Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:27])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:27])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2]
Reactant: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12
Reactant: CN1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nn12
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
1.23 g (3 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride are dissolved in 40 ml of dichloromethane and cooled to 0° C. After addition of a spatula tip of DMAP, 0.90 g (9.00 mmol) of N-methylpiperazine are added, and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic phase is washed twice with water and dried over sodium sulphate and the solvent is removed under reduced pressure. Crystallization from ether gives 1.25 g (88%) of a colourless solid.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][NH2:12])=[CH:13][CH:14]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(N2CCOCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(N2CCOCC2)cc1
Temperature: 25 °C

Procedure:
4-(4-Morpholinyl)benzonitrile (1.24 g, 6.6 mmol) in THF (25 mL) at 0° C. was treated with LiAlH4 (2.5 g, 65.9 mmol) and refluxed for 1 hour. The mixture was cooled to room temperature and quenched by careful addition of 1N NaOH and then H2O. The mixture was concentrated, extracted with diethyl ether. The combined ethereal extracts were washed with saturated NaHCO3 solution, dried over Na2SO4, and evaporated in vacuo to provide the title compound which was dried over MgSO4 as a THF:diethylether solution before the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH:17]2[CH2:21][CH2:20][CH2:19][O:18]2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]([CH3:31])([C:25]1[N:29]=[C:28]([CH3:30])[O:27][N:26]=1)[NH2:24]>>[CH3:22][C:23]([NH:24][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH:17]2[CH2:21][CH2:20][CH2:19][O:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:25]1[N:29]=[C:28]([CH3:30])[O:27][N:26]=1)[CH3:31]
Reactant: Cc1nc(C(C)(C)N)no1
Reactant: O=C(O)c1ccc(C2CCCO2)c(-c2cccc(Cl)c2)n1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C3CCCO3)c(-c3cccc(Cl)c3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=427.1 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:7].[BH4-].[Na+]>C(O)C.C1COCC1>[CH3:1][N:2]([CH3:3])[CH2:5][CH:6]([C:8]1[CH:9]=[CH:10][C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14])[OH:7]
Reactant: CNC
Reactant: COC(=O)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(O)CN(C)C)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dimethylamine (33% in ethanol, 156 ml) was added to a stirred suspension of methyl 5-(bromoacetyl)-2-(phenylmethoxy)benzoate (105.8 g) in absolute ethanol (1 l) and THF (1 l). The resulting solution was stirred at RT for 2 h, treated with NaBH4 (25 g) and stirred at RT overnight. The solvent was removed in vacuo and H2O (500 ml) was added to the residue. The mixture was extracted with EA (2×500 ml), the combined extracts were washed with H2O and BR, dried (Na2SO4) and concentrated in vacuo. The product was purified twice by [FCS] eluted with EA-methanol-triethylamine (80:20:1) to give the title compound as a fawn solid (59.8 g) m.p. 79°-81°.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:16]([O:19][CH2:20][CH2:21][OH:22])([CH3:18])[CH3:17].[H-].[Na+]>CN(C=O)C>[Cl:11][C:9]1[C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([O:22][CH2:21][CH2:20][O:19][CH:16]([CH3:18])[CH3:17])[N:10]=1
Reactant: CC(C)OCCO
Reactant: NC(=O)c1cc(C(F)(F)F)c(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OCCOc1nc(Cl)c(C(F)(F)F)cc1C(N)=O
Reaction time: 2 h
Yield: 45.3 %

Procedure:
