Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[C:34](Cl)(=[O:36])[CH3:35].CS(C)=O>C1C=CC=CC=1>[C:34]([N:14]([CH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)CCCCCNC(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)CCCCCN(C(C)=O)C(c1ccccc1)c1ccccc1
Yield: 99.6 %

Procedure:
Analogously to Example 19, 8 g of ethyl 6-benzhydrylaminocaproate and 3.5 g of ethyl diisopropylamine are dissolved in 100 ml of benzene and reacted with 2.1 g of acetyl chloride. As reaction product one obtains 9 g of ethyl N-acetyl-6-benzhydrylaminocaproate as a viscous non-distillable oil. The saponification of this ester gives 7.3 g (87.5%) of N-acetyl-6-benzhydrylaminocaproic acid (M.P. 119° to 120°).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[CH:11][C:10]([C:13](Cl)=[O:14])=[CH:9][N:8]=1.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([NH2:26])[CH:21]=[CH:20]2.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([NH:26][C:13]([C:10]1[CH:9]=[N:8][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:12][CH:11]=1)=[O:14])[CH:21]=[CH:20]2
Reactant: Nn1ccc2cc(F)ccc21
Reactant: O=C(Cl)c1cnc(-c2ccccn2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nn1ccc2cc(F)ccc21)c1cnc(-c2ccccn2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
A solution of 2-pyridin-2-yl-pyrimidine-5-carboxylic acid chloride (1 mmol) in EtOAc (20 mL) is added to a stirred solution of 5-fluoro-indol-1-ylamine (1 mmol) and K2CO3 (2 mmol) in EtOAc (10 mL) and H2O (20 mL) at rt, and the reaction mixture is stirred at rt overnight. EtOAc is evaporated in vacuo, and the resulting solid is collected by filtration. The solid is purified by silica gel chromatography eluting with 0-10% MeOH in DCM to afford 2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-indol-1-yl)-amide (65 mg, 20%) as a solid. MS: 334 (M+H); 1H NMR (300 MHz, CD3OD): δ 6.56 (m, H) 7.04 (m, H), 7.28-7.79 (m, 3H), 8.04 (m, H), 8.49 (m, H), 8.81 (m, H), 9.48 (s, 2H), 12.22 (s, N—H). IC50=18 nM.
Reaction SMILES: [NH2:1][C:2]([CH3:12])=[CH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].O[C:14](=[C:17]1C(=O)OC(C)(C)[O:19][C:18]1=O)[CH2:15][CH3:16]>>[C:4]([C:3]1[C:18](=[O:19])[CH:17]=[C:14]([CH2:15][CH3:16])[NH:1][C:2]=1[CH3:12])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(N)=CC(=O)c1ccccc1
Reactant: CCC(O)=C1C(=O)OC(C)(C)OC1=O
Product: CCc1cc(=O)c(C(=O)c2ccccc2)c(C)[nH]1
Temperature: 120 °C
Yield: 4.4 %

Procedure:
A mixture of 3-amino-1-phenyl-2-buten-1-one (2.3 g) and 5-(1-hydroxypropylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (4.0 g) was heated at 120° C. for 1 hour. The mixture was cooled to ambient temperature and the residue was purified by flash chromatography eluting with dichloromethane/methanol (19:1 v/v) to give 3-benzoyl-1,4-dihydro-6-ethyl-2-methyl-4-oxopyridine (C) (0.15 g) as a solid, m.p. 203° C.; NMR (d6 -DMSO): 1.2(t, 3H), 2.07(s, 3H), 2.5(q, 2H), 5.96(s, 1H), 7.44-7.50(m, 2H), 7.57-7.60(m, 1H), 7.72-7.76(m, 2H), 11.3(broad s, 1H); mass spectrum (chemical ionisation, ammonia): 242(M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:27])[CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:24]3[CH2:25][CH2:26][CH:21]([N:20]([CH3:27])[CH3:19])[CH2:22][CH2:23]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)C1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 23.8 %

