Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[CH:17]=[C:18]2[N:27]([CH3:28])[CH:26]=[CH:25][C:19]2=[N:20][C:21]=1[C@@H:22]([NH2:24])[CH3:23].CC([O-])(C)C.[K+].C([O-])(O)=O.[Na+]>O1CCOCC1>[NH2:24][C@H:22]([C:21]1[N:20]=[C:19]2[CH:25]=[CH:26][N:27]([CH3:28])[C:18]2=[CH:17][C:16]=1[N:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C@@H:2]([CH3:1])[CH2:7]1)[CH3:23]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1Br
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](N)c1nc2ccn(C)c2cc1N1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Temperature: 90 °C
Yield: 38.5 %

Procedure:
To a 250 mL round-bottom flask were added (S)-tert-butyl 2-methylpiperazine-1-carboxylate (3.94 g, 19.7 mmol) and (S)-1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (2.5 g, 9.8 mmol) in 1,4-dioxane (23 mL). To the resulting solution was added potassium 2-methylpropan-2-olate (1 M in THF, 21 mL, 21 mmol), and the mixture was heated to 90° C. for 1 hour. After cooling for 10 minutes, the red mixture was poured into 300 mL of saturated NaHCO3 and then extracted with EtOAc (3×). The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo to give crude product, which was purified by preparative HPLC (acid mode, 25-50% ACN/water gradient). The product-containing fractions were combined, concentrated in vacuo, and partitioned between saturated NaHCO3 and EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound (1.41 g, 38.4%). ESI-MS m/z [M+H]+ calc'd for C20H31N5O2, 374. found 374.
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[C:6]2[N:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[N:5]2[N:4]=1)[CH3:2].[Cl:18]N1C2C=CC=CC=2N=N1>ClCCl>[Cl:18][C:17]1[C:3]([CH2:1][CH3:2])=[N:4][N:5]2[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][CH:8]=[N:7][C:6]=12
Reactant: Cln1nnc2ccccc21
Reactant: CCc1cc2nccc(-c3cccnc3)n2n1
Solvent: ClCCl
Product: CCc1nn2c(-c3cccnc3)ccnc2c1Cl

Procedure:
As for Example 34, 1.95 g. of 2-ethyl-7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine is reacted with 1.47 g. of N-chlorobenzotriazole in 50 ml. of dichloromethane to give the product of the example, m.p. 132°-133° C.
Reaction SMILES: C(OC([C:6]1[C:10]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:13]([Cl:26])[CH:12]=2)=[CH:9][S:8][C:7]=1[NH:27][C:28](=[O:34])[CH2:29][C:30](OC)=[O:31])=O)C.[H-].[Na+].Cl.C(OCC)C>C1COCC1>[Cl:26][C:13]1[CH:12]=[C:11]([C:10]2[C:6]3[C:30]([OH:31])=[CH:29][C:28](=[O:34])[NH:27][C:7]=3[S:8][CH:9]=2)[CH:16]=[C:15]([Cl:17])[C:14]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1c(-c2cc(Cl)c(OCc3ccccc3)c(Cl)c2)csc1NC(=O)CC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=c1cc(O)c2c(-c3cc(Cl)c(OCc4ccccc4)c(Cl)c3)csc2[nH]1
Yield: 78.6 %

Procedure:
To a solution of 1.91 g (3.65 mmol) of 4-(4-benzyloxy-3,5-dichloro-phenyl)-2-(2-methoxycarbonyl-acetylamino)-thiophene-3-carboxylic acid ethyl ester in 20 mL of THF was added 600 mg (15 mmol) of 60% NaH in mineral oil. The reaction was stirred at reflux under N2 for 18 h, then the excess NaH was quenched by the addition of 10 mL of water. The THF was removed in vacuo, then the remaining solution was taken up in 30 mL of 2M NaOH(aq.) and 30 mL of ethanol. This was stirred at 80° C. for 5 h, then concentrated to remove most of the ethanol. The remaining solution was diluted with 100 mL of water, and extracted with diethyl ether (2×30 mL). The ether layers were discarded, along with a small amount of precipitate that formed in the aqueous layer. The stirred aqueous layer was made acidic with 4M HCl to give a precipitate. Diethyl ether was added and the mixture was stirred to suspend the precipitate in the ether layer, then most of the water was decanted. The precipitate was filtered, and washed with water, then diethyl ether to give 1.20 g (79%) of the titled compound as a tan solid. MS (ESI) m/e 417.7, (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 5.05 (s, 1H) 5.76 (s, 1H) 7.23 (s, 1H) 7.43 (m, 2H) 7.58 (m, 2H) 11.15 (s, 1H).
Reaction SMILES: [NH2:1][C@H:2]([CH3:5])[CH2:3][OH:4].[CH3:6][C@@H:7]1[CH2:9][O:8]1>O>[OH:8][C@H:7]([CH3:9])[CH2:6][NH:1][C@H:2]([CH3:5])[CH2:3][OH:4]
Reactant: C[C@@H](N)CO
Reactant: C[C@@H]1CO1
Solvent: O
Product: C[C@H](CO)NC[C@@H](C)O
Temperature: 0 °C

