Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([CH2:12][OH:13])[CH2:7]1.Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[OH-].[Na+]>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([CH2:12][O:13][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7]1
Reactant: COCOC[C@@H]1CCC[C@H](CO)C1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCOC[C@@H]1CCC[C@H](COCC(=O)OC(C)(C)C)C1
Temperature: 10 °C
Reaction time: 6 h
Yield: 84.1 %

Procedure:
1.65 g of (cis-3-methoxymethoxymethylcyclohexyl)methanol and 5.1 g of tert-butyl bromoacetate are dissolved in 20 ml of toluene, and 1.50 g of tetrabutylammonium hydrogensulfate are added. The suspension is cooled to 10° C. 20 ml of 50% NaOH are added to the suspension. The mixture is stirred at 10° C. for 6 h and the aqueous phase is then removed and extracted with methyl tert-butyl ether. The combined organic phases are dried over MgSO4 and concentrated. Flash column chromatography on silica gel (heptane/ethyl acetate 10/1→2/1) gives 2.23 g of tert-butyl [cis-3-(methoxymethoxymethyl)cyclohexylmethoxy]acetate as a colorless oil.
Reaction SMILES: C([O-])(=[O:3])C.Cl[CH2:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:9](=[CH:10][C:11]3[CH2:20][CH2:19][CH2:18][C:12]=3[CH:13]=2)[N:8]=1>CN(C=O)C>[OH:3][CH2:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:9](=[CH:10][C:11]3[CH2:20][CH2:19][CH2:18][C:12]=3[CH:13]=2)[N:8]=1
Reactant: O=c1[nH]c(CCl)nc2cc3c(cc12)CCC3
Reactant: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=c1[nH]c(CO)nc2cc3c(cc12)CCC3
Temperature: 40 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A solution of caesiun acetate (14.4 g, 75.2 mmol) in dry DMF (40 ml) was heated to 60° C. under argon for 30 min. The mixture was cooled to 40° C. and a suspension of 2-chloromethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4-one (L. Skelton, V. Bavetsias, A. Jackman, WO 00/050417-A1; 2.2 g, 9.4 mmol) in dry DMF (60 ml) was added via a cannula. The mixture was heated to 80° C. under argon for 16 h. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was suspended in water (50 ml) and MeOH (20 ml). The pH was adjusted to 12.5 with 1M sodium hydroxide solution and the brown suspension was stirred for 2 h at room temperature. The insoluble brown solid was removed by filtration and the resulting solution was acidified to pH 5 with 1M hydrochloric acid. The precipitate was collected by filtration, washed with acidified water and dried in vacuo over P2O5 to yield the product as a pale yellow solid (1.17 g, 58%); m.p. 205-210° C.; 1H NMR (DMSO-d6) δ 2.07 (quin, J=7.4 Hz, 2H, 7-H), 2.98 (q, J=6.95 Hz, 4H, 6-H and 8-H), 4.38 (s, 2H, 2-CH2), 7.46 (s, 1H, 9-H), 7.92 (s, 1H, 5-H); MS (FAB-m/z): Found 217 [(M+H)+, 100%]; HRMS: measured 217.0977; calculated for C12H13N2O2 (M+H)+: 217.0977; Found C, 64.01; H, 5.23; N, 12.34. C12H13N2O2.½H2O requires C, 63.93; H, 5.77; N, 12.43%.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:7]=[CH:8][C:9]=1[B:10]1[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]1.[Br:24][CH2:25][CH2:26][CH2:27]Br>CN(C=O)C>[Br:24][CH2:25][CH2:26][CH2:27][CH:19]([C:6]1[CH:7]=[CH:8][C:9]([B:10]2[O:14][C:13]([CH3:15])([CH3:16])[C:12]([CH3:17])([CH3:18])[O:11]2)=[C:4]([Cl:3])[CH:5]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: BrCCCBr
Reactant: COC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCCBr)c1ccc(B2OC(C)(C)C(C)(C)O2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.1 %