Procedure:
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (0.30 g, 1.06 mmol) in anhydrous THF (5 mL) were added dimethyl-piperidin-4-yl-amine (0.27 g, 2.11 mmol), sodium triacetoxyborohydride (0.34 g, 1.60 mmol) and glacial acetic acid (90 μL, 1.59 mmol). The resulting solution was stirred at RT for 17 h, then partitioned between EtOAc and a sat. aqueous solution of NaHCO3. The organic layer was isolated, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a white solid (0.10 g, 27%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([NH2:7])=[O:6].[C:8]1([C:14]#[C:15][C:16]2[S:20][C:19]([CH:21]=O)=[CH:18][CH:17]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[SH:23][CH:24]([CH2:28][C:29]([OH:31])=[O:30])[C:25](O)=[O:26].C(N(C(C)C)CC)(C)C>C(#N)C>[C:5]([CH2:4][CH2:3][N:2]1[C:25](=[O:26])[CH:24]([CH2:28][C:29]([OH:31])=[O:30])[S:23][CH:21]1[C:19]1[S:20][C:16]([C:15]#[C:14][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:17][CH:18]=1)(=[O:6])[NH2:7]
Reactant: O=Cc1ccc(C#Cc2ccccc2)s1
Reactant: NCCC(N)=O
Reactant: O=C(O)CC(S)C(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: NC(=O)CCN1C(=O)C(CC(=O)O)SC1c1ccc(C#Cc2ccccc2)s1

Procedure:
A mixture of β-alanine amide hydrochloride (3.11 g, 25 mmol), 5-(phenylethynyl)thiophene-2-carboxaldehyde (5.31 g, 25 mmol), mercaptosuccinic acid (11.26 g, 75 mmol) and diisopropylethylamine (3.6 g, 27.5 mmol) was stirred in acetonitrile (300 mL) at reflux for forty eight hours. The solvent was evaporated and the residue was shaken with 2 N HCl (500 mL) and ethyl acetate (3×200 mL) The ethyl acetate solution was washed with water then brine and dried (MgSO4) and evaporated. The product was purified on a 600 mL. silica dry column by elution with dichloromethane:acetic acid (99:1) followed by dichloromethane:methanol:acetic acid (95:5:1). The appropriate fractions were evaporated. The residue was washed with ether and dried to provide the title compound as a white solid: (2.44 g, 23.5%): m.p. 175-178. 1H-NMR (DMSO-d6) δ 12.6 (broad, 1H), 7.56-7.57 (d, 1H, J=2.4 Hz), 7.54-7.55 (d, 1H, J=3.6 Hz), 7.4-7.46 (m, 4H), 7.28-7.32 (m, 2H), 6.90(s, 1H), 6.15 (s, 0.5 H), 6.12-6.13 (d, 0.5H, J=1.6 Hz), 4.24-4.28 (m, 1H), 4.15-4.19 (dd, 0.5H, J=3.6 Hz), 2.97-3.09 (m, 1H), 2.64-2.74 (m, 1H), 2.36-2.46 (m, 1H), 2.08-2.21 (m, 1H); MS(ESI) 413[M-H], 415[M+H]. Analytical HPLC; Capcell Pak C18, 30% acetonitrile: 70% 0.1% aqueous TFA.51 trans: 49 cis. FTIR (ATR) 1650, 1720 cm−1. Anal. (C20H18N2O4S2) calc. C, 57.95; H, 4.38; N, 6.76. obs. C, 57.59; H, 4.34; N, 6.56.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[O:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][NH2:20])[CH2:15][CH2:14]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[F:54][C:55]1[CH:63]=[CH:62][C:58]([C:59](O)=[O:60])=[CH:57][CH:56]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[O:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([CH2:19][NH:20][C:59](=[O:60])[C:58]2[CH:62]=[CH:63][C:55]([F:54])=[CH:56][CH:57]=2)[CH2:17][CH2:18]1
Reactant: NC[C@H]1CC[C@H](Oc2ccnc3c(F)cccc23)CC1
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC[C@H]1CC[C@H](Oc2ccnc3c(F)cccc23)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{trans-4-[(8-Fluoroquinolin-4-yl)oxy]cyclohexyl}methylamine (1.82 g mg, 6.63 mmol) was dissolved in tetrahydrofuran (415 mL). After adding HATU (2.78 g, 7.30 mmol), diisopropylethylamine (1.30 mL, 7.30 mmol) and 4-fluorobenzoic acid (1.02 g, 7.30 mmol), the reaction mixture was stirred overnight at room temperature. After chromatography, the desired product was obtained at 71% yield (1.96 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]=1[C:13]1[C:14]2[NH:21][CH:20]=[C:19]([C:22](O)=[O:23])[C:15]=2[N:16]=[CH:17][N:18]=1)[CH3:2].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:22]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:5]4[C:6]5[O:10][CH2:9][O:8][C:7]=5[CH:11]=[CH:12][C:4]=4[O:3][CH2:1][CH3:2])[C:14]=3[NH:21][CH:20]=2)=[O:23])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOc1ccc2c(c1-c1ncnc3c(C(=O)O)c[nH]c13)OCO2
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: CCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-ethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A69) and commercially available 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][C:5]1[O:9][C:8]([C:10]([O:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:23](=[NH:25])[NH2:24])[CH:19]=3)[CH:14]=2)=[O:11])=[CH:7][CH:6]=1.[C:26]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28][CH2:27]1.C([O-])(=O)C.[Na+]>CN(C=O)C>[ClH:1].[C:30]([CH2:29][CH2:28][CH2:27][C:26]([NH:3][CH2:4][C:5]1[O:9][C:8]([C:10]([O:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:23](=[NH:24])[NH2:25])[CH:19]=3)[CH:14]=2)=[O:11])=[CH:7][CH:6]=1)=[O:33])([OH:32])=[O:31]
Reactant: O=C1CCCC(=O)O1
Reactant: N=C(N)c1ccc2cc(OC(=O)c3ccc(CN)o3)ccc2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(CNC(=O)CCCC(=O)O)o3)ccc2c1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
To 8 g of 6-amidino-2-naphthyl 5-aminomethyl-furan-2-carboxylate dihydrochloride, 3.6 g of glutaric anhydride and 1.72 g of anhydrous sodium acetate was added 50 ml of DMF, and the resulting mixture was stirred at 20° C. for 20 hours.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Br[CH:6]([CH3:10])[C:7]([OH:9])=[O:8].C(=O)(O)[O-].[Na+].[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O.Cl>O>[C:20]([O:19][C:17]([N:4]([CH:1]1[CH2:3][CH2:2]1)[C@@H:6]([CH3:10])[C:7]([OH:9])=[O:8])=[O:16])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NC1CC1
Reactant: CC(Br)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1CC1
Reaction time: 48 h

