Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:17]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(I)ccc1NS(C)(=O)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)ccc1N(C)S(C)(=O)=O
Reaction time: 24 h
Yield: 92.4 %

Procedure:
To a solution of methyl 5-iodo-2-((methylsulfonyl)amino)benzoate (Preparation 49, 0.50 g) and K2CO3 (0.41 g) in DMF (10 mL) is added iodomethane (0.10 mL) at ambient temperature. After 24 hrs, the solvent is removed in vacuo and the residue is partitioned between Et2O (20 mL) and water (20 mL). The organic layer is separated, dried over MgSO4, filtered, and concentrated in vacuo. The crude yellow liquid is purified by silica gel column chromatography (4/1, hexanes/EtOAc) to afford 0.48 g (92%) of the title compound as a white solid. Physical characteristics: m.p. 105-106° C.; 1H NMR (300 MHz, CDCl3) δ8.22, 7.86, 7.18, 3.91, 3.27, 2.96; IR (diffuse reflectance) 1718, 1443, 1330, 1289, 1258, 1150, 1056, 970, 964, 957, 888, 839, 772, 732, 712 cm−1; MS (ESI+) m/z 370 (MH+). Anal. Found: C, 32.74; H, 3.30; N, 3.81.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[O:11][CH2:12][CH:14]1[CH2:15][O:16]1
Reactant: COc1ccc(O)cc1OC
Reactant: ClCC1CO1
Product: COc1ccc(OCC2CO2)cc1OC

Procedure:
The title compound was prepared from 3,4-dimethoxy-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[CH:5][CH:4]=1.Cl[C:19]1[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[N:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:19]2[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[N:22]=[C:21]([C:29]([F:31])([F:32])[F:30])[N:20]=2)=[CH:8][CH:7]=1)([O-:17])=[O:16]
Reactant: FC(F)(F)c1nc(Cl)c2c(n1)CCCC2
Reactant: NCc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1-c1ccc(CNc2nc(C(F)(F)F)nc3c2CCCC3)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A mixture of 2.56 g (11.2 mmol) of 2-(4'-aminomethylphenyl)nitrobenzene, 2.88 g (12.2 mmol) of 4-chloro-5,6,7,8-tetrahydro-2-trifluoromethylquinazoline, and 8.0 g (58 mmol) of potassium carbonate in DMF was stirred at 100° C. overnight. The reaction mixture was quenched with water and extracted intomethylene chloride/tetrahydrofuran. The organic phase was washed with brine, dried over potassium carbonate, and purified by flash chromatography (elutions of ether/petroleum ether (1:2, then 1:1), then 10% ether/methylene chloride) to give 3.86 g (81%) of 5,6,7,8-tetrahydro-N-[(2'-nitro[1,1'-biphenyl]-4-yl)methyl]-2-(trifluoromethyl)-4-quinazolinamine, mp 150°-151° C.
Reaction SMILES: [Br:1][CH2:2][C:3]1[S:7][C:6]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:5]=2[CH:4]=1.[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1>[Br-:1].[Cl:12][C:10]1[CH:9]=[CH:8][C:6]2[S:7][C:3]([CH2:2][P+:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:4][C:5]=2[CH:11]=1
Reactant: Clc1ccc2sc(CBr)cc2c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: Clc1ccc2sc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2c1
Product: [Br-]
Temperature: 140 °C

Procedure:
A mixture of 2.50 g (9.56 mmol) 2-bromomethyl-5-chlorobenzo[b]thiophene and 2.51 g (9.57 mmol) triphenylphosphine in 50 ml xylene was heated at 140° C. After 3 h the reaction mixture was cooled to room temperature, and the phosphonium salt was filtered off, washed with xylene and tert.-butylmethylether, successively, and dried in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH2:16][CH2:17][CH2:18]O)[C:7]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:8][C:4]=2[CH:3]=1.S(Cl)([Cl:24])=O>ClC(Cl)Cl>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH2:16][CH2:17][CH2:18][Cl:24])[C:7]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: OCCCn1c(Cc2ccccc2)nc2cc(Cl)ccc21
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCCCn1c(Cc2ccccc2)nc2cc(Cl)ccc21
Reaction time: 6 h