A mixture of 2,6-dichloro-5-(trifluoromethyl)nicotinamide (0.35 g, 1.35 mmol) and 2-isopropoxyethanol (0.14 g, 1.35 mol) in DMF (20 mL) was added sodium hydride (59 mg, 1.48 mmol) in portions at 0° C. The mixture was stirred at r.t for 2 hrs, quenched by water, extracted by EtOAc and the organic layer was concentrated in vacuo to afford 6-chloro-2-(2-isopropoxyethoxy)-5-(trifluoromethyl)nicotinamide (0.2 g, 45.4%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 8.45 (s, 1H), 8.05 (bs, 1H), 7.63 (bs, 1H), 4.54-4.52 (m, 2H), 3.75-3.72 (m, 2H), 3.64-3.58 (m, 1H), 1.07-1.06 (d, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[C:6]([CH:12]=O)[C:5]2=[O:14].[NH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[NH2:16].[OH-].[K+].Cl>C(O)(C)C.C(Cl)Cl.O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([OH:8])=[C:4]([C:5]([C:6]2[CH:12]=[N:16][N:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:7]=2)=[O:14])[CH:3]=1
Reactant: O=Cc1coc2ccc(Br)cc2c1=O
Reactant: NNc1ccccn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: O
Product: O=C(c1cnn(-c2ccccn2)c1)c1cc(Br)ccc1O
Reaction time: 0.25 h
Yield: 99.5 %

Procedure:
To a suspension of 6-bromo-3-formylchromone (253 mg) in isopropanol (3 mL) and CH2Cl2 (2 mL) was added 2-hydrazinopyridine (109 mg), and the mixture was stirred for 15 min to form a yellow slurry. The slurry was added KOH (0.25 g) in water (0.25 mL), and the reaction was heated to reflux for 1 h. The reaction mixture was diluted with water, added 3% HCl until pH<1 and extracted with CH2Cl2 (2×). The extract was washed with water and brine, dried (MgSO4) and concentrated to give 342 mg orange foam, which was purified by flash chromatography (SiO2, EA:Hep, 1:1) to give 53 mg (15%) yellow solid: LC/MS (an10p8): Rt 5.0 min, m/z 343.5 [M+H]+; 1H NMR (CDCl3): δ 6.98 (d, J=8.9 Hz, 1H), 7.31 (ddd, J=7.3, 4.9, 0.9 Hz, 1H), 7.60 (dd, J=8.9, 2.5 Hz, 1H), 7.87-7.93 (m, 1H), 8.03 (d, J=2.4 Hz, 1H), 8.04-8.09 (m, 1H), 8.02 (s, 1H), 8.47-8.51 (m, 1H), 9.13 (s, 1H), 11.94 (s, 1H); 13C NMR (CDCl3): δ 110.9, 113.3, 120.8, 121.6, 122.8, 123.1, 130.5, 133.5, 138.9, 139.3, 143.3, 148.7, 161.9, 191.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]#[CH:14])[C:5](Cl)=[O:6].[CH3:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[NH2:22].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[NH:22][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]#[CH:14])=[C:2]([F:1])[CH:3]=1
Reactant: C#CCOc1ccc(C(=O)Cl)cc1F
Reactant: CC1CCCCC1N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCOc1ccc(C(=O)NC2CCCCC2C)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
To a mixture of 5 ml of ethyl acetate and 0.30 g of 3-fluoro-4-(2-propynyloxy)benzoyl chloride were added 0.19 g of 2-methylcyclohexylamine and 0.20 g of triethylamine in order at room temperature. The mixture obtained was stirred at room temperature for 1 hour. Then, ethyl acetate was added to the reaction mixture and the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was washed in order with methyl tert-butyl ether and hexane to obtain 0.38 g of N-(2-methylcyclohexyl)-3-fluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 34 of the present invention) represented by the formula:
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:18][CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[N:21]1([CH2:20][CH2:19][O:18][C:2]2[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Clc1ncccc1OCCOC1CCCCO1
Reactant: OCCN1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: OCCOc1cccnc1OCCN1CCCC1
Temperature: 50 °C
Reaction time: 48 h
Yield: 71.8 %

Procedure:
A solution of 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (from Example 4; 100 mg, 0.39 mmol), 1-(2-hydroxyethyl)pyrrolidine (68 μl, 0.58 mmol) and 1.0 M potassium tert-butoxide in tert-butanol (0.8 mL, 0.80 mmol) in 4 mL of toluene was heated at 100° C. for 1 day. The organic phase was washed with 3×2 mL of water and 2 mL of brine. The organic phase was shaken at 50° C. with 4 mL of 2.0 M acetic acid for 2 days. The aqueous phase was washed with 3×3 mL of ethyl acetate, made basic by addition of potassium hydroxide, saturated with sodium chloride and extracted with 3×2 mL of ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 71 mg (0.28 mmol, 72%) of the title compound as a colorless oil. LC-UV purity 95%. MS m/z 253 (M+1)+, calc. 253 (M+1)+.
