Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.C1C(=O)N([Br:18])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:18][C:8]1[N:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]2=[N:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccn2ccnc2c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1ccn2c(Br)cnc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
7-Chloro-imidazo-[1,2-a]-pyridine (1 eq, 38.9 mmol, 5.93 g) is dissolved in DMF (20 ml) at 0° C. and NBS (1.1 eq, 42.8 mmol, 7.61 g) is added. The reaction mixture is stirred for 1 h at 0° C. and is diluted with EtOAc. The reaction mixture is washed with NaHCO3 and brine, dried over MgSO4, filtered and evaporated. The product is purified by flash column chromatography eluting with 8:2 DCM/MeOH to afford 3-bromo-7-chloro-imidazo-[1,2-a]-pyridine as a brown solid; [M+H]+=232
Reaction SMILES: [C:1]([C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:6]([NH2:7])=[CH:5][C:4]=1F)#[N:2].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH:23]([CH3:27])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[OH-].[Na+]>CS(C)=O.C(N(C(C)C)CC)(C)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:4]2[C:3]([C:1]#[N:2])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[C:6]([CH:5]=2)[NH2:7])[CH:23]([CH3:27])[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: N#Cc1cc([N+](=O)[O-])c(N)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1cc(N)c([N+](=O)[O-])cc1C#N
Temperature: 140 °C
Reaction time: 12 h
Yield: 76.4 %

Procedure:
To a solution of 8.00 g of 4-cyano-3-fluoro-6-nitroaniline (which was synthesized following J. Med. Chem. 1994, 37, 467) and 17.60 g of 1-tert-butoxycarbonyl-3-methylpiperazine in 25 ml of dimethylsulfoxide, 23 ml of diisopropylethylamine was added and stirred for 3 hours at 140° C. and 12 hours at room temperature. 1N aqueous sodium hydroxide solution was added to the reaction liquid which then was extracted with chloroform. The chloroform layer was dried on anhydrous magnesium sulfate and the solvent was distilled off. The residue was washed with chloroform-methanol, to provide 12.2 g of the title compound as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][N:24]4[CH:28]=[CH:27][N:26]=[CH:25]4)=[CH:17][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C=O>[C:33]1([CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[O:9][CH:10]=[C:11]([CH2:13][O:14][C:15]4[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][N:24]5[CH:28]=[CH:27][N:26]=[CH:25]5)=[CH:17][CH:16]=4)[N:12]=3)=[CH:6][CH:7]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: Oc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(C(Oc2ccc(-c3nc(COc4ccc(CCCn5ccnc5)cc4)co3)cc2)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 43 %

Procedure:
To a solution of 2-(4-hydroxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole (250 mg) in N,N-dimethylformamide (10 ml) was added sodium hydride (oily, 60%, 30 mg) and stirred at room temperature for one hour, to which chlorodiphenylmethane (270 mg) was added and stirred at 80° C. for 6 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with 1N-sodium hydroxide and water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate-methanol (50:1, v/v), crystals of 2-(4-diphenylmethoxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole (155 mg, 43%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 106-107° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[F:6][C:7]([F:25])([F:24])[C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12](Cl)[CH:11]=[C:10]([C:20]([F:23])([F:22])[F:21])[N:9]=1.O>CN(C=O)C>[CH2:1]([N:3]([CH2:4][CH3:5])[C:12]1[CH:11]=[C:10]([C:20]([F:23])([F:22])[F:21])[N:9]=[C:8]([C:7]([F:25])([F:24])[F:6])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: CCNCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N(CC)CC)cc(C(F)(F)F)nc1C(F)(F)F
Reaction time: 8 h
Yield: 63.9 %