Procedure:
To a mixture of (R)-2-aminopropan-1-ol (15 g, 200 mmol) in 200 mL water stirred at 0° C. was added (R)-2-methyloxirane (13 g, 220 mmol) dropwise using a syringe pump over 3 h. The mixture was stirred at 0° C.—RT over 4 h. The mixture was concentrated in vacuo with to remove water. The mixture was vacuum distilled to remove the unreacted alaninol at first (60° C. fraction), then collected the 110-115° C. fraction to give the (R)-2-((R)-2-hydroxypropylamino)propan-1-ol as a sticky pale yellow oil.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[C:13][Si](C)(C)C)[CH:8]=2)[N:3]1[CH2:18][C:19]([O:21]C)=[O:20].O[Li].O>>[C:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:18][C:19]([OH:21])=[O:20])[C:2](=[O:1])[CH:11]=[CH:10]2)#[CH:13]
Reactant: COC(=O)Cn1c(=O)ccc2cc(C#C[Si](C)(C)C)ccc21
Agent: [Li]O
Solvent: O
Product: C#Cc1ccc2c(ccc(=O)n2CC(=O)O)c1

Procedure:
Methyl 2-(2-oxo-6-((trimethylsilyl)ethynyl)quinolin-1(2H)-yl)acetate (0.128 mmol) was subjected to the protocol in Example 1.53.4, except with LiOH.H2O instead of NaOH. Retention time (min)=1.435, method [1], MS(ESI) 228.1 (M+H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:16][S:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:24][C:23]2[CH:22]=[CH:21][C:20]([S:17]([CH3:16])(=[O:19])=[O:18])=[CH:26][CH:25]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(C)(=O)=O)cc2)CC1
Yield: 50 %

Procedure:
Using general procedure A, 1-Boc-4-piperidone (2.01 g, 10.09 mmol) and 4-(methanesulfonyl)aniline hydrochloride (1.69 g, 8.13 mmol) afforded 4-(4-methanesulfonyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (1.44 g, 50%).
Reaction SMILES: [C:1]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][N:19]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:20]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]4[CH:33]=[CH:34][C:35]([CH:37]([OH:40])[CH2:38][CH3:39])=[CH:36][C:22]=4[N:21]=3)[CH2:14][CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.OI1(=O)C2C=CC=CC=2C(=O)O1.C(OCC)(=O)C>CS(C)=O>[C:1]1([CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][N:19]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:46])([CH3:47])[CH3:48])[C:20]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:31])[CH3:32])[C:23]4[CH:33]=[CH:34][C:35]([C:37](=[O:40])[CH2:38][CH3:39])=[CH:36][C:22]=4[N:21]=3)[CH2:16][CH2:17]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCC(O)c1ccc2c(c1)nc(N(COCC[Si](C)(C)C)CC1CCN(Cc3cccc4ccccc34)CC1)n2COCC[Si](C)(C)C
Agent: O=C1OI(=O)(O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCC(=O)c1ccc2c(c1)nc(N(COCC[Si](C)(C)C)CC1CCN(Cc3cccc4ccccc34)CC1)n2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1-[2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-5-yl]-propan-1-ol (72 mg, 0.10 mmol) in dimethylsulfoxide (1 ml) was added to a solution of 1-hydroxy-1-oxo-1H-1λ5-benzo[d][1,2]iodoxol-3-one (44 mg, 0.157 mmol) in dimethylsulfoxide (1 ml), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into ice water (50 ml) and stirred at room temperature for 30 minutes, after which ethyl acetate was added and stirring was continued vigorously for 10 minutes for extraction. After washing with saturated aqueous sodium bicarbonate and then with saturated brine, the mixture was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1-[2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-5-yl]-propan-1-one.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][C:2]21[CH2:18][C:10]1[CH:11]=[C:12]3[C:16](=[CH:17][C:9]=1[CH2:8][CH2:7][CH2:6]2)[NH:15][N:14]=[CH:13]3.I[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=1.[C@@H]1(N)CCCC[C@H]1N.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[CH3:26][C:22]1[CH:21]=[C:20]([N:15]2[C:16]3[C:12](=[CH:11][C:10]4[CH2:18][C:2]5([O:1][CH2:5][CH2:4][O:3]5)[CH2:6][CH2:7][CH2:8][C:9]=4[CH:17]=3)[CH:13]=[N:14]2)[CH:25]=[CH:24][N:23]=1
Reactant: Cc1cc(I)ccn1
Reactant: c1n[nH]c2cc3c(cc12)CC1(CCC3)OCCO1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(-n2ncc3cc4c(cc32)CCCC2(C4)OCCO2)ccn1
Temperature: 100 °C
Yield: 79 %