Reaction SMILES: CC([N:5]([C@@:9]([CH3:33])([C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[C:27]3[C:28]4([CH2:31][O:32][C:26]=3[CH:25]=[CH:24][CH:23]=2)[CH2:30][CH2:29]4)=[CH:19][CH:20]=1)=[O:13])[CH2:10][CH3:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>ClCCl>[C:28]12([C:27]3[C:22]([O:21][C:18]4[N:17]=[CH:16][C:15]([NH:14][C:12](=[O:13])[C@:9]([CH3:33])([CH2:10][CH3:11])[NH2:5])=[CH:20][CH:19]=4)=[CH:23][CH:24]=[CH:25][C:26]=3[O:32][CH2:31]1)[CH2:29][CH2:30]2
Reactant: CC[C@](C)(C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1)N(C(=O)[O-])C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC[C@](C)(N)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1,1-dimethylethyl[(1R)-1-methyl-1-({[6-(spiro[1-benzofuran-3,1′-cyclopropan]-4-yloxy)-3-pyridinyl]amino}carbonyl)propyl]carbamate (Intermediate 92, 106 mg) in dry dichloromethane (2 ml) at 0° C. TFA (0.360 ml, 4.67 mmol) was added. The mixture was stirred at this temperature for 5 minutes, then allowed to warm up at room temperature. After 2 hours UPLC/MS showed the absence of the starting material and the presence of the desired compound: toluene (5 ml) was added and the mixture was concentrated under vacuum. The residue was loaded on a SCX cartridge (1 g), which was eluted with methanol and a 1M NH3 solution in methanol. The basic eluate was concentrated under vacuum to afford the title compound as a brown oil (68 mg) which was used in the following experiment without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]([C:17]([O:19][CH3:20])=[O:18])[N:4]([CH3:16])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]O)[CH:9]=2)=[CH:6][N:7]=1.N1C=CC=CC=1.S(Cl)([Cl:29])=O>C1COCC1>[NH2:1][C:2]1[CH:3]([C:17]([O:19][CH3:20])=[O:18])[N:4]([CH3:16])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][Cl:29])[CH:9]=2)=[CH:6][N:7]=1
Reactant: COC(=O)C1C(N)=NC=C(c2cccc(CO)c2)N1C
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)C1C(N)=NC=C(c2cccc(CCl)c2)N1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
Methyl 3-amino-6-(3-hydroxymethylphenyl)-N-methylpyrazine-2-carboxylate (75 mg, 0.3 mmol) was taken into THF (2 mL) followed by addition of pyridine (120 uL, 1.5 mmol) and the solution was cooled to 0° C. Thionyl chloride (42 uL, 0.6 mmol) was added to the mixture by syringe followed by warming to room temperature. The mixture was then stirred for two hours and partitioned with ethyl acetate and 1 M aqueous hydrochloric acid. The organic layer was washed with water (1x) then brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated followed by silica gel flash chromatography using ethyl acetate:hexanes (1:1) as eluent. The pure fractions were combined and concentrated then dried in vacuo to give methyl 3-amino-6-(3-chloromethylphenyl)-N-methylpyrazine-2-carboxylate (30 mg, 37% yield) as a yellow solid: MS (EI) for C13H13N3O2Cl: 278, 280 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[CH:5]=[N:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][CH:8]=1.C[Si]([C:25]#[N:26])(C)C>>[CH3:20][C:18]1[CH:17]=[C:4]([CH:5]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][CH:8]=2)[C:25]#[N:26])[CH:3]=[C:2]([CH3:1])[CH:19]=1
Reactant: C[Si](C)(C)C#N
Reactant: Cc1cc(C)cc(C=Nc2ccc(S(N)(=O)=O)cc2)c1
Product: Cc1cc(C)cc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)c1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(3,5-dimethylbenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a pale yellow powder (yield 90%).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH2:8]/[C:7](=[CH:11]\N(C)C)/[C:6]1=O)([CH3:4])([CH3:3])[CH3:2].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([NH:38][C:39]([NH2:41])=[NH:40])[CH:29]=[CH:30][C:31]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1>>[C:1]([CH:5]1[C:6]2[N:41]=[C:39]([NH:38][C:28]3[CH:29]=[CH:30][C:31]([N:32]4[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]4)=[C:26]([O:25][CH3:24])[CH:27]=3)[N:40]=[CH:11][C:7]=2[CH2:8][CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CN(C)/C=C1\CCCC(C(C)(C)C)C1=O