Procedure:
To a stirred mixture of 45 parts of 5-chloro-2-(phenylmethyl)-1H-benzimidazole-1-propanol and 225 parts of trichloromethane are added dropwise 29.75 parts of sulfinyl chloride. Upon completion, stirring is continued for 6 hours at reflux temperature. The reaction mixture is evaporated and the residue is taken up in water. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 5-chloro-1-(3-chloropropyl)-2-(phenylmethyl)-1H-benzimidazole as a solid residue.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[S:14])[N:11]([CH3:15])[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[CH:22]=1.[CH3:23]I>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([S:14][CH3:23])[N:11]([CH3:15])[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[CH:22]=1
Reactant: CI
Reactant: CN1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NN1C
Temperature: 6 °C

Procedure:
The reaction vessel was charged with 11.5 grams (479 moles) of sodium hydride (99%) and 850 ml of dry N,N-dimethylformamide. To this mixture, 132 grams (437 moles) of 7-chloro-1,3-dihydro-3-methyl-5-phenyl-2H-1,3,4-benzotriazepine-2-thione (Example 15) was added with stirring using a screw feed solid addition apparatus while the system was flushed with dry nitrogen. Thirty minutes after addition was completed, the resulting reaction mass was cooled to about 6° C. and 30.0 ml (482 moles) of methyl iodide was added quickly with stirring. The temperature of the reaction mixture rose to about 20° C. The reaction mass was stirred for an additional 30 minutes in an ice bath and for about two hours at ambient temperature. The reaction mixture was poured into about 7 liters of ice water. The yellow precipitate which formed was collected, washed with water, and dissolved in about 1 liter of diethyl ether. The ether solution was washed with water, dried with magnesium sulfate, and concentrated in vacuo on a rotary evaporator. The title compound was left as a viscous yellow-orange oil which solidified on triturating with 100 ml of hexane. The resulting yellow product had a melting point of 100° C. to 102° C. Elemental analysis was used to confirm the structure.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:19]=2[O:18][CH2:17][C:16](=O)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH2:36].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([NH:36][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CCN
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)COc1cc(F)ccc1-3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(NCCN(C)C)COc1cc(F)ccc1-3
Reaction time: 0.08 h

Procedure:
To a solution of foregoing crude ketone (from Step 4) in DCE (0.06 M) was added N,N-dimethylethane-1,2-diamine (1.0 eq) and HOAc (1.5 eq.), followed by solid sodium triacetoxyborohydride (1.5 eq). NaOH (20 eq., 1 N) was added after 16 h, and after stirring for 5 min the mixture was taken into EtOAc and washed with water and brine. Drying over Na2SO4 and concentration i. vac. gave the crude product, which was used without further purification; MS (ES+) m/z 494 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1)([O-])=O.[H][H]>CCOC(C)=O.CO.[Ni]>[N:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:11]=1[NH:10][C:5]1[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccccc1Nc1ncccn1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccccc1Nc1ncccn1
Yield: 72.2 %

Procedure:
To a solution of (2-nitrophenyl)-pyrimidin-2-yl-amine (13.2 g, 61.1 mmol) in a mixture of EtOAc (450 mL) and CH3OH (350 mL) was added Raney Nickle (16 g (water wet)) and the reaction mixture hydrogenated under 1 atm hydrogen at ambient temperature for 3 h. The catalyst was separated by filtration and the filtrate concentrated in vacuo to a red-brown solid which upon trituration with cold CH3OH (250 mL) gave the title compound (8.21 g, 44.1 mmol) as a grey solid: 1H NMR (CDCl3, 400 MHz): 8.38 (d, 2H, J=4.9 Hz), 7.37 (d, 1H, J=7.9 Hz), 7.08 (t, 1H), 7.00 (br s, 1H), 6.83 (m, 2H), 6.67 (t, 1H), 3.60 (br s, 2H); TLC (EtOAc/Hexanes(2:1)): Rf =0.33.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:13]=[CH:12]SC=2NC(=O)[C:7]=1[C:8]#[N:9].C(O[C:17]([C:19]1[C:24](=[O:25])[NH:23][C:22]2[S:26][CH:27]=[CH:28][C:21]=2[C:20]=1[OH:29])=[O:18])C.C1(N)CCCCC1>>[CH:8]1([NH:9][C:17]([C:19]2[C:24](=[O:25])[NH:23][C:22]3[S:26][CH:27]=[CH:28][C:21]=3[C:20]=2[OH:29])=[O:18])[CH2:7][CH2:2][CH2:3][CH2:13][CH2:12]1
Reactant: N#Cc1c(Cl)c2ccsc2[nH]c1=O
Reactant: CCOC(=O)c1c(O)c2ccsc2[nH]c1=O
Solvent: NC1CCCCC1
Product: O=C(NC1CCCCC1)c1c(O)c2ccsc2[nH]c1=O