Procedure:
To a solution of 1.5 ml (21.5 mmol, 3.85 eq) of cyclopropylamine in 1 ml of water are added 0.5 ml (5.57 mmol, 1 eq) of (+)-2-bromo-propionic acid. 2 ml of saturated sodium bicarbonate are added after 2 h, and the reaction mixture is stirred for 48 h and then concentrated. The residue is dissolved in 5 ml of 1 N sodium hydroxide and 5 ml of THF. 1.00 g (4.58 mmol, 0.82 eq) of (BOC)2O is added, and the reaction mixture is stirred for 48 h and then acidified with 1 N HCl, until the pH is acidic. The organic layer is separated, washed with 1 N HCl and brine, dried over sodium sulfate, filtered and concentrated. The residue is purified by column chromatography on silica gel (CH2Cl2/MeOH/TFA/H2O 90/10/0.5/1) to give the product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([O-:14])=[O:13])=[C:10]([F:17])[CH:9]=2)=[CH:6][C:5]([C:18]2[CH2:19][CH2:20]S[CH2:22][CH:23]=2)=[CH:4][N:3]=1.OO[S:26]([O-:28])=O.[K+]>CC(C)=O.O.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([O:14][C:5]([CH3:18])([CH3:6])[CH3:4])=[O:13])=[C:10]([F:17])[CH:9]=2)=[CH:6][C:5]([C:18]2[CH2:19][CH2:20][S:26](=[O:28])[CH2:22][CH:23]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(C2=CCSCC2)cc1-c1ccc(C(=O)[O-])c(F)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2cc(C3=CCS(=O)CC3)cnc2N)cc1F
Reaction time: 0.33 h
Yield: 74 %

Procedure:
A 0° C. solution of 4-(2-amino-5-(3,6-dihydro-2H-thiopyran-4-yl)pyridin-3-yl)-2-fluorobenzoate in acetone (20 mL) was treated with a solution of oxone (227 mg, 0.369 mmol) in water (5 mL). After 20 min, the reaction was diluted with ethyl acetate (50 mL) and water (50 mL). The layers were separated and the aqueous layer was washed with ethyl acetate (50 mL). The combined organics were washed with water (30 mL) and brine (30 mL), dried over magnesium sulfate, filtered and concentrated to provide tert-butyl 4-(2-amino-5-(1-oxido-3,6-dihydro-2H-thiopyran-4-yl)pyridin-3-yl)-2-fluorobenzoate (220 mg, 74% yield). LCMS (m/z): 403.5 (MH+), 0.66 min.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:13][N:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.P(Cl)(OCC)(OCC)=O.[N:42]1[CH:47]=[CH:46][CH:45]=[N:44][C:43]=1[CH2:48][CH2:49][CH2:50][CH:51]=O>C1COCC1>[N:42]1[CH:47]=[CH:46][CH:45]=[N:44][C:43]=1[CH2:48][CH2:49][CH2:50]/[CH:51]=[CH:1]/[S:2]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[N:12]=[CH:13][C:14]([O:17][CH2:18][C:19]([F:22])([F:20])[F:21])=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:4])=[O:3]
Reactant: O=CCCCc1ncccn1
Reactant: CS(=O)(=O)N1CCN(c2ncc(OCC(F)(F)F)cn2)CC1
Agent: CCOP(=O)(Cl)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(/C=C/CCCc1ncccn1)N1CCN(c2ncc(OCC(F)(F)F)cn2)CC1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 95.6 %