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(C(C)(C)C)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from crude 2-tert-butyl-6-[1-dimethylamino-meth-(E)-ylidene]-cyclohexanone (100 mg, 0.48 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (111 mg, 0.30 mmol) using in analogous manner the procedure described in example 45b). Obtained as a yellow solid (59 mg, 50%). MS ISP (m/e): 392.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.43 (s, 1H), 8.22 (s, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.43 (d, 1H), 7.19 (d, 1H), 7.02 (s, 1H), 3.78 (s, 3H), 2.51-2.65 (m, 2H), 2.14 (s, 3H), 1.91 (m, 2H), 1.73 (m, 1H), 1.40 (m, 1H), 1.03 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH2:15][C:16]([NH2:18])=[O:17].C[O:20][C:21](=O)[C:22]([C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=O.CC([O-])(C)C.[K+]>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:15]1[C:16](=[O:17])[NH:18][C:21](=[O:20])[C:22]=1[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1
Reactant: CN1CCN(c2ccc(N)c(CC(N)=O)c2)CC1
Reactant: COC(=O)C(=O)c1c[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(N)c(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[2-amino-5-(4-methyl-piperazin-1-yl)-phenyl]-acetamide (124 mg, 0.50 mmol) and (1H-indol-3-yl)-oxo-acetic acid methyl ester (183 mg, 0.90 mmol) in dry THF (4.0 mL) is added a solution of 1.0 M t-BuOK in THF (2.0 mL, 2.0 mmol) at 0° C. under argon. After stirring for 30 min at 0° C. and 30 min at RT, TLC indicates the complete consumption of the acetamide. The dark red reaction mixture is partitioned between EtOAc (25 mL) and brine (25 mL), and the layers are separated. The pH of the aqueous layer is adjusted to 6 with a sat., aqueous NH4Cl solution. The aqueous layer is extracted with EtOAc (2×25 mL) and the combined organic layers are washed with brine (25 mL), dried over Na2SO4, and concentrated at reduced pressure. The crude product is purified by FCC (EtOAc/AcOH/H2O 5.5:1:1) to afford the title compound as its water soluble acetate salt. Red solid. 1H NMR (DMSO-d6, 400 MHz): δ 1.70 (s, 9H, CH3COO−), 2.25 (s, 3H), 2.22-2.38 (m, 4H), 2.78-2.84 (m, 4H), 6.51 (d, J=8.7 Hz, 1H), 6.63 (d, J=2.8 Hz, 1H), 6.64-6.68 (m, 2H), 6.77 (dd, J=8.7 Hz, J=2.8 Hz, 1H), 6.97-7.02 (m, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.90 (s, 1H), 11.91 (bs, 1H). ES+-MS: 402 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@@:9]12[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C@@H:10]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2.C[S-].[Li+].Cl>CN(C)P(N(C)C)(N(C)C)=O.O>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@@:9]12[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C@@H:10]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2
Reactant: COc1ccccc1[C@]12CCN(C)C[C@H]1c1ccccc1O2
Agent: C[S-]
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CN1CC[C@]2(c3ccccc3O)Oc3ccccc3[C@@H]2C1
Yield: 79.3 %

Procedure:
A mixture of 1.51 g of cis-1,2,3,4,4a,9b-hexahydro-4a-(2-methoxyphenyl)-2-methyl-benzofuro[3,2-c]pyridine and 1.56 g of lithium thiomethoxide in 13 ml of dry hexamethylphosphoramide was heated at 140° under a drying tube for 4 hours. The cooled reaction mixture was diluted with 150 ml of water and the pH adjusted to 7 by slow addition of 2 N HCl with stirring. As the pH reached neutral, product started to precipitate out. The mixture was cooled to 0° and stirred for 30 minutes. The precipitated material was collected, washed with water and then a small amount of ether, and dried to afford 1.14 g (79.5%) of crystalline solid, m.p. s 178, 188°-191°. Recrystallization from ethanol gave 0.90 (62.7%) of colorless crystals, m.p. s 197, 197.5°-199°.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[O:14]1CCOCC1.Cl>O>[N:9]1[CH:10]=[CH:11][CH:12]=[N:13][C:8]=1[C:5]1[CH:4]=[CH:3][C:2](=[O:14])[NH:7][CH:6]=1
Reactant: C1COCCO1
Reactant: Fc1ccc(-c2ncccn2)cn1
Agent: Cl
Solvent: O
Product: O=c1ccc(-c2ncccn2)c[nH]1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 53 %

Procedure:
A resealable tube was charged with 2-(6-fluoropyridin-3-yl)pyrimidine (0.150 g, 0.856 mmol), dioxane (3.0 mL), and water (1.00 mL). Concentrated hydrochloric acid (37%)(0.25 mL) was added, the system was flushed with argon, the tube was sealed, and the reaction mixture stirred at 100° C. for 1.5 hours. The reaction mixture was then partitioned between EtOAc and saturated aqueous NaHCO3 solution. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 5-(pyrimidin-2-yl)pyridin-2(1H)-one (0.079 g, 0.456 mmol, 53% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.45 (dd, J=9.59, 0.78 Hz, 1H), 7.33 (t, J=4.89 Hz, 1H), 8.32 (td, J=10.07, 2.35 Hz, 2H), 8.79 (d, J=4.89 Hz, 2H), 11.96 (br. s., 1H). m/z (ESI) 174 (M+H)+.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].[CH3:13][O:14][C:15](=[O:34])[CH2:16][NH:17][C:18]1[C:23]([F:24])=[CH:22][C:21]([Br:25])=[CH:20][C:19]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:13][O:14][C:15](=[O:34])[CH2:16][N:17]([S:2](=[O:4])(=[O:3])[NH:5][C:6]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7])[C:18]1[C:23]([F:24])=[CH:22][C:21]([Br:25])=[CH:20][C:19]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)CNc1c(F)cc(Br)cc1OCc1ccccc1
Reactant: CC(C)(C)O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN(c1c(F)cc(Br)cc1OCc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1.25 g (8.83 mmol) of chlorosulfonyl isocyanate in 15 mL of methylene chloride is added dropwise a solution of 650 mg (8.83 mmol) of t-butanol in 5 mL methylene chloride. The solution is stirred at room temperature for 45 min. then a solution of 2.30 g (6.25 mmol) of (2-benzyloxy-4-bromo-6-fluorophenylamino)-acetic acid methyl ester and 1.25 g (12.4 mmol) of triethylamine in 10 mL methylene chloride is added dropwise. The mixture is stirred at room temperature for 3 h then is washed with water. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residual oil is purified by flash chromatography using 15% ethyl acetate/methylene chloride to elute the product as an oil: 1H NMR (CDCl3): δ 7.46-7.33 (m, 6H), 6.98 (d, J=9.1 Hz, 1H), 6.95 (s, 1H), 5.15 (s, 2H), 4.68 (d, J=18 Hz, 1H), 4.41 (d, J=18 Hz, 1H), 3.64 (s, 3H), 1.45 (s, 9H); MS (M−H)−=547.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1)([O-:11])=[O:10].C(N(CC)CC)C>C(#N)C>[CH2:1]([N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:17][CH:16]=2)[CH2:19][CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Yield: 63.8 %

Procedure:
Benzyl bromide (1.42 mL, 11.6 mmol) was added to a solution of 1-(4-nitrophenyl)piperazine (2.0 g, 11.6 mmol) in acetonitrile (30 mL) with triethylamine (2.68 mL, 19.32 mmol) and refluxed for 12 h. The mixture was concentrated in vacuo and the residue partitioned between water and ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 1-benzyl-4-(4-nitrophenyl)piperazine (2.2 g, 77%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[C:24]([F:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([F:28])[C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f42) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(O[C:16](=O)[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([C:24](=[O:29])N(OC)C)[CH2:20][CH2:19]1)(C)(C)C.[O:31]=[C:32]1[NH:37][C:36]2[CH:38]=[C:39](C=O)[CH:40]=[CH:41][C:35]=2[S:34][CH2:33]1>>[CH3:1][C:2]1[C:7]2[N:8]=[C:9]([C:24]([C@H:21]3[CH2:20][CH2:19][C@H:18]([NH:17][CH2:16][C:39]4[CH:40]=[CH:41][C:35]5[S:34][CH2:33][C:32](=[O:31])[NH:37][C:36]=5[CH:38]=4)[CH2:23][CH2:22]3)=[O:29])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Reactant: Cc1cccc2scnc12
Product: Cc1cccc2sc(C(=O)[C@H]3CC[C@H](NCc4ccc5c(c4)NC(=O)CS5)CC3)nc12

Procedure:
Using 4-methyl-benzothiazole (5 mmol, obtained by reductive deamination of 2-amino-4-methylbenzothiazole), [trans-4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (2.5 mmol) and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde (0.3 mmol) in according to the same protocol as that described for example 1, steps 1.a to 1.c, the title compound was obtained as a yellowish solid (55 mg).