Procedure:
Sodium hydride (0.153 g, 3.83 mmol) was added in one portion to methyl 2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (Intermediate 2-7; 1.08 g, 3.48 mmol) in DMF (20 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes. 1,3-Dibromopropane (0.392 mL, 3.83 mmol) was added to the reaction and was stirred at 0° C. for 5 minutes. Sodium hydride (0.153 g, 3.83 mmol) was added in one portion to the reaction and stir at 0° C. for 1 hour. The reaction mixture was quenched with saturated NH4Cl (50 mL). The reaction mixture was diluted with EtOAc (75 mL), and washed sequentially with water (4×50 mL) and saturated brine (50 mL). dried over MgSO4 The organic layer was evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 5-bromo-2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pentanoate (0.362 g, 24.12%) as a colourless gum.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].P(Cl)(Cl)(Cl)=[O:14].[Li]>>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:14])=[O:5]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(Cl)c1cc(F)c(Cl)nc1Cl
Agent: [Li]
Product: O=C(O)c1cc(F)c(Cl)nc1Cl

Procedure:
An improved process for the preparation of 2,6-dichloro-5-fluoronicotinoyl chloride is described where a 2,6-dihydroxy-5-fluoronicotinic acid ester is converted in one step using phosphorus oxychloride and a lithium reagent to 2,6-dichloro-5-fluoronicotinoyl chloride and subsequent basic hydrolysis affords 2,6-dichloro-5-fluoronicotinic acid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][N:10]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:11]1[N:16]=[C:15]([N:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][N:12]=1.C(N(CC)CC)C>CN(C)C(=O)C>[CH3:9][N:10]([CH:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:22][CH2:21]1)[C:11]1[N:16]=[C:15]([N:17]([CH3:18])[CH3:19])[CH:14]=[CH:13][N:12]=1
Reactant: ClCc1ccccc1
Reactant: CN(C)c1ccnc(N(C)C2CCNCC2)n1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CN(C)c1ccnc(N(C)C2CCN(Cc3ccccc3)CC2)n1
Temperature: 75 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
A mixture of chloromethylbenzene (1.9 g), intermediate 2 (3 g) and triethylamine (2.62 g) in N,N-dimethylacetamide (55 ml) was stirred for 2 hours at 75° C. The reaction mixture was poured out into ice-water and extracted with toluene. The separated organic layer was washed three times with water, dried, filtered and the solvent evaporated. The residue was dissolved in boiling petroleum ether and treated with activated charcoal. The mixture was filtered warm over dicalite, and the filtrate was concentrated. The concentrate was cooled on an ice-bath and the resulting precipitate was filtered off and dried, yielding 2.3 g (54.4%) of N2,N4,N4-trimethyl-N2-[1-(phenylmethyl)-4-piperidinyl]-2,4-pyrimidinediamine (comp. 8).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH2:18])[C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)=[CH:2]1.[CH3:19][N:20]([CH3:34])[C:21]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:18][CH:24]2[CH2:23][CH2:22][C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([N:20]([CH3:34])[CH3:19])[CH2:26][CH2:25]2)[C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)=[CH:2]1
Reactant: Cc1csc([C@@H](N)Cc2c[nH]c3ccccc23)n1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1csc([C@H](Cc2c[nH]c3ccccc23)NC2CCC(c3ccccc3)(N(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (S)-2-(1H-indol-3-yl)-1-(4-methylthiazol-2-yl)ethylamine (500 mg, 1.94 mmol) and 4-dimethylamino-4-phenylcyclohexanone (421 mg, 1.94 mmol) in anhydrous tetrahydrofuran (40 mL) was mixed with sodium sulphate (1.00 g) and stirred for 3 h at room temperature. After adding acetic acid (291 mg, 287 μL, 4.85 mmol), sodium triacetoxyboron hydride (574 mg, 2.71 mmol) was added and the mixture stirred overnight at room temperature. The mixture was then filtered, the filtrate concentrated to low volume in a vacuum, the residue mixed with 1M potassium carbonate solution (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product (750 mg) was purified by flash chromatography (100 g, 20×4.0 cm) with ethyl acetate/methanol [97:3→9:1 and 1% NH3 in each case (33% in water)].
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]([C:20]1[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=1)([F:19])[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:28]=[O:29].CO>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]([C:20]1[CH:21]=[C:22]([NH:26][C:28]([NH:27][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:29])[CH:23]=[CH:24][CH:25]=1)([F:19])[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN=C=O
Reactant: Nc1cccc(C(F)(F)COCCCCCCOCc2ccccc2)c1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)Nc1cccc(C(F)(F)COCCCCCCOCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.8 %