Procedure:
A 100 mL round-bottom flask equipped with an air cooled reflux container was charged with 5,7,8,9-tetrahydro-1H-spiro[cyclohepta[f]indazole-6,2′-[1,3]dioxolane] (81) (3.00 g, 12.3 mmol), 4-iodo-2-methylpyridine (3.84 g, 14.7 mmol), CuI (0.234 g, 1.23 mmol), (+/−)-trans-cyclohexane-1,2-diamine (0.295 mL, 2.46 mmol) and K3PO4 (5.21 g, 24.6 mmol) in 1,4-dioxane (31 mL). The reaction mixture was heated at about 100° C. for about 21 h. The reaction was allowed to cool and then it was filtered through a pad of Celite® and rinsed with EtOAc (3×10 mL). The filtrate was concentrated then the residue was purified on silica gel (120 g), using a gradient of 10-100% EtOAc in DCM). Collection and concentration of the appropriate fractions gave 1-(2-methylpyridin-4-yl)-5,7,8,9-tetrahydro-1H-spiro[cyclohepta[f]indazole-6,2′-[1,3]dioxolane] (82, R1=2-methylpyridin-4-yl) (3.26 g, 79%); LC/MS, method 3, Rt=1.86 min, MS m/z 336 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:5]2[CH:6]([C:15]3[C:16](=O)[NH:17][C:18](=[O:21])[NH:19][CH:20]=3)[C:7]3[C:8]([CH:13]=[CH:14][C:4]=2[CH:3]=1)=[N:9][CH:10]=[CH:11][CH:12]=3.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>>[CH3:1][C:2]1[CH:24]=[CH:23][C:5]2[CH:6]([C:15]3[C:16](=[S:34])[NH:17][C:18](=[O:21])[NH:19][CH:20]=3)[C:7]3[C:8]([CH:13]=[CH:14][C:4]=2[CH:3]=1)=[N:9][CH:10]=[CH:11][CH:12]=3
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc2c(c1)C=Cc1ncccc1C2c1c[nH]c(=O)[nH]c1=O
Product: Cc1ccc2c(c1)C=Cc1ncccc1C2c1c[nH]c(=O)[nH]c1=S

Procedure:
The title compound was prepared from the product of step (iv) (0.53 g) and Lawesson's reagent (0.675 g) according to the method of example 2 step (ii). Purification was by chromatography eluting with 50% acetone in iso-hexane followed by trituration with acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C([N-]C(C)C)(C)C.[Li+].[Br:15][C:16]1[CH:17]=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1.CO.C(O)(=O)C>[Br:15][C:16]1[C:17]([C:4]2[S:3][C:2]([Cl:1])=[CH:6][CH:5]=2)=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1
Reactant: Clc1cccs1
Reactant: Clc1ncc(Br)cn1
Agent: CC(C)[N-]C(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: Clc1ncc(Br)c(-c2ccc(Cl)s2)n1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-chlorothiophene (0.467 mL, 5 mmol) in anhydrous tetrahydrofuran (5 mL) with treated with a solution of lithium diisopropylamide (2 M in THF, 2.75 mL, 5.5 mmol) at −40° C. under a nitrogen atmosphere. After 15 min, the reaction was allowed to warm up to −10° C. and held at that temperature for 20 min. The reaction was then cooled back down to −40° C. and 5-bromo-2-chloropyrimidine (1.06 g, 5.5 mmol), dissolved in anhydrous THF (10 mL) was added to the reaction slowly. After 2 h, a mixture of 1:1 methanol/acetic acid (2 mL) was added to the reaction. After 15 min, a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.36 g, 6 mmol) in 10 mL of THF was added. The reaction was stirred for an additional 15 min and then the cooling bath was removed. The mixture was stirred for 1 h and then cooled to 0° C. with an ice bath. 5 N sodium hydroxide (5 mL) was added to the reaction mixture which was stirred for an additional 5 min. The reaction was then diluted with ethyl acetate (20 mL) and water (20 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, concentrated and purified by flash chromatography using a gradient of 5 to 20% ethyl acetate in hexanes to obtain a yellow solid. Yield=0.6 g. MS (M+H)+ 311/313.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([F:29])[C:26]([CH2:30][N:31]2[CH2:36][CH2:35][S:34](=[O:38])(=[O:37])[CH2:33][CH2:32]2)=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([CH2:30][N:31]3[CH2:32][CH2:33][S:34](=[O:38])(=[O:37])[CH2:35][CH2:36]3)=[C:27]([F:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: O=S1(=O)CCN(Cc2ccc(Cl)nc2F)CC1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(CN4CCS(=O)(=O)CC4)c(F)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (25 mg, 0.08 mmol) and 4-[(6-chloro-2-fluoropyridin-3-yl)methyl]thiomorpholine 1,1-dioxide (22 mg, 0.08 mmol) as starting materials.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=[O:13].S(Cl)([Cl:18])(=O)=O>C(Cl)(Cl)Cl>[Cl:18][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:12]([OH:14])=[O:13])[CH:4]=1
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cc(Cl)c2ccccc2c1O

