (s, 2H), δ 2.56 (t, 2H), δ 2.24 (s, 2H), δ 1.55 (m, 14H), δ 1.23 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 165.9, 164.3, 164.2, 161.9, 150.3, 149.3, 148.2, 137.6, 122.4, 111.0, 110.8, 107.3, 107.1, 106.8, 106.6, 85.5, 49.3, 40.4, 29.9, 29.5, 29.1, 28.7, 28.2, 27.9, 27.5, 25.4 ppm; HRMS (ESI) calcd for C24H31F2N7O3 (M+) 503.2456, found 503.2458, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-3,5-difluorobenzamide hydrochloride (0.115 g, 59% yield). 1H NMR (400 MHz, CD3OD) δ 8.55 (s, 1H), δ 7.42 (d, 2H), δ 7.29 (t, 1H), δ 6.51 (s, 1H), δ 4.84 (t, 2H), δ 3.96 (q, 2H), δ 2.89 (t, 2H), δ 2.49 (t, 2H), δ 1.79 (m, 2H), δ 1.75 (m, 2H), δ 1.44 (m, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 164.5, 164.4, 127.6, 126.9, 110.6, 110.6, 110.3, 108.5, 107.1, 106.8, 106.6, 52.5, 39.5, 30.4, 27.9, 27.8, 27.6, 24.0, 23.8, 23.1 ppm; HRMS (ESI) calcd for C19H23F2N7O (M+) 403.1932, found 403.1926.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:24][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([CH:22]=[O:23])[CH:17]=[CH:16]3.[BH4-].[Na+]>CO.CS(C)=O>[OH:23][CH2:22][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][C:12]3[CH2:11][C@:3]4([C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:24][C:13]=3[CH:14]=2)[N:19]=1
Reactant: O=Cc1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: O=C1Nc2ncccc2[C@@]12Cc1cc3ccc(CO)nc3cc1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of (s)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carbaldehyde (80 mg, 0.25 mmol, described in Intermediate 10) in a mixture of MeOH (5 mL) and DMSO (1 mL) was added sodium borohydride (19 mg, 0.51 mmol). The resulting mixture was stirred at ambient temperature for 1 h, then the MeOH was removed in vacuo. The residue was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (20 mL). The aqueous layer was extracted further with CH2Cl2 (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z=318 (M+1).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][C:32]=2[CH:37]=O)=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C.N1CCCCC1>[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][C:32]=2[CH:37]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=3)[NH:13][C:12]2=[O:18])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.7 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (95 mg, 75%).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2C(Cl)=NC=[N:8][C:7]=2[CH:6]=[CH:5]1)[CH:2]=[CH2:3].[H-].[Na+].CI.[CH3:18][N:19]([CH:21]=[O:22])[CH3:20]>O>[CH2:1]([N:4]1[C:12]2[C:21](=[O:22])[N:19]([CH3:20])[CH:18]=[N:8][C:7]=2[CH:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1ccc2ncnc(Cl)c21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: C=CCn1ccc2ncn(C)c(=O)c21
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a room temperature solution of 5-allyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (220 mg, 1.3 mmol, 1 equiv.) in 3 mL of DMF was added 60% NaH (100 mg, 2.5 mmol, 2 equiv.) followed by MeI (0.18 ml, 1.8 mmol, 1.5 equiv.). After 30 minutes, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC (5-90% CH3CN/water+0.1% TFA). The desired fractions were combined and concentrated to remove CH3CN. The remaining aqueous mixture was extracted with EtOAc, dried, filtered, and evaporated to provide 152 mg (64%) of 5-allyl-3-methyl-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one as a yellow oil which was used without further purification.
Reaction SMILES: Cl[C:2]1([CH:8]=[N:9][OH:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH2:3]1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=[CH2:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21]2([O:10][N:9]=[C:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:24]2)[CH2:20][CH2:19]1)=[O:17])([CH3:13])([CH3:12])[CH3:14]
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: ON=CC1(Cl)C=CC=CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(c1ccccc1)=NO2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 1-chloro-1-hydroxyiminomethylbenzene (C) (93.6 g, 601 mmol) in DCM (400 ml) was slowly added dropwise to a solution of 4-methylene piperidine-1-carboxylic acid tert-butyl ester (B) (39.5 g, 200 mmol) in DCM (400 ml) at 0° C. A solution of triethylamine (6.7 ml) in DCM (400 ml) was then slowly added dropwise and the resulting mixture was stirred for 48 hours at RT.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[NH:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1.Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C(N(CC)CC)C>CC(O)C>[F:22][C:2]([F:1])([F:21])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([CH:15]3[CH2:16][CH2:17][N:18]([C:24]4[N:32]=[CH:31][N:30]=[C:29]5[C:25]=4[NH:26][CH:27]=[N:28]5)[CH2:19][CH2:20]3)[NH:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: FC(F)(F)Oc1cccc(-c2c[nH]c(C3CCNCC3)n2)c1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: FC(F)(F)Oc1cccc(-c2c[nH]c(C3CCN(c4ncnc5nc[nH]c45)CC3)n2)c1
Temperature: 80 °C
Yield: 64.9 %

