Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15](=[O:21])[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C@H:10]([CH3:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:34][C:35]1[CH:40]=[C:39]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH:38]=[CH:37][C:36]=1[C:46](=[N:48]O)[NH2:47]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:10]([C:11]1[O:13][N:48]=[C:46]([C:36]2[CH:37]=[CH:38][C:39]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])=[CH:40][C:35]=2[Cl:34])[N:47]=1)[CH3:14])[C:15]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:21])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Nc1ccc(C(N)=NO)c(Cl)c1
Reactant: C[C@H](C(=O)O)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C[C@H](c1nc(-c2ccc(NS(C)(=O)=O)cc2Cl)no1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the product from Step B (132.0 mg, 0.44 mmol) in dichloromethane (5 mL) was added 1,1′-carbonyldiimidazole (148.0 mg, 0.91 mmol). After stirring at room temperature for 1 h, 2-chloro-N′-hydroxy-4-[(methylsulfonyl)amino]benzenecarboximidamide (Intermediate 6, 145.0 mg, 0.55 mmol) was added. After stirring at room temperature for 2 h, the reaction was quenched with saturated aqueous ammonium chloride solution. The organic phase was then dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in 10 mL of toluene and heated at 110° C. for 12 h. The toluene was removed under reduced pressure and the residue was then purified by preparative thin layer chromatography (silica gel, 30:70 hexanes/ethyl acetate) to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C@@H:7]2[CH2:9][C@H:8]2[C:10](=O)[CH3:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl.[CH3:20][O:21][NH2:22]>CO>[CH3:20][O:21][N:22]=[C:10]([C@@H:8]1[CH2:9][C@H:7]1[C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:11]
Reactant: CON
Reactant: CC(=O)[C@@H]1C[C@H]1c1ccc(Cl)s1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C(C)[C@@H]1C[C@H]1c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.1 %

Procedure:
To a stirred solution of trans 1-[2-(5-chloro-thiophen-2-yl)-cyclopropyl]-ethanone (1.0 g; 5.0 mmol) in methanol (10 ml) at ambient temperature was added pyridine (0.85 ml; 10.3 mmol) and methoxyamine hydrochloride (0.86 g; 10.3 mmol). The reaction mixture was stirred for 20 hours at ambient temperature then poured on water (50 ml) and extracted with dichloromethane (3×20 ml). Combined organic layers were dried over anhydrous sodium sulphate. The solvent was removed in vacuo to afford 1.0 g (92% of theory) of trans 1-[2-(5-Chloro-thiophen-2-yl)-cyclopropyl]-ethanone O-methyl-oxime as an E/Z mixture in form of a clear oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([S:8](Cl)(=[O:10])=[O:9])=[N:6][N:7]=1.O1CCCC1.[CH3:17][NH:18][CH2:19][C:20]1[O:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>O>[CH3:1][NH:2][C:3]1[S:4][C:5]([S:8](=[O:10])(=[O:9])[N:18]([CH3:17])[CH2:19][C:20]2[O:24][CH:23]=[CH:22][CH:21]=2)=[N:6][N:7]=1
Reactant: CNc1nnc(S(=O)(=O)Cl)s1
Reactant: CNCc1ccco1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CNc1nnc(S(=O)(=O)N(C)Cc2ccco2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8.4 g. of 2-methylamino-1,3,4-thiadiazole-5-sulfonyl chloride (see Preparation 1) in 100 ml. of tetrahydrofuran, cooled to about 0° C., there was added dropwise 4.4 g. of methylfurfurylamine. After the addition had been completed, 4.1 g. of triethylamine was added to the mixture dropwise and the mixture was then stirred at ambient room temperature overnight. The reaction product mixture was filtered to remove any salt. The filtrate was concentrated to yield an oil. Water was added to the oil. A precipitate formed which was filtered off and dried. The precipitate weighed about 6.2 g. and had a melting point of about 109°-112° C. It was identified as 2-methylamino-5-[N-methyl-N-furfurylsulfamoyl]-1,3,4-thiadiazole. It was used without further purification in the preparation of some of the final products of the invention.
Reaction SMILES: Cl.N[C@@H]1C[C@H](NC2C(C)=NC3C(N=2)=C([C:18]2[NH:26][C:25]4[CH2:24][CH2:23][NH:22][C:21](=[O:27])[C:20]=4[CH:19]=2)C=CC=3)C1.ClCCOCCCl.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:26]1[C:25]2[CH2:24][CH2:23][NH:22][C:21](=[O:27])[C:20]=2[CH:19]=[CH:18]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@H]1C[C@@H](N)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCOCCCl
Product: O=C1NCCc2[nH]ccc21
Temperature: 150 °C
Reaction time: 1.17 h
Yield: 20 %

Procedure:
A suspension of 2-(3-((cis-3-aminocyclobutyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one hydrochloride (Example 435; 26.0 mg, 0.065 mmol), bis(2-chloroethyl) ether (Aldrich; 0.015 mL, 0.130 mmol), and DIPEA (0.068 mL, 0.391 mmol) in DMF (1.0 mL) was stirred in a sealed flask at 150° C. for 70 min. The reaction mixture was then concentrated onto silica gel and chromatographically purified (silica gel, 0-10% (2M NH3 in MeOH)/DCM). Product-containing fractions were combined and diluted with DCM (20 mL), and the resulting mixture was sequentially washed with half-saturated brine (30 mL) and water (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-(2-methyl-3-((1s,3s)-3-morpholinocyclobutyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (5.8 mg, 0.013 mmol, 21% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 12.63 (1H, br. s.), 7.95 (1H, dd, J=7.5, 1.3 Hz), 7.68 (1H, dd, J=8.1, 1.3 Hz), 7.41 (1H, t, J=7.8 Hz), 7.14 (1H, d, J=2.0 Hz), 5.25-5.