Procedure:
To a suspension of 30.0 g 1-Hydroxy-naphthalene-2-carboxylic acid in 600 ml chloroform a mixture of 14.9 ml sulfuryl chloride and 20 ml chloroform was added dropwise. After stirring the reaction for 8 h at room temperature the precipitated product was isolated by filtration, washed with dichloromethane and recrystallized from isopropanol/water to yield 25.1 g of 4-chloro-1-hydroxy-naphthalene-2-carboxylic acid as off-white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([O:4][C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](O)=[O:18])=[CH:11][CH:10]=1)=[O:6])[CH3:3].C(=O)([O-])[O-].[NH4+:25].[NH4+]>>[CH3:1][C:2]([CH3:20])([O:4][C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH2:25])=[O:18])=[CH:11][CH:10]=1)=[O:6])[CH3:3]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CCC(=O)O)cc1
Agent: O=C([O-])[O-]
Product: CC(C)(C)OC(=O)NCc1ccc(CCC(N)=O)cc1
Yield: 84 %

Procedure:
Prepared analogously to Example 63a) from 4-[[[(1,1-dimethylethoxy)carbonyl]amino]methyl]benzene propanoic acid, N,N'-carbonyldiimidazole and ammonium carbonate in a yield of 84% of theory. Colourless crystals, which were used in the following step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH:30][CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:30]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][CH3:29])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCNCCC
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCCN12
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.1 %

Procedure:
A suspension of 1.85 g (4.74 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 30 ml of N,N-dimethylformamide was treated with 2.40 g (23.7 mmol) of dipropylamine. After stirring at room temperature for 16 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with methylene chloride/methanol 19:1 as the eluent. There were obtained 2.03 g (94%) of (S)-8-chloro-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one as a pale yellow oil; [α]D20 =+29.3° (MeOH, c=1%).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH3:10])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][O:12][CH2:11][C@H:9]([NH2:8])[CH3:10])=[CH:19][CH:18]=1
Reactant: C[C@H](COCc1ccc(F)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)COCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 85.1 %

Procedure:
Dissolve (R)-2-(tert-butoxycarbonylamino)-3-(4-fluorobenzyloxy)-propane (2.18 g, 7.7 mmol) in DCM (50 mL), add trifluoroacetic acid (25 mL), and stir at 0° C. for 20 min. Evaporate and purify by SCX chromatography to give the title compound as a colorless oil (1.2 g, 85%). MS (ES+) m/z: 184 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:56])[CH2:3][CH2:4][N:5]([C:42]([C:44]2[S:48][C:47]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[N:46][C:45]=2[CH3:55])=[O:43])[C:6]2[CH:41]=[CH:40][CH:39]=[CH:38][C:7]=2/[C:8]/1=[CH:9]/[C:10]([NH:12][CH2:13][C:14]1[N:15]=[CH:16][N:17](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:18]=1)=[O:11]>C(O)(=O)C>[F:56][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:42]([C:44]2[S:48][C:47]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[N:46][C:45]=2[CH3:55])=[O:43])[C:6]2[CH:41]=[CH:40][CH:39]=[CH:38][C:7]=2/[C:8]/1=[CH:9]/[C:10]([NH:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)=[O:11]
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)NCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c2ccccc21
Solvent: CC(=O)O
Product: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)NCc2c[nH]cn2)c2ccccc21
Yield: 84.9 %