Procedure:
To yield compounds of structure (III) with R2 as carbonitrile, and R1 and R3 as defined above, 4-chloro-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile, depicted by formula (50), was used as a key intermediate. To prepare this intermediate, 4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester, depicted by formula (40), was reacted with cyclohexylamine to yield intermediate 4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid cyclohexylamide, depicted by formula (48). This intermediate was converted to 4,6-dichloro-thieno[2,3-b]pyrdine-5-carbonitrile, depicted by formula (49), by reacting with phosphorous oxychloride, which was then converted into 4-chloro-6-oxo-6,7-dihydro-2-thieno[2,3-b]pyridine-5-carbonitrile, depicted by formula (50), as shown in Scheme 25.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]([CH2:25][C:26](O)=[O:27])[CH3:24])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[CH2:29]([O:31][C:32](=[O:47])[CH2:33][CH2:34][NH:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=1)[CH3:30].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:29]([O:31][C:32](=[O:47])[CH2:33][CH2:34][N:35]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=1)[C:26](=[O:27])[CH2:25][N:23]([C:21](=[O:22])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:24])[CH3:30]
Reactant: COc1cc(CC(=O)N(C)CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: CCOC(=O)CCNCc1ccc(OC)c(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCN(Cc1ccc(OC)c(OC)c1)C(=O)CN(C)C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.1 %