Procedure:
To a solution of Intermediate 58 (3.9 g, 10.7 mmol) in methylene chloride (35 mL) was added ethyl isocyanatoacetate (1.38 mL, 12.3 mmol). The mixture was stirred at room temperature for 5 hours. The crude reaction was cooled to 0° C. and then methanol (2.3 mL) was added. The mixture was stirred at room temperature for 0.5 hours and the solvent was removed under reduced pressure. Purification by column cromatography using methylene chloride/methanol (from pure methylene chloride to 98:2) as eluent gave the title compound (5.1 g, 95%) as oil.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:14][C@@H:15]1[C@@H:23]([C@@H:24]([OH:26])[CH3:25])[O:22][C@H:21]2[C@H:17]([N:18]=[C:19]([N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[S:20]2)[C@H:16]1[O:36][CH2:37][CH:38]=[CH2:39])[CH:12]=[CH2:13].C(N(CC)CC)C>ClCCl>[C:24]([C@H:23]1[O:22][C@H:21]2[C@H:17]([N:18]=[C:19]([N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33])[S:20]2)[C@@H:16]([O:36][CH2:37][CH:38]=[CH2:39])[C@@H:15]1[O:14][CH2:11][CH:12]=[CH2:13])(=[O:26])[CH3:25]
Reactant: C=CCO[C@H]1[C@H](OCC=C)[C@H]2N=C(N(C)C(=O)OC(C)(C)C)S[C@H]2O[C@@H]1[C@H](C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C=CCO[C@@H]1[C@H]2N=C(N(C)C(=O)OC(C)(C)C)S[C@H]2O[C@H](C(C)=O)[C@H]1OCC=C
Temperature: -20 °C
Reaction time: 4 h
Yield: 72.6 %

Procedure:
A solution of DMSO (52 g, 672 mmol) in dichloromethane (500 mL) was treated with oxalyl dichloride (64 g, 505 mmol) at −78° C. for 1 hour, then a solution of 117 (36 g, 84 mmol) in dichloromethane (150 mL) was added. The resulted solution was stirred for 4 hours at −20° C. followed by the addition of triethylamine (85 g, 841 mmol) at −78° C. After stirring at −20° C. for additional 1 hour, the reaction was quenched with water (600 mL), extracted with dichloromethane (2×300 mL). The organic layers combined, washed with brine (2×200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by silica gel column, eluted with 3% 20% ethyl acetate in petroleum ether to afford 118 (26 g, 73%) as a yellow syrup; [M+H]+ 427.0; 1H NMR (300 MHz, CDCl3) δ 6.02 (d, J=6.3 Hz, 1H), 5.82-5.99 (m, 2H), 5.17-5.35 (m, 4H), 4.20-4.29 (m, 1H), 4.03-4.29 (m, 5H), 3.71-3.77 (m, 2H), 3.25 (s, 3H), 2.14 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][S:12][CH3:13])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)O)=[C:17]([CH3:30])[CH:16]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:5]2[C:4]3[C:8](=[C:9]([CH2:11][S:12][CH3:13])[CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][CH:6]=2)=[C:17]([CH3:30])[CH:16]=1
Reactant: CSCc1cc(F)cc2cc[nH]c12
Reactant: Cc1cc(Cl)ccc1C(O)c1ccc(F)cc1
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3)c[nH]c12
Product: CSCc1cc(F)cc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3C)c[nH]c12
Temperature: 80 °C
Reaction time: 4 h

Procedure:
The title compound was prepared starting from 500 mg (2.56 mmol) of the compound from Example 11A and 706 mg (2.56 mmol) of the compound from Example 83A in analogy to the synthesis of the compound from Example 278. A difference was that stirring at 80° C. was for only 4 h. 616 mg (56% of theory) of the target compound were obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21](Cl)=[O:22])=[CH:15][CH:14]=1.[OH-].[NH4+:30]>O1CCCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([NH2:30])=[O:22])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-(2-Quinolinylmethyloxy)benzyl)benzoyl chloride (0.05 mol) in tetrahydrofuran (300 ml) is treated with concentrated ammonium hydroxide (25 ml). The reaction mixture is stirred overnight at room temperature and then evaporated and partitioned between ethyl acetate and water. The ethyl acetate fraction is dried and evaporated to give 3-(4-(2-quinolinylmethyloxy)benzyl)benzamide.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[F:15][C:16]1[CH:17]=[C:18]([OH:28])[CH:19]=[C:20]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([O:28][CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]3)[CH:19]=[C:20]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:21]=1
Reactant: Oc1cc(F)cc(C2CCOCC2)c1
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Product: Cn1c(=O)ccc2cc(COc3cc(F)cc(C4CCOCC4)c3)ccc21
Yield: 46 %