Procedure:
To a stirred suspension of 2-[4-(methylsulfonyl)piperazin-1-yl]-5-(2,2,2-trifluoroethoxy)pyrimidine (850 mg, 2.50 mmol) in THF (25 mL) at −78° C. was added LHMDS (5.5 mL, 5.5 mmol) dropwise and the reaction stirred for 15 minutes. Diethyl chlorophosphate (0.4 mL, 2.75 mmol) was then added and stirred for 15 minutes. The solution was then treated drop wise with a solution of 4-pyrimidin-2-ylbutanal (413 mg, 2.75 mmol) in THF (5 mL), allowed to warm to −20° C. and stirred for 1 hour. The reaction was then quenched by addition of a saturated solution of NH4Cl (100 mL), extracted twice with EtOAc (2×100 mL), combined organics were washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil. This was then purified by flash chromatography (silica gel, 50% EtOAc/hexanes) to give 2-(4-{[(1E)-5-pyrimidin-2-ylpent-1-en-1-yl]sulfonyl}piperazin-1-yl)-5-(2,2,2-trifluoroethoxy)pyrimidine as a yellow solid (1.13 g, 2.39 mmol, 96%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]([CH3:25])([CH3:24])[N:5]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][CH2:7][C:6]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28].N1C=CC=CC=1>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:26])[C:4]([CH3:25])([CH3:24])[N:5]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][CH2:7][C:6]1=[S:28]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)C(C)(C)N1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(C)(C)N1C(=S)CN=C(c2ccccc2)c2cc(Cl)ccc21

Procedure:
A mixture of 0.01 mole of 7-chloro-α,α-dimethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-acetic acid methyl ester, 0.0105 mole of phosphorus pentasulfide and 100 ml. of pyridine is heated under reflux for about 24 hours. The mixture is evaporated and the residue thus obtained is dissolved in methylene chloride-water. The organic layer is separated, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated to remove the solvent. The residue thus obtained is chromatographed on silica gel and eluted to give 7-chloro-α,α-dimethyl-2,3-dihydro-2-thioxo-5-phenyl-1H-1,4-benzodiazepin-1-acetic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[CH3:7][N+:8]([CH3:23])([CH3:22])[CH2:9][CH2:10][N:11]([CH3:21])[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1.[H][H]>O.[Pd]>[CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([N:11]([CH3:21])[CH2:10][CH2:9][N+:8]([CH3:23])([CH3:22])[CH3:7])=[CH:17][CH:16]=1
Reactant: CN(CC[N+](C)(C)C)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Agent: COS(=O)(=O)[O-]
Solvent: O
Product: CN(CC[N+](C)(C)C)c1ccc(N)cc1
Reaction time: 2 h

Procedure:
10 g (28.6 mmol) of the compound from Step 9.2 was dissolved in 80 mL of water and hydrogenated in the presence of 1 g of Pd/C (10%) under 9 bar of hydrogen pressure. After 2 hours, the catalyst was filtered off and the filtrate was evaporated to dryness. This gave 9.3 g (99.6% of the theoretical) of a brown oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][C:18]([CH3:21])(O)[CH3:19])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:3][CH2:2]1.C[Si]([C:31]#[N:32])(C)C.S(=O)(=O)(O)[OH:34].C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][C:18]([NH:32][CH:31]=[O:34])([CH3:19])[CH3:21])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:22][C:23]([CH3:25])([CH3:26])[CH3:24])[CH2:3][CH2:2]1
Reactant: O=S(=O)(O)O
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC(C)(C)O)ccc2n1CC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC(C)(C)NC=O)ccc2n1CC1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
To a mixture of 1-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropan-2-ol (Step E, 996 mg, 2.63 mmol) and trimethylsilyl cyanide (1.4 mL, 10.5 mmol) was added sulfuric acid (3 mL) at −30° C. The whole was warm to room temperature and stirred for 18 h. To the reaction mixture was added water at 0° C. and stirred for 1 h. Then, the resulting mixture was poured into potassium carbonate aqueous solution (20 mL) at 0° C. and extracted with dichloromethane (30 mL×3). The combined organic layer was dried over sodium sulfate and concentrated to afford the title compound (330 g, 31%) as a white amorphous.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([Cl:16])[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.O.[NH2:24][NH2:25]>C(O)C>[Cl:16][C:6]1[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:4][N:3]=[C:2]2[NH:24][N:25]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=12
Reactant: NN
Reactant: O=C(c1ccccc1)c1c(Cl)nnc(-c2ccccc2)c1Cl
Solvent: O
Solvent: CCO
Product: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Temperature: 40 °C
Reaction time: 1 h
Yield: 8.5 %