Procedure:
A solution of ({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetic acid [18.4 g, Reference Example 1] and 3-(3,4-dimethoxy-benzylamino)-propionic acid ethyl ester [13.4 g, Reference Example 2(a)] in dimethylformamide (400 ml) was treated with [O-(7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate] (19.1 g) and diisopropylethylamine (10.5 ml). After stirring at ambient temperature for 20 hours the reaction mixture was evaporated to dryness. The residue was treated with water (800 ml) followed by hydrochloric acid (175 ml 1 M) and the mixture was extracted twice with ethyl acetate (500 ml). The combined organic extracts were washed with hydrochloric acid (500 ml, 1M), then with water (400 ml), then with saturated aqueous sodium bicarbonate solution (500 ml), then dried over magnesium sulphate and then evaporated. The residual oil was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (49:1, v/v) to give the title compound as a fawn coloured foam (26.4 g), m.p. 97-105° C. [Elemental analysis:- C,63.4; H,6.7; N,8.7% Calculated for C34H42N4O8.0.5H2O:- C,63.3; H,6.8; N,8.8%].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([NH:12][CH3:13])[CH:6]=[CH:5]2.[Cu][C:15]#[N:16]>N1C=CC=CC=1>[CH3:13][NH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:15]#[N:16])[CH:11]=[CH:10]2
Reactant: CNc1ccc2cc(Br)ccc2c1
Reactant: N#C[Cu]
Solvent: c1ccncc1
Product: CNc1ccc2cc(C#N)ccc2c1
Temperature: 220 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
A solution of 6-bromo-N-methyl-2-naphthylamine (2.0 g, 8.5 mmol) in pyridine (50 ml) was added to copper (I) cyanide (1.1 g, 12.3 mmol). The mixture was stirred at 220° C. for 4 hours. The reaction mixture was allowed to cool to room temperature, extracted with dichloromethane, washed with an aqueous solution of hethylene diamine (10 vol %), and purified by column chromatography using hexane/ethyl acetate (4:1) as an eluting solvent to give the title compound (1.1 g, yield: 71%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O-:20])=[O:19])[CH2:14][CH:13]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=[CH:8][CH:7]=1.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:33]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:9]([CH3:12])([CH3:10])[CH3:8])=[O:19])[CH2:14][CH:13]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=[CH:8][CH:7]=1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C([O-])N1CCC(c2ccc(OCCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(k), by acylating (3RS,4RS)-4-[4-(3-hydroxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with benzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-(3-benzoyloxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; Rf : 0.84 (SiO2, hexane:ethyl acetate=1:1). (d) A mixture of 1.0 g (3.41 mmol) of tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate, 471 mg (34.1 mmol, 10 eq.) of potassium carbonate and 607 ml (5.11 mmol, 1.5 eq.) of benzyl bromide in 30 ml of dimethylformamide was stirred at room temperature for 2 hours and at 80° C. for 15 hours. Subsequently, 471 mg (34.1 mmol, 10 eq.) of potassium carbonate and 607 ml (5.11 mmol, 1.5 eq.) of benzyl bromide were again added and the mixture was stirred at 80° C. for a further 6 hours. The reaction mixture, cooled to room temperature, was poured into 300 ml of an ice/water mixture and extracted three times with 250 ml of ethyl acetate. The organic phases were washed once with water and once with saturated sodium chloride solution, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The yellow oil (1.82 g) was separated on silica gel using an eluent gradient of 4:1 to 3:2 of a mixture of hexane and ethyl acetate as the eluent. There were obtained 620 mg (72% of theory) of tert-butyl (3RS,4RS)-4-(4-benzyloxy-phenyl)-3-hydroxy-piperidine-1-carboxylate which, after recrystallization from a mixture of methylene chloride and hexane, gave 361 mg (28% of theory) as a white, crystalline product; MS: 383 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[NH:15][CH2:14][CH:13]2[C:23]([O:25][CH3:26])=[O:24])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:27][C:28]1[CH:32]=[CH:31][N:30]([C:33]2[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[C:35]([Cl:42])[CH:34]=2)[N:29]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]([C:37]([C:36]3[CH:40]=[CH:41][C:33]([N:30]4[CH:31]=[CH:32][C:28]([CH3:27])=[N:29]4)=[CH:34][C:35]=3[Cl:42])=[O:38])[CH2:14][CH:13]2[C:23]([O:25][CH3:26])=[O:24])(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: COC(=O)C1CNc2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Reactant: Cc1ccn(-c2ccc(C(=O)Cl)c(Cl)c2)n1
Product: COC(=O)C1CN(C(=O)c2ccc(-n3ccc(C)n3)cc2Cl)c2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1

Procedure:
As described in Example 65, methyl 4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate was reacted with 4-(3-methyl-1-pyrazolyl)-2-chlorobenzoyl chloride to give methyl 4-(4-methoxybenzenesulfonyl)-1-[2-chloro-4-(3-methyl-1-pyrazolyl)phenylcarbonyl]-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate as a white solid. Anal. for C29H27ClN4O6S: Calc'd: C, 58.3; H, 4.6; N, 9.4. Found: C,58.2; H, 4.9; N, 8.9.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](Cl)=[O:13])[CH2:10][CH2:9]1)(=[O:7])[CH3:6].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:5]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](=[O:13])[C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)(=[O:7])[CH3:6]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 80 %

Procedure:
A mixture of 93 g of (0.7 mole) of aluminum chloride in 150 ml of fluorobenzene was stirred while 70 g (0.37 mole) of 1-acetylisonipecotic acid chloride was added in small portions. After the addition was complete, the mixture was refluxed for 1 hr. The mixture was poured onto ice and the 2 resulting layers were separated. The aqueous layer was extracted twice with chloroform and the chloroform extracts were added to the fluorobenzene which was separated previously. The organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and 73.7 g (80% yield) of 1-acetyl-4-(p-fluorobenzoyl)piperidine was obtained as a crystalline residue. Recrystallization from ligroin-isopropyl ether gave a white, crystalline product melting at 75°-78° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@@H:3]1C(O)=O.ClC(OCC)=O.[N-:21]=[N+]=[N-].[Na+]>CC(C)=O.O.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:14])[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@@H:3]1[NH2:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)[C@@H](C(=O)O)[C@@H]1c1ccccc1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CC1(C)[C@@H](N)[C@@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 69.3 %