Procedure:
Add 4-(4-(3-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)piperidine (200 mg, 0.642 mmol), 6-chloropurine (105 mg, 0.679 mmol), and triethylamine (95 μL, 0.681 mmol) to 2-propanol (5 mL). Heat the mixture at 80° C. for 3 h. Cool the mixture to room temperature and concentrate in vacuo. Triturate the solid in CH2Cl2 (10 mL). Purify the remaining solid by silica gel chromatography (60 g, eluting with 40% methanol/methylene chloride, 0.500 L) to provide 6-(4-(4-(3-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-7H-purine (179 mg, 65%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@:6]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]1[CH3:17])[CH2:5]2.[Cl:18]N1C(=O)CCC1=O>CC(O)=O>[NH2:1][C:2]1[C:3]([Cl:18])=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@:6]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]1[CH3:17])[CH2:5]2
Reactant: CN1C(=O)NC(=O)[C@]12Cc1ccc(N)cc1C2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CN1C(=O)NC(=O)[C@]12Cc1ccc(N)c(Cl)c1C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(R)-5′-Amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (265 mg, 1.15 mmol, described in Intermediate 8) was dissolved in AcOH (7 mL) and N-chlorosuccinimide (145 mg, 1.09 mmol) was added in one portion. The mixture was stirred at ambient temperature for 5 h, then the solvent was removed in vacuo. The residue was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (70 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 0:100, to give (R)-5′-amino-4′-chloro-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione, which eluted first, and the title compound, which eluted second. MS: m/z=266 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:26]=[CH:25][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:16]=[C:17]([O:19][C@@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:18]=2)[C:13]([OH:15])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:27]([O:29][C:30](=[O:39])[CH2:31][S:32][C:33]1[S:37][C:36]([NH2:38])=[N:35][CH:34]=1)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:39])[CH2:31][S:32][C:33]1[S:37][C:36]([NH:38][C:13](=[O:15])[C:12]2[CH:16]=[C:17]([O:19][C@@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:18]=[C:10]([O:9][C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:26][CH:25]=3)[CH:11]=2)=[N:35][CH:34]=1)[CH3:28]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O)c1
Reactant: CCOC(=O)CSc1cnc(N)s1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O[C@@H](C)COC)c2)s1

Procedure:
The title compound was prepared from 3-(4-methanesulfonyl-phenoxy)-5-((S)-2-methoxy-1-methyl-ethoxy)-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[C:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:27])[CH3:26]>>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([N:31]3[CH2:32][CH2:33][N:28]([C:25](=[O:27])[CH3:26])[CH2:29][CH2:30]3)=[O:17])=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Product: CC(=O)N1CCN(C(=O)c2ccc3c(OC(C)C)nc(Nc4cc(C)[nH]n4)cc3c2)CC1

Procedure:
Similar procedure as described in example 384 was used, starting from 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid and 1-acetylpiperazine to give 1-{4-[1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carbonyl]-piperazin-1-yl}-ethanone. LC-MS: m/e 437 (MH+).