Procedure:
A solution of 190 mg of (Z)-[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]-N-[(1-trityl-1H-imidazol-4-yl)methyl]-acetamide in 20 ml of a 90% aqueous solution of acetic acid was stirred at 60° C. for 1.5 hours. After evaporating the solvent therefrom, ethyl acetate and 3N hydrochloric acid were added to undergo liquid separation. The aqueous layer was neutralized with potassium carbonate and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of NaCl and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was collected by filtration and washed with ethyl acetate to give 110 mg of (Z)-[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]-N-[(1H-imid-azol-4-yl)methyl]acetamide as a colorless powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.CN(C=O)C.Cl.[OH:32][C:33]1[N:37]([CH2:38][CH3:39])[N:36]=[CH:35][CH:34]=1>C(Cl)(Cl)Cl.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([C:9]([C:34]2[CH:35]=[N:36][N:37]([CH2:38][CH3:39])[C:33]=2[OH:32])=[O:11])[CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CCn1nccc1O
Reactant: COCCOc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(OCCOC)c2C)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoic acid (200 mg, 6.90×10−4 mol) in chloroform (15 mL) were added oxalyl chloride (0.5 mL) and DMF in a catalytic amount. The reaction mixture was stirred at room temperature for 30 minutes, and the solvent was distilled off under reduced pressure. The residue was dissolved in anhydrous THF (20 mL), and 5-hydroxy-1-ethylpyrazole hydrochloride (134 mg, 9.01×10−4 mol), triethylamine (139 mg) and N,N-dimethylaminopyridine (170 mg) were added. The mixture was heated at refluxed temperature for 1 hour. The reaction mixture was allowed to cool to room temperature, and then ethyl acetate (200 mL) was added. The mixture was washed twice with a saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was dissolved in anhydrous acetonitrile (10 mL), and triethylamine (139 mg) and acetone cyanohydrin in a catalytic amount were added, followed by stirring for 12 hours at room temperature. The solvent was distilled off under reduced pressure to obtain crude 5-hydroxy-1-ethylpyrazol-4-yl 3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)phenyl ketone.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][S:11](Cl)(=[O:13])=[O:12])([O-])=O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH:1]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:10][S:11]1(=[O:13])=[O:12]
Reactant: O=[N+]([O-])c1ccccc1CS(=O)(=O)Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=S1(=O)Cc2ccccc2N1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
The title compound was prepared using the method described in WO 98/32438 A1. To a solution of 2-nitro-alpha-toluenesulfonyl chloride (5.1 g, 21.6 mmol) in anhydrous ethyl acetate (250 mL) was added tin (II) chloride (19.3 g, 86 mmol). The reaction was stirred overnight at 70° C., then poured onto ice and neutralized with saturated aqueous sodium bicarbonate. The solution was filtered through Celite, extracted with ethyl acetate, and the organic layer concentrated. To the crude residue was added anhydrous methylene chloride (200 mL) and triethylamine (5 mL). The solution was stirred overnight at room temperature and concentrated under reduced pressure. The product was obtained by silica gel column chromatography (30-100% ethyl acetate in hexanes) followed by recrystallization from methylene chloride/hexanes to give a white solid. (0.24 g, 6.5%). 1H NMR (CDCl3, 300 MHz) δ 7.30-7.22 (m, 2H), 7.07-7.02 (t, 1H, J=7.4 Hz), 6.89-6.86 (dd, 1H, J=0.6, 8.1 Hz), 6.66 (br s, 1H), 4.39 (s, 1H).
Reaction SMILES: [C:1]1([CH:11]2[S:15][CH:14]([CH2:16]O)[CH2:13][S:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.OCC1CSC[S:21]1>>[C:1]1([CH:11]2[S:15][CH:14]([CH2:16][SH:21])[CH2:13][S:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OCC1CSC(c2cccc3ccccc23)S1
Reactant: OCC1CSCS1
Product: SCC1CSC(c2cccc3ccccc23)S1

Procedure:
The same method was followed as in Example 1 except that 2-(α-naphtyl)-4-hydroxymethyl-1,3-dithiolane produced in Example 3 was used in stead of 4-hydroxymethyl-1,3-dithiolane synthesized in Manufacturing Example 1 to obtain 2-(α-naphtyl)-4-mercaptomethyl-1,3-dithiolane represented by the following formula (2-7).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Cl:21][CH2:22][C:23](=O)[CH2:24][CH2:25][CH3:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([CH2:24][CH2:25][CH3:26])[CH2:22][Cl:21])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: CCCC(=O)CCl
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Product: CCCC(CCl)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine can be reacted with 1-chloro-2-pentanone to give 7-chloro-2-[(2-chloro-1-propylethylidene) hydrazino]-5-phenyl-3H-1,4-benzodiazepine.