Procedure:
Using a similar procedure to that described in Example 14, 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one was reacted with 4-(5-fluoro-3-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran to give 4-[5-fluoro-3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]-3,4,5,6-tetrahydro-2H-pyran in 46% yield, m.p. 126°-127° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)[CH:5]=[C:4]([C:29]2[C:34]([O:35]CC3C=CC(OC)=CC=3)=[CH:33][CH:32]=[CH:31][C:30]=2[O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)[N:3]=1.[ClH:50]>O1CCOCC1.C(OCC)(=O)C>[ClH:50].[NH2:1][C:2]1[N:3]=[C:4]([C:29]2[C:30]([O:45][CH2:46][CH:47]3[CH2:49][CH2:48]3)=[CH:31][CH:32]=[CH:33][C:34]=2[OH:35])[CH:5]=[C:6]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[C:7]=1[CH2:8][S:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(CSc3ccccc3)c(N)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1nc(-c2c(O)cccc2OCC2CC2)cc(C2CCCNC2)c1CSc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of tert-butyl 3-{2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-3-[(phenylsulfanyl)methyl]-4-pyridinyl}-1-piperidinecarboxylate in 1,4-dioxane (2 mL) was added 4N HCl in dioxane (2 mL). The mixture was stirred at room temperature overnight, and diluted with ethyl acetate. The resulting precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give 2-[6-amino-5-[(phenylsulfanyl)methyl]4-(3-piperidinyl)-2-pyridinyl]-3-(cyclopropylmethoxy)phenol hydrochloride.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([CH:10]=O)=[CH:8][S:9][C:4]2=[CH:3][CH:2]=1.[NH:12]([CH2:19][CH2:20][C:21]#[N:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[NH:12]([CH:19]=[C:20]([CH2:10][C:7]1[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[S:9][CH:8]=1)[C:21]#[N:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CCCNc1ccccc1
Reactant: O=Cc1csc2ccccc12
Solvent: O
Product: N#CC(=CNc1ccccc1)Cc1csc2ccccc12

Procedure:
The title compound was prepared from thianaphthene-3-carboxaldehyde (W. J. King and F. F. Nord, J. Org. Chem. 1948, 13, 635) and 3-anilinopropionitrile by the procedure of Example 4A (29%); mp 168°-170° dec. Anal. Calcd for C18H14N2S: 0.1 H2O: C, 73.99; H, 4.90; N, 9.59; S, 10.97. Found: C, 74.03; H, 5.21; N, 9.59; S, 11.01.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[CH2:13][S:12](=[O:15])(=[O:14])[CH2:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1>CO.N.[Pd]>[F:18][C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][C:6]=1[C@:8]1([CH3:17])[CH2:13][S:12](=[O:14])(=[O:15])[CH2:11][C:10]([NH2:16])=[N:9]1
Reactant: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)CC(N)=N1
Agent: [Pd]
Agent: N
Solvent: CO
Product: C[C@@]1(c2ccccc2F)CS(=O)(=O)CC(N)=N1
Reaction time: 2 h
Yield: 86.6 %

Procedure:
To a solution of (R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (750 mg, 2.24 mmol, Eq: 1.00) in methanol (150 ml) and 7 M ammonia in methanol (959 μl, 6.71 mmol, Eq: 3) at room temperature added Pd/C (238 mg, 224 mmol, Eq: 0.1) and the mixture was hydrogenated at room temperature for 2 hours. Extracted with dichloromethane and some 25% ammonium hydroxide solution. Dried the organic layer over Na2SO4, filtered off and evaporated totally, dried in HV to give the (R)-5-(2-fluoro-phenyl)-5-methyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (497 mg, 1.94 mmol, 86.7% yield) as a white foam. MS (ISP): m/z=257.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:26]([CH3:27])=[CH:25][C:5]2[N:6]([C:19](=[O:24])[CH2:20][N:21]([CH3:23])[CH3:22])[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[NH:12][N:13]=3)[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:30][N:31]([CH3:36])[CH2:32][CH2:33][CH2:34]Cl>CN(C)C=O.C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[C:26]([CH3:27])=[CH:25][C:5]2[N:6]([C:19](=[O:24])[CH2:20][N:21]([CH3:23])[CH3:22])[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[N:12]([CH2:34][CH2:33][CH2:32][N:31]([CH3:36])[CH3:30])[N:13]=3)[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1C)-n1c(n[nH]c1=O)-c1cccnc1N2C(=O)CN(C)C
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: Cc1cc2c(cc1C)-n1c(nn(CCCN(C)C)c1=O)-c1cccnc1N2C(=O)CN(C)C
Reaction time: 22 h