Procedure:
Diethylamine (2.1 ml, 0.020 mol) was slowly added to a solution of 3.0 g (0.009 mol) of product of Example 19 in 15 ml of DMF and stirred overnight. Reaction mixture was poured into water, extracted with ether, washed with water, dried (MgSO4) and concentrated. The residue was kugelrohr distilled twice at 28 Pa, pot temperature 76° C., to afford 2.06 g (63.2%) of product as a yellow oil, nD25 1.4593.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1>>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:27][CH2:26][CH2:25][C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: NCCc1ccncc1
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CC(C)N1C(=O)C(NCCc2ccncc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and (2-pyridin-4-ylethyl)amine in a similar manner as described for Example 118. 1H NMR (500 MHz CDCl3): δ 1.59 (d, 6H), 2.58 (t, 2H), 3.18 (q, 2H), 4.37-4.45 (m, 1H), 5.44 (t, 1H), 6.71-6.73 (m, 2H), 7.46-7.57 (m, 5H), 8.44-8.46 (m, 2H); 13C NMR (125 MHz CDCl3): δ 20.37, 35.42, 44.14, 47.90, 107.90, 123.96, 125.15, 129.14, 130.19, 131.83, 135.12, 146.48, 150.27, 158.57; Mass Spectrum: M+H+ 372.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Cl:28]C1C=CC=CC=1>>[C:1]([C:3]1[C:8]([CH2:9][Cl:28])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: Cc1cccnc1C#N
Reactant: Clc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: N#Cc1ncccc1CCl

Procedure:
The 2-cyano-3-chloromethylpyridine was prepared by chlorination of 2-cyano-3-methylpyridine in chlorobenzene with benzoylperoxide by gradual addition of SO2Cl2 at 80° C. 2-Cyano-3-chloromethylpyridine was obtained in 60-65% conversion. The main impurities are 2-cyano-3-dichloromethylpyridine and unreacted 2-cyano-3-methylpyridine, which do not cause problems in the process of this Preparation.
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].C(OC([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][C@@H:21]([C:23]([OH:25])=[O:24])[NH2:22])=O)C1C=CC=CC=1>[OH-].[Na+]>[C:3]([CH2:2][N:22]([CH2:2][C:3]([OH:5])=[O:4])[C@H:21]([C:23]([OH:25])=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17][NH2:16])([OH:5])=[O:4]
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C(O)CBr
Agent: [Na+]
Agent: [OH-]
Product: NCCCC[C@@H](C(=O)O)N(CC(=O)O)CC(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Bromacetic acid (28 g, 200 mmole) was dissolved in 100 ml of 2 M sodium hydroxide (NaOH) and cooled to 0° C. A solution of 28 g (100 mmole) of N'-benzyloxycarbonyl-L-lysine in 150 ml of 2 M NaOH was slowly added dropwise into the bromacetic acid solution while stirring in a 0° C. cooling bath. After 2 hours, the cooling bath was removed and the solution was stirred overnight at room temperature. The solution was then heated for two hours at 50° C. and 300 ml of 1 M hydrochloric acid (HCl) was added dropwise. The mixture was then cooled to room temperature allowing the N'-benzyloxycarbonyl-nitrilotriacetic acid (Z-NTA) to precipitate. The Z-NTA was collected by filtration and further purified by dissolving in 1 M NaOH, re-precipitating with the same amount of 1 M HCl and filtering. The dissolving and precipitating cycle was repeated twice.
Reaction SMILES: N[CH:2](C1C=CC(OC)=C(OC)C=1)CC(O)=O.[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=1)[CH2:19][C:20]([OH:22])=[O:21]>>[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=1)[CH2:19][C:20]([O:22][CH3:2])=[O:21]
Reactant: CCCOc1ccc(C(N)CC(=O)O)cc1OC
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC
Product: CCCOc1ccc(C(N)CC(=O)OC)cc1OC