Procedure:
To a solution of trans-2,2-dimethyl-3-phenyl-cyclopropanecarboxylic acid (1.78 g, 9.4 mmol) in acetone was added water (4 mL) followed, at −5° C., by ethyl chloroformate (0.982 mL, 10.34 mmol). The reaction mixture was stirred for 20 minutes and then a solution of sodium azide (731 mg, 11.28 mmol) in water (8 mL) was added. The resulting mixture was stirred for 45 minutes and then diluted with a 1:1 mixture of water and toluene. The organic layer was separated, dried over Na2SO4, filtered and heated at 100° C. for 1 hour. The solvent was then removed under reduced pressure and an aqueous solution of HCl (8 M, 30 mL) was added, and the resulting mixture was heated at reflux for 45 minutes. The reaction mixture was cooled and an aqueous solution of HCl (10%) was added; the resulting mixture was washed with ethyl ether, then basified by addition of NaOH. The resulting mixture was extracted with ethyl ether, and the combined organic extracts were dried over Na2SO4, filtered, and evaporated under reduced pressure to give 1.05 g (70% yield) of trans-2,2-dimethyl-3-phenyl-cyclopropylamine.
Reaction SMILES: O[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.C(=O)([O-])[O-:15].[Cs+].[Cs+].Br[CH:21]([CH3:23])[CH3:22]>CN(C)C=O>[CH:21]([O:15][C:7]1[C:8]2[C:3](=[CH:2][C:11]([O:12][CH3:13])=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=1)([CH3:23])[CH3:22]
Reactant: CC(C)Br
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2ccccc2c1O
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc2c(OC(C)C)cccc2c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
A mixture of 5-hydroxy-6-methoxynaphthalene (2.10 g, 12.1 mmole), cesium carbonate (19.7 g, 60.5 mmole), N,N-dimethylformamide (12 ml) and 2-bromopropane (3.50 ml, 36.9 mmole) was stirred in a 40° C. oil bath overnight. The reaction mixture was filtered and the solid residue was rinsed thoroughly with ethyl ether. The filtrate and the washings were combined and concentrated in vacuo to remove most of the solvents. The brown residue was partitioned between water and ether and the layers were separated. The ether layer was washed with water. The combined aqueous layers were back extracted with ether. The ether extracts were combined, washed with brine and dried over sodium sulfate. Filtration and concentration gave a crude which was purified by column chromatography (2.5→5% ethyl acetate/hexanes) to give 1-isopropoxy-6-methoxynaphthalene (2.23 g, 86% yield) as a light brown oil. 1H NMR (CDCl3) δ 8.17 (1H, d, phenyl), 7.05-7.38 (4H, m, phenyl), 6.72 (1H, dd, phenyl), 4.73 (1H, m, CH of iPr), 3.92 (3H, s, OCH3), 1.42 (6H, d, 2 CH3 of iPr). Step 3:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:19]=1.[NH2:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:26])=[CH:23][C:22]=1[O:37][CH3:38].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:15]1([N:7]2[CH2:8][CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:20][C:21]4[CH:36]=[CH:35][C:24]([C:25]([NH:27][CH:28]5[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]5)=[O:26])=[CH:23][C:22]=4[O:37][CH3:38])=[N:19][C:6]2=3)[CH2:18][CH2:17][CH2:16]1
Reactant: CC1CN(C2CCC2)c2nc(Cl)ncc2N(C)C1=O
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(C)C(=O)N2C
Yield: 58.6 %

Procedure:
A solution of 0.050 g (0.00018 mole) of (rac)-2-chloro-9-cyclobutyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-52), 0.047 g (0.00018 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.053 g (0.00028 mole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 180 degrees for 2 hours in a microwave reactor. The reaction mixture was concentrated and the residue diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane-methanol (100:0-75:25 n) to give 0.0535 g of (rac)-4-(9-cyclobutyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-52) as white powder. HRMS (ES+) m/z Calcd for C27H37N7O3+H [(M+H)+]: 508.3031. Found: 508.3031.