Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].[ClH:23].Cl>C(O)C>[ClH:23].[NH:21]([N:22]=[C:10]1[CH2:9][CH:8]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH2:7][C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]1=2)[C:18]([NH2:20])=[NH:19]
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1ccsc1)C2
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccsc1)C2
Yield: 107.9 %

Procedure:
A mixture of 4-methyl-7-(3-thienyl)-5,6,7,8-tetrahydroquinolin-5-one (243 mg), aminoguanidine hydrochloride (122 mg) and concentrated hydrochloric acid (0.2 ml) in ethanol (3 ml) was refluxed for 2 hours. The reaction solution was cooled, and precipitated crystals were filtered, washed with ethanol and dried to give 5-guanidinoimino-4-methyl-7-(3-thienyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 100) (362 mg) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:10])=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.CN(C=O)C.Cl[CH2:17][C:18](=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21].C([O-])([O-])=O.[K+].[K+]>O>[CH3:1][O:2][C:3]1[C:4]([CH3:10])=[C:5]([S:9][CH2:17][C:18](=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: COc1cccc(S)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)CSc1cccc(OC)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-methoxy-2-methylbenzenethiol (2.52 g) and DMF (dry) (10 mL) were added methyl 4-chloroacetoacetate (2.114 mL) and K2CO3 (2.60 g) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (3.65 g).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[C:22]([C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:23]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C(O)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)c1cc(Br)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
Phenylacetic acid (1.09 g, 80 mmoles) was dissolved in 5 ml dichloromethane. To this mixture, oxalylchloride (1.01 g, 80 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 5 ml dichloromethane. To this mixture, 4-bromoanisole (1 g, 5.34 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (1.06 g, 80 mmoles) was added and the reaction mixture was warmed to RT and stirred overnight. The reaction mixture was quenched by the addition of 2N HCl and extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography to afford the title compound as white solid (1 g, 66% yield). MP: 83-86° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 11.56(s,1H), 8.01(d, J=2.2 Hz, 1H), 7.64(dd, J=8.8, 2.5 Hz, 1H), 7.32(t, 2H), 7.29(m,3H), 6.96(d, J=8.8 Hz,1H), 4.43(s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([N+:8]([O-])=O)[CH:7]=1.[NH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15](=[O:16])[NH:8][C:6]=2[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: Nc1ccccc1C(=O)O
Product: O=C1Nc2cc(Br)ccc2Nc2ccccc21
Yield: 31.8 %

Procedure:
5-Bromo-2-fluoronitrobenzene (1.6 g, 7.4 mmol) and 2-aminobenzoic acid (0.50 g, 3.6 mmol) were reacted according to GP7 to give 331 mg of the title compound (166JO31). MS (ESI) 289 (MH+). Purity for MH+ (UV) 93%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:21])[CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[O:15][C:5]=3[C:4]=2[CH:3]=1.O>C(O)(=O)C.Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:21])[CH:13]=[C:14]([C:16]([OH:18])=[O:17])[O:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1cc(=O)c2c(o1)c1cc(Cl)ccc1n2C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cn1c2ccc(Cl)cc2c2oc(C(=O)O)cc(=O)c21
Temperature: 0 °C

Procedure:
A mixture of 3.5 g (0.012 mole) of ethyl 8-chloro-4,5-dihydro-5-methyl-4-oxopyrano[3,2-b]indole-2-carboxylate in 50 ml glacial acetic acid and 10 ml conc. hydrochloric acid was stirred at reflux for 3 hr, then cooled and added to 500 g ice--H2O. The crude product was filtered, washed with 50% aqueous ethanol, and air dried. A suspension of the product in 75 ml of chloroform was stirred for 90 min at room temperature, then filtered. After recrystallization twice from DMF-water, the final product was dried for several hours under high vacuum at 100°. The yellow flakes obtained had a mpt. of 290°-dec.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:24])[CH:3]=1.[O:25]1[CH2:29][CH:28]=[N:27][C:26]1=[O:30]>>[F:24][C:4]1[CH:3]=[C:2]([N:27]2[CH2:28][CH2:29][O:25][C:26]2=[O:30])[CH:7]=[C:6]([F:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: O=C1N=CCO1
Reactant: Cc1ccc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)nc1
Product: Cc1ccc(N2CCN(C(=O)c3c(F)cc(N4CCOC4=O)cc3F)CC2)nc1
Yield: 63.7 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-bromo-2,6-difluorophenyl)[4-(5-methylpyridin-2-yl)piperazin-1-yl]methanone (396 mg) described in Preparation Example 185 and oxazolin-2-one (104 mg), the title compound (256 mg) was obtained.
Reaction SMILES: [CH2:1]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C(Cl)(Cl)Cl>[CH2:1]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[O:13])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C1COCCN1
Reactant: CCCCCCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCCCCCc1ccc(C(=O)N2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 7 h
Yield: 87.7 %