Procedure:
The title compound was prepared following the method for preparing Intermediate 6 except that 3-amino-3-(3,4-dimethoxy-phenyl)propionic acid was substituted with 3-amino-3-(3-methoxy-4-propoxy-phenyl)propionic acid. 1H NMR (CDCl3): δ 6.77-6.86 (m, 3H), 4.32 (q, 1H, J=5 Hz), 3.87-3.95 (m, 2H), 3.80 (s, 3H), 3.61 (s, 3H), 2.62 (d, 2H, J=5 Hz), 1.76 (s, 2H), 0.97 (t, 3H, J=6 Hz).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:40]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCCCCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccn4)ccc3n2C)cc1
Yield: 60 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)amide hydrochloride and n-nonyl chloroformate. Yield: 60% of theory, C36H45N7O5 (655.8); Rf value: 0.48 (silica gel; dichloromethane/methanol=9:1); EKA mass spectrum: (M+H)+=656; (M+H+Na)++=339.8; (M+Na)+=678.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:9](=[O:16])[NH:10][C:11](SC)=[N:12][CH:13]=2)[CH:2]=1.[Br:17][C:18]1[C:19]([CH2:24][S:25][CH2:26][CH2:27][NH2:28])=[N:20][CH:21]=[CH:22][CH:23]=1>>[Br:17][C:18]1[C:19]([CH2:24][S:25][CH2:26][CH2:27][NH:28][C:11]2[NH:10][C:9](=[O:16])[C:8]([CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:13][N:12]=2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CSc1ncc(Cc2cccnc2)c(=O)[nH]1
Reactant: NCCSCc1ncccc1Br
Product: O=c1[nH]c(NCCSCc2ncccc2Br)ncc1Cc1cccnc1

Procedure:
5-(3-Pyridylmethyl)-2-methylthio-4-pyrimidone (1.27 g) was reacted with 2-(3-bromo-2-pyridylmethylthio)-ethylamine (1.35 g) according to the procedure in Example 2. The reaction mixture was triturated with hot water to give 2-[2-(3-bromo-2-pyridylmethylthio)-ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone, and this product was treated with dilute hydrobromic acid to give the title compound, m.p. 217°-220.5° (ex-methanol)
Reaction SMILES: [NH2:1][C:2]([CH3:29])([CH3:28])[CH2:3][NH:4][CH:5]([C:9]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:26])[C:16]2[C:11](=[CH:12][C:13]([Cl:27])=[CH:14][CH:15]=2)[N:10]=1)[CH:6]([CH3:8])[CH3:7].C(N(CC)CC)C.[F:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][C:46]=1[CH3:47])[C:41](Cl)=[O:42]>ClCCl>[CH2:19]([N:18]1[C:17](=[O:26])[C:16]2[C:11](=[CH:12][C:13]([Cl:27])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:5]([NH:4][CH2:3][C:2]([NH:1][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][C:46]([CH3:47])=[C:38]([F:37])[CH:39]=1)([CH3:29])[CH3:28])[CH:6]([CH3:8])[CH3:7])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1ccc(C(=O)Cl)cc1F
Reactant: CC(C)C(NCC(C)(C)N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NC(C)(C)CNC(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1F
Yield: 68.3 %

Procedure:
To a solution of (±)-2-[1-(2-amino-2-methyl-propylamino)-2-methyl-propyl]-3-benzyl-7-chloro-3H-quinazolin-4-one (133 mg, 0.32 mmol) in dichloromethane (3 mL) was added triethylamine (90 μL, 0.64 mmol), followed by 3-fluoro-4-methylbenzoyl chloride (51 μL, 0.35 mmol). The resultant solution was stirred at ambient temperature for 3 hours, quenched with saturated aqueous sodium bicarbonate (5 mL) and diluted with dichloromethane (5 mL). The aqueous layer was extracted with dichloromethane (5 mL) and the combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10–20% ethyl acetate/hexanes) to give (±)-N-{2-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propylamino]-1,1-dimethyl-ethyl }-3-fluoro-4-methyl-benzamide (120 mg, 68%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)(=[O:13])=[O:12])=[O:4].[C:24]1(O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([O:10][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:7][N:6]1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)(=[O:13])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccc(OC)c(OC)c1
Reactant: Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](Oc2ccccc2)CN1S(=O)(=O)c1ccc(OC)c(OC)c1
Temperature: 25 °C