Procedure:
A mixture of (3,5-dichloro-6-phenylpyridazin-4-yl)(phenyl)methanone (150 mg, 0.46 mmol) and hydrazine hydrate (27 mg, 0.55 mmol) in ethanol (0.5 mL) was stirred at 40° C. for 1 h in a sealed tube. The reaction mixture was cooled and filtered, and the residue was washed with diethyl ether. The filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (silica gel, gradient 0 to 20% ethyl acetate/isohexane) yielding Compound 9 as a white solid (12 mg).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH3:24])=[CH:11][N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:8][CH:7]=1)=[O:5].[C:26]1([Mg]Cl)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>O1CCCC1>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:12]2[C:13]3[C:9](=[CH:8][CH:7]=[C:6]([C:4]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:5])[CH:14]=3)[C:10]([CH3:24])=[CH:11]2)=[CH:17][CH:18]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: COc1ccc(Cn2cc(C)c3ccc(C(=O)N(C)OC)cc32)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(C)c3ccc(C(=O)c4ccccc4)cc32)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A stirred solution of N-methoxy-1-(4-methoxybenzyl)-3-methyl-N-methyl-1H-indole-6-carboxamide (2.215 g, Example 25) in tetrahydrofuran (55 ml) was treated with a solution of phenylmagnesium chloride in tetrahydrofuran (9.83 ml, 2M). The solution was stirred at 0° C. for 2 hours then poured into a mixture of ice and 1N hydrochloric acid (10 ml) and then partitioned between ethyl acetate (50 ml) and water (50 ml). The organic layer was dried over sodium sulphate then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and hexane (1:2, v/v) to yield the title compound (2.05 g) as a yellow solid, m.p. 146-147° C. [Elemental analysis:—C,80.80; H,6.00; N,3.80%. Calculated for C24H21NO2:—C,81.10; H,5.96; N,3.94%].
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C-:15]#[N:16].[K+]>CO.O.P([O-])([O-])([O-])=O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:1]([C:15]#[N:16])[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:3]=1
Reactant: C1CNCCN1
Reactant: [C-]#N
Reactant: O=Cc1cccnc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#CC(c1cccnc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 11.9 %

Procedure:
A solution of nicotinaldehyde (5.1 ml, 54 mmol) in methanol (60 ml) was added to a stirred solution of piperazine (14.0 g, 160 mmol) and potassium cyanide (5.4 g, 83 mmol) in water (60 ml) and 1M phosphate buffer solution (pH 7.3: 60 ml). The reaction mixture was stirred for 48 h at ambient temperature and partitioned between water (80 ml) and ethyl acetate (2×100 ml). The organics were dried over anhydrous sodium sulphate, filtered and concentrated. Chromatography (silica gel: 2% methanol in DCM) gave 4-(3-pyridylcyanomethyl)piperazine (1.3 g, 12%) as a colourless oil.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][C:32]1[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[C:33]=1[CH2:34]Cl.Cl>CC(N(C)C)=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:34][C:33]3[C:36]([CH3:41])=[CH:37][C:38]([CH3:40])=[CH:39][C:32]=3[CH3:31])[C:8]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Reactant: Cc1cc(C)c(CCl)c(C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)c(Cn2c(=O)c(C(=O)NCC(=O)O)c(O)n(C3CCCCC3)c2=O)c(C)c1
Reaction time: 8 h
Yield: 13.8 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (1.0 g, 7.24 mmoles) and 2,4,6-trimethylbenzyl chloride (339 mg, 1.5 mmoles) in dimethylacetamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution (1.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated to give the title compound (61 mg, 13%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.07 (s, 1 H), 10.07 (s, 1 H), 6.77 (s, 2 H), 4.99 (s, 2 H), 4.59 (t, J=12.00 Hz, 1 H), 4.08-4.14 (m, 2 H), 2.21-2.29 (m, 8 H), 2.14-2.20 (m, 4 H), 1.77 (d, J=12.63 Hz, 2 H), 1.52-1.64 (m, 3 H), 1.27 (q, J=12.88 Hz, 2 H), 1.05-1.17 (m, 1 H).