Procedure:
The compound ([5]-(53)-75) (7.60 g) prepared in Example 61 was dissolved in anhydrous chloroform (152 ml). Then, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.37 g), 1-hydroxybenzotriazole (4.48 g), and morpholine (6.31 g) were added to the solution. The reaction mixture was stirred at room temperature for 7 hours. After the reaction was completed, chloroform was added. The solution was washed with 0.5N HCl aqueous solution, 0.5N NaOH aqueous solution, and distilled water. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Kieselgel 60=150 g, hexane/ethyl acetate=1/1) to obtain the above-captioned compound ([5]-(54)-75) (8.50 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:18]([CH2:23][CH:24]=[CH2:25])[C:19]([O:21]C)=[O:20])[C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([F:17])[CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:18]([CH2:23][CH:24]=[CH2:25])[C:19]([OH:21])=[O:20])[C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([F:17])[CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[C@H](C(=O)OC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CC[C@H](C(=O)O)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of the product from Step B (1.57 g, 4.358 mmol) in THF (30 mL) and water (20 mL) was added lithium hydroxide (1.2 g, 50.0 mmol). After stirring at room temperature for 12 h, the reaction was quenched with 1N hydrochloric acid. The organic phase was separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic layers were washed with brine and concentrated in vacuo to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([CH3:25])[CH:19]=1)=[O:10].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[C:20]([CH3:25])[CH:19]=1)=[O:10]
Reactant: OB(O)c1cccnc1
Reactant: Cc1cc(C(=O)NCCCCCC(=O)Nc2ccccc2N)ccc1Br
Product: Cc1cc(C(=O)NCCCCCC(=O)Nc2ccccc2N)ccc1-c1cccnc1
Yield: 63 %

Procedure:
The procedure of Example 81 was repeated except for using N-(5-(2-aminophenylcarbamoyl)pentyl)-4-bromo-3-methylbenzamide instead of N-(5-(2-aminophenylcarbomoyl)pentyl)-3-bromo-2-methylbenzamide, and 3-pyridinyl boronic acid instead of phenyl boronic acid to obtain the title compound (32 mg, 63%).
Reaction SMILES: [NH4+:1].[Cl:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([S:15](Cl)(=[O:17])=[O:16])[CH:14]=1)=[O:8]>O1CCCC1>[Cl:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([S:15]([NH2:1])(=[O:17])=[O:16])[CH:14]=1)=[O:8]
Reactant: [NH4+]
Reactant: COc1ccc(C(=O)CCCCCl)cc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CCCCCl)cc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 25% aqueous ammonium solution was added dropwise to a solution of 5-(5-chloropentanoyl)-2-methoxybenzenesulfonyl chloride (3.00 g) obtained in Reference Example 65 in tetrahydrofuran (50 ml) under ice-cooling. After stirring at room temperature for 30 minutes, the solvent was evaporated under reduced pressure, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as colorless crystals (2.54 g) having a melting point of 135 to 136° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH2:12][CH2:13]Cl)=[C:10](Cl)[C:9]2[C:4](=[C:5]([CH3:16])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[CH3:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>C(O)CCC>[CH3:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[N:21]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([CH3:16])[C:4]=3[N:3]=[C:2]([CH3:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: Cc1ccccc1N
Reactant: Cc1nc2c(C)cccc2c(Cl)c1CCCl
Agent: Cl
Solvent: CCCCO
Product: Cc1ccccc1N1CCc2c(C)nc3c(C)cccc3c21
Yield: 22.5 %

Procedure:
2,8-Dimethyl-3-(2-chloroethyl)-4-chloroquinoline (7.63 g, 30 mmol) and 2-methylaniline hydrochloride (4.31 g, 30 mmol) in 1-butanol (100 ml) wereheated at reflux for 4 days, then the solvent evaporated, the crude producttaken up in dichloromethane, washed with aqueous sodium bicarbonate, dried and evaporated. Chromatography (silica gel, 2% methanolic ammonia in dichloromethane) and recrystallisation from aqueous ethanol gave 1-(2-methylphenyl)-4,6-dimethyl-2,3-dihydropyrrolo-[3,2-c]quinoline (1.95 g, 23%), m.p. 126°-128°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH3:17][C:18]([CH2:20][C:21]([CH:23]([F:25])[F:24])=[O:22])=O>>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:18]([CH3:17])[C:20]([C:21](=[O:22])[CH:23]([F:25])[F:24])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)CC(=O)C(F)F
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Product: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C(F)F
Yield: 36 %

Procedure:
The title compound was prepared from (2-Amino-5-bromo-phenyl)-phenyl-methanone [example A16] and 1,1-difluoroacetylacetone according to the procedure of example 1, except that the residue was purified by chromatography on aminated silica gel with heptane/ethyl acetate (5:1). Yield: 36%. MS: m/z=377 (M).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[N:27]=[C:28]=[S:29]>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:28](=[S:29])[NH:27][C:20]1[C:21]([CH3:26])=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=1[Cl:18]
Reactant: Cc1cc(Cl)cc(Cl)c1N=C=S
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2c(C)cc(Cl)cc2Cl)c1NCCCO
Temperature: 60 °C
Reaction time: 17 h
Yield: 78.8 %

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (1.50 g, 5.80 mmol) and 1,5-dichloro-2-isothiocyanato-3-methylbenzene (1.64 g, 7.52 mmol) in tetrahydrofuran (15 mL) was stirred at 60° C. for 17 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a brown powder (2.18 g, 4.57 mmol, 79%).
Reaction SMILES: [NH2:1][C:2]([C:18]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]2[C:19]=1[CH:20]=[CH:21][N:22]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:9]=2[N:8]=1)[C:3]([F:6])([F:5])[F:4].[C:37]([O:41][CH2:42][CH3:43])(=[O:40])[CH:38]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:16]([C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:7]([C:2]([C:18]3[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([NH:1][CH2:38][C:37]([O:41][CH2:42][CH3:43])=[O:40])[C:3]([F:6])([F:5])[F:4])=[N:8][C:9]=2[CH:15]=1)#[N:17]
Reactant: CCOC(=O)C=O
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(N)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)CNC(c1nc2cc(C#N)ccc2[nH]1)(c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C)C(F)(F)F
Temperature: 60 °C

Procedure:
To a suspension of (±)-tert-butyl 4-(1-amino-1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 139-A) (117 mg, 0.234 mmol) in DCE (2.34 mL) was added ethyl glyoxylate (50% in toluene) (93 μL, 0.468 mmol) and this was stirred at 60° C. After 5 minutes this was cooled to room temperature, then sodium triacetoxyborohydride (298 mg, 1.405 mmol) was added and this was stirred again at 60° C. After stirring overnight the reaction was quenched with sat. aq. sodium bicarbonate, extracted with EtOAc, dried with MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-50% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 586.3 (M+H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([CH3:11])=[C:8]([CH3:10])[CH:9]=1)=[O:4].C([Li])(C)(C)C.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([CH3:11])=[C:8]([CH3:10])[C:9]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:4]
Reactant: CNC(=O)c1cc(C)c(C)s1
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1sc(C)c(C)c1C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 10 (0.40 g, 2.37 mmole) in 20 mL dry THF was cooled to −70° C. and stirred during the addition of t-butyllithium (5.21 mmole). After 30 minutes of stirring benzoyl chloride (0.42 g=0.35 mL, 3 mmole) was added and the mixture was warmed to room temperature. Workup consisted of quenching the reaction with saturated aqueous NH4Cl and extraction of product into ethyl acetate. The extract was dried over MgSO4, evaporated and product purified by chromatography on silica gel eluted with hexane-ethyl acetate 1:1. Yield 0.356 g, 55% 1H NMR(CDCl3) δ: 1.83 (s, 3H, CH3), 2.37 (s, 3H, CH3), 2.79 (d, 3H, NHCH3), 6.58 (br s, 1H, NH), 7.42–7.78 (m, 5H, ArH).
Reaction SMILES: C([O:8][C:9]1[CH:38]=[CH:37][C:12]2[NH:13][C:14]([C:19]3[C:24](=[O:25])[N:23]([NH:26][CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:22]4[CH:33]=[CH:34][S:35][C:21]=4[C:20]=3[OH:36])=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)C1C=CC=CC=1.I[Si](C)(C)C>C(#N)C.O>[CH:27]1([NH:26][N:23]2[C:24](=[O:25])[C:19]([C:14]3[NH:13][C:12]4[CH:37]=[CH:38][C:9]([OH:8])=[CH:10][C:11]=4[S:16](=[O:18])(=[O:17])[N:15]=3)=[C:20]([OH:36])[C:21]3[S:35][CH:34]=[CH:33][C:22]2=3)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2sccc2n1NC1CCCCC1
Agent: C[Si](C)(C)I
Solvent: O
Solvent: CC#N
Product: O=c1c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2sccc2n1NC1CCCCC1
Temperature: 25 °C
Yield: 85.8 %