Procedure:
N-(3,4-Dimethoxybenzenesulfonyl)-[(2S,4R)-4-hydroxy-2-pyrrolidinecarboxylic acid] methyl ester (8) (1.00 g, 2.90 mmol), phenol (0.41 g, 4.34 mmol) and triphenylphosphine (1.14 g, 4.34) are combined in THF (10 mL). The mixture is cooled in an ice-bath and diethyl azodicarboxylate (0.76 g, 4.34 mmol) is added dropwise over 30 minutes. The reaction is allowed to warm to ambient temperature with overnight stirring. The reaction mixture is concentrated at reduced pressure and treated with ether. The mixture is decanted and the organic extract is concentrated. The residue is purified via silica gel chromatography (40% ethyl acetate in hexanes) affording the desired product as a solid. CIMS: MH+ 422
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[N:21]1([C:26]2[N:31]=[C:30]([CH:32]=O)[CH:29]=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[N:22]1>>[N:21]1([C:26]2[N:31]=[C:30]([CH2:32][N:1]3[CH:2]([C:11]4[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=4[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]3=[O:9])[CH:29]=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[N:22]1
Reactant: O=Cc1cccc(-n2cccn2)n1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-n2cccn2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 6-(1H-pyrazol-1-yl)picolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 407.07 g/mol.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]([CH2:20][C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[CH2:24][N:25]2[CH:29]([C:30](O)=[O:31])[CH2:28][CH2:27][S:26]2(=[O:34])=[O:33])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:6]([F:38])[C:5]([O:39][CH3:40])=[CH:4][CH:3]=1.Cl.[CH:42]12[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:50][CH:44]([CH2:45]3)[CH:43]1[NH2:52])[CH2:49]2>>[CH:42]12[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:50][CH:44]([CH2:45]3)[CH:43]1[NH:52][C:30]([CH:29]1[CH2:28][CH2:27][S:26](=[O:33])(=[O:34])[N:25]1[CH2:24][C:23]1[CH:35]=[CH:36][CH:37]=[C:21]([CH2:20][N:9]([CH2:8][C:7]3[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([O:39][CH3:40])[C:6]=3[F:38])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:14])([CH3:15])[CH3:13])[CH:22]=1)=[O:31])[CH2:49]2
Reactant: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)O)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: Cl
Product: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)NC4C5CC6CC(C5)CC4C6)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Yield: 66.2 %

Procedure:
2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1 dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (Intermediate 7, 0.093 g, 0.155 mmol) was reacted with 2-adamantanamine hydrochloride (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 0.036, 0.192 mmol) to form 2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid adamantan-2-ylamide (0.075 g, 66%). m/z=731 (M+1); HRMS: calcd for C39H57ClFN4O4S. Calc [M+H+] 731.3768. found 731.3773.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17]>CN(C)C=O>[F:13][C:14]1[CH:21]=[CH:20][C:19]([O:10][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH3:9])=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: N#Cc1c(F)cccc1F
Reactant: C[C@H](O)c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc(F)c(C#N)c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A solution of (S)-1-(3-chlorophenyl)ethanol (20.4 g, 130.26 mmol) in dimethylformamide was added to a cooled (0° C.) slurry of sodium hydride (5.73 g, 143.29 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour. Again, cooled (0° C.), then a solution of 2,6-difluorobenzonitrile (19.93 g, 143.29 mmol) in dimethylfomamide was added, stirred overnight at room temperature. The reaction mixture was poured on crushed ice-water, stirred, extracted with ether, dried, filtered and concentrated to afford 30.0 g of 2-fluoro-5-[(S)-1-(3-chlorophenyl)ethoxy]benzonitrile.
Reaction SMILES: O.[OH-].[Li+].[OH:4][CH2:5][C@@H:6]([O:9][C:10]1[CH:11]=[C:12]([O:25][C:26]2[N:27]=[CH:28][C:29]([C:32]([O:34]C)=[O:33])=[N:30][CH:31]=2)[CH:13]=[C:14]([C:16]([NH:18][C:19]2[CH:23]=[CH:22][N:21]([CH3:24])[N:20]=2)=[O:17])[CH:15]=1)[CH2:7][CH3:8]>O.C1COCC1>[OH:4][CH2:5][C@@H:6]([O:9][C:10]1[CH:11]=[C:12]([O:25][C:26]2[N:27]=[CH:28][C:29]([C:32]([OH:34])=[O:33])=[N:30][CH:31]=2)[CH:13]=[C:14]([C:16]([NH:18][C:19]2[CH:23]=[CH:22][N:21]([CH3:24])[N:20]=2)=[O:17])[CH:15]=1)[CH2:7][CH3:8]
Reactant: CC[C@@H](CO)Oc1cc(Oc2cnc(C(=O)OC)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H](CO)Oc1cc(Oc2cnc(C(=O)O)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
Lithium hydroxide monohydrate (6 mg, 0.14 mmol) in water (1 mL) was added to a solution of methyl 5-[(3-{[(1S)-1-(hydroxymethyl)propyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylate (25 mg, 0.06 mmol) in THF (1 mL). The mixture was allowed to stir at RT for 16 hours. The THF was removed in vacuo and the resulting solution was partitioned between water (10 mL) and ethyl acetate (25 mL), the ethyl acetate layer was washed with brine (10 mL) and dried (MgSO4). The aqueous layer was then adjusted to pH 7 by addition of 1M hydrochloric acid and extracted with ethyl acetate (25 mL). The ethyl acetate layer was washed with brine (10 mL) and dried (MgSO4). The ethyl acetate extracts were combined and evaporated to give the required product (12 mg). m/z 428.44 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)N.N([O-])=O.[Na+].[BrH:16]>[Cu]Br>[Br:16][C:8]1([O:10][CH3:11])[CH:7]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH2:9]1
Reactant: COc1cc(N)cc(OC)c1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Product: COC1=CC=CC(Br)(OC)C1
Reaction time: 0.33 h
Yield: 40 %