Procedure:
In the manner given in Example 25, to 6,7-dimethyl-2,9-dihydro-9-[(dimethylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one in dimethylformamide is added a solution of sodium hydride in mineral oil. The mixture is allowed to react to about 95° C. for 40 minutes and after cooling [3-(dimethylamino)-propyl]chloride in xylene is added. The mixture is kept at 95°-100° C. for a period of 22 hours, evaporated and worked up as in example 25 to give 6,7-dimethyl-2,9-dihydro-2-[3-(dimethylamino)propyl]-9-[(dimethylamino)-acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one.
Reaction SMILES: [CH3:1][N:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([CH2:18][CH2:19][NH:20][C:21](=[O:29])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[CH2:3][CH2:4][C:5](Cl)=[O:6].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)C(Cl)Cl>[CH3:1][N:2]1[C:8]2[CH:17]=[CH:16][C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:18][CH2:19][NH:20][C:21](=[O:29])[CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:10]=3[C:9]=2[C:5](=[O:6])[CH2:4][CH2:3]1
Reactant: CN(CCC(=O)Cl)c1ccc2cccc(CCNC(=O)Cc3ccccc3)c2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)C(Cl)Cl
Product: CN1CCC(=O)c2c1ccc1cccc(CCNC(=O)Cc3ccccc3)c21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The product obtained in Step C (3 mmol), dissolved in 1,1,2,2-tetrachloroethane (30 ml), is added dropwise to a solution of aluminium chloride (10 mmol) in the same solvent (20 ml) under nitrogen. The reaction mixture is heated at 60° C., with stirring, until the reaction has ceased and it is then poured into a mixture of ice (10 g) and concentrated HCl (0.3 ml); stirring is continued for one hour. The aqueous phase is extracted twice with chloroform; the combined organic phases are then dried over magnesium sulphate and concentrated under reduced pressure. The residue is chromatographed on silica gel to yield the title product.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:36])([F:35])[F:34])=[C:23]([CH3:37])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl.C([O:45]CC)C.CCCCCC>CC(C)=O>[CH3:37][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([OH:45])=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:34])([F:36])[F:35]
Reactant: CCOCC
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 2,2,2-trichloro-1-(10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)ethanone of Step E (2.3 g, 3.9 mmol) in acetone (20 mL) was added 2.5 N sodium hydroxide (3.1 mL, 7.8 mmol). After stirring overnight, the reaction mixture was acidified with 2 N hydrochloric acid (4.3 mL, 8.6 mmol) and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown solid. Trituration with diethyl ether/hexane provided the title compound (1.32 g) as a white solid, m.p. 233–235° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=O)[CH3:3].[C:7]12[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12]C(=O)O[C:8]2=[O:9]>N1C=CC=CC=1>[CH3:3][C@H:2]1[NH:1][C:8](=[O:9])[C:7]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:12][C:4]1=[O:6]
Reactant: C[C@@H](N)C(=O)O
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: c1ccncc1
Product: C[C@H]1NC(=O)c2ccccc2NC1=O
Yield: 20.7 %

Procedure:
Following the procedure of Example 5, D-alanine (73.6 mmol) and isatoic anhydride (61.3 mmol) were allowed to reflux in pyridine (50 mL) to give (3R)-3-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (12.7 mmol) as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].Cl[C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22]>>[CH3:24][O:23][C:21](=[O:22])[CH2:20][C:19]([NH:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10](=[O:11])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:25]
Reactant: CCc1cccc(C(=O)c2ccccc2)c1N
Reactant: COC(=O)CC(=O)Cl
Product: CCc1cccc(C(=O)c2ccccc2)c1NC(=O)CC(=O)OC

Procedure:
The title compound was prepared in analogy to example 21 step A from (2-amino-3-ethyl-phenyl)-phenyl-methanone and methyl 3-chloro-3-oxopropanoate. White solid. MS (ESI): 326.2 (M+H)+.