Procedure:
The product of Example 324D (0.114 g, 0.21 mmol) in dry acetonitrile (11 mL) at 25° C. was reacted with iodotrimethylsilane (0.29 mL, 2.1 mmol) at 50° C. for 4 hours. The reaction was cooled to 25° C. and diluted with water (50 mL). The resulting precipitate was collected by filtration and dried under reduced pressure to give the title compound (0.083 g, 87% yield). MS (ESI−) m/z 459 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.20 (m, 5 H) 1.66 (m, 5 H) 6.51 (s, 1 H) 7.18 (m, 2 H) 7.48 (d, J=5.52 Hz, 1 H) 7.57 (d, J=9.56 Hz, 1 H) 8.29 (d, J=5.15 Hz, 1 H) 10.42 (s, 1 H) 14.04 (s, 1 H) 14.93 (s, 1 H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:16]([O-])=O)[CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1.[H][H]>[Ni].C(O)C>[CH3:1][N:2]([CH3:19])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH2:16])[CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: CN(C)C1CCc2[nH]c3ccc([N+](=O)[O-])cc3c2C1
Agent: [Ni]
Solvent: CCO
Product: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1

Procedure:
3-(Dimethylamino)-6-amino-1,2,3,4-tetrahydrocarbazole is prepared by dissolving 0.1 mole of 3-(dimethylamino)-6-nitro1,2,3,4-tetrahydrocarbazole (Example 10) in 400 ml. absolute ethyl alcohol and hydrogenating over Raney nickel at about 350 psig and at room temperature until the required amount of hydrogen has reacted. The resulting 3-(dimethylamino)-6-amino-1,2,3,4-tetrahydrocarbazole can be isolated and purified using conventional procedures.
Reaction SMILES: [OH-].[Na+:2].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([OH:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9]>O.CC(C)=O>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([O-:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9].[Na+:2]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C
Yield: 81.1 %

Procedure:
A solution of sodium hydroxide (0.57 g) in water:acetone (40:60 v/v, 11.4 ml) was added dropwise to a solution of amorphous ibandronic acid (4.5 g) in water:acetone (40:60 v/v, 64.4 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 2 hours to obtain a pH of 4.5. Then the solution was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was isolated by vacuum filtration, washed with acetone (2×15 ml), and dried in a vacuum oven at 50° C. for 21 hours to obtain 3.9 g of ibandronate sodium crystal form QQ.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[CH3:29][C:30]1[CH:31]=[N:32][NH:33][CH:34]=1>>[CH3:26][C:23]1[C:22]([CH2:27][N:32]2[CH:31]=[C:30]([CH3:29])[CH:34]=[N:33]2)=[C:21]([C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4([C:4]([OH:3])=[O:5])[CH2:7][CH2:8]4)=[CH:14][CH:13]=3)=[CH:20][CH:19]=2)[O:25][N:24]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Reactant: Cc1cn[nH]c1
Product: Cc1cnn(Cc2c(C)noc2-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-methyl-1H-pyrazole.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9]C)=O.O.[CH:12]([NH2:14])=O>>[N:1]1[C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7](=[O:9])[NH:14][CH:12]=1
Reactant: NC=O
Reactant: COC(=O)c1ccsc1N
Solvent: O
Product: O=c1[nH]cnc2sccc12
Yield: 66 %

Procedure:
A solution of methyl 2-aminothiophene-3-carboxylate (3.0 g, 19.1 mmol) in formamide (95 ml) was heated at 190° C. for 4 hours. The cooled mixture was poured into water. The precipitate was filtered off, washed with water and dried. The crude product was purified by silica gel chromatography (CH2Cl2/MeOH 50:1) to yield the title compound as a white solid (1.93 g, 66%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][C:18]#[N:19]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[C:17](=[CH:6]/[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])/[C:18]#[N:19])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Product: COc1ccc(/C(C#N)=C/c2ccccc2[N+](=O)[O-])cc1OC
Yield: 83.6 %

Procedure:
2-Nitrobenzaldehyde (1.51 g) and 3,4-dimethoxybenzyl cyanide (1.77 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (2.59 g, yield: 84%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[S:11])[S-:10])[CH:5]=[CH:4][CH:3]=1.C([NH+](CC)CC)C.Cl[CH2:20][C:21](=[O:24])[CH2:22][CH3:23]>O>[CH2:22]([C:21]1([OH:24])[CH2:20][S:11][C:9](=[S:10])[N:8]1[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)[CH3:23]
Reactant: CCC(=O)CCl
Reactant: Cc1cccc(NC(=S)[S-])n1
Agent: CC[NH+](CC)CC
Solvent: O
Product: CCC1(O)CSC(=S)N1c1cccc(C)n1
Reaction time: 3 h
Yield: 71.1 %

Procedure:
The procedure of Example 1 is followed but starting with triethylammonium (6-methylpyrid-2-yl)dithiocarbamate (71.0 g) and 1-chlorobutan-2-one (26.6 g) in distilled water (300 cc) at 20° C. The reaction is carried out for 3 hours at 20° C. After recrystallisation of the product from ethanol (250 cc), there is obtained 4-ethyl-4-hydroxy-3-(6-methylpyrid-2-yl)-thiazolidine-2-thione (45.0 g) melting at 118° C.