Procedure:
100 mmol of 3,5-dimethoxyaniline were mixed with 75 ml of 48% hydrobromic acid. 150 mmol of sodium nitrite powder were added portionally over 20 minutes with rigorous stirring. The reaction was monitored by iodine-starch test paper until the paper turned blue. The resulting diazonium salt solution was added to a pre-prepared boiling solution of 50 mmol copper (I) bromide in 7 ml of 48% hydrobromic acid. The addition was complete after 20 minutes. The reaction mixture was then heated for 30 minutes with rigorous stirring. Steam distillation of the reaction mixture provided a white solid product with a yield of 40%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.S(Cl)([Cl:14])=O.CN(C)C=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COc1ccc(C(=O)Cl)cc1
Reaction time: 0.25 h

Procedure:
A slurry of 22.5 g. (0.15 mole of 4-methoxybenzoic acid in benzene at reflux is treated with 12.5 ml. (0.15 mole) of thionyl chloride and 1 ml. of N,N-dimehtyl formamide. After stirring for 15 minutes the solution is evaporated and cooled to provide 4methoxybenzoyl chloride as a yellow solid. The solid is dissolved in carbon disulfide and added to 20 g. (0.15 mole) of aluminum chloride slurried in 200 ml. of carbon sulfide. To this mixture is added 30 g. (0.15 mole) of 2,6-di(t-butyl)phenol. After stirring for two hours at room termperature, the resulting mixture is poured into a dilute hydrochloric acid-ice mixture, then extracted with three portions of dichloromethane. The organic layer is dried, then evaporated to provide a residue which is recrystallized twice from a benzene-hexane mixture to provide 4-(4-methoxybenzoyl)-2,6-di(t-butyl)phenol, m.p. 141°-142.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:13][CH2:12][N:11]3[C:5]2=[C:6]([CH:26]=1)[C:7]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)=[N:8][C:9]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:10]=13>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[C:4]2[CH:13]=[CH:12][N:11]3[C:5]2=[C:6]([CH:26]=1)[C:7]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)=[N:8][C:9]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:10]=13
Reactant: Cc1ccc2c(c1)N=C(N1CCN(C)CC1)c1cc(Br)cc3c1N2CC3
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)N=C(N1CCN(C)CC1)c1cc(Br)cc3ccn-2c13
Yield: 42.7 %

Procedure:
To a solution of 4-bromo-6-(4-methyl-1-piperazinyl)-9-methyl-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (5.7 g, 13.8 mmoles) in chloroform (540 ml) was added manganese dioxide (25 gm), and the mixture was heated under reflux for 4 days. The mixture was filtered, and the filter cake washed with dichloromethane. The filtrate was concentrated under vacuum. The residue was purified on a silica gel column, eluted with 2% methanol/dichloromethane. The fractions (75-100 ml each) containing pure product were pooled and concentrated. Recrystallization from a small volume of 2-propanol yielded 2.41 g (42%) of product, mp 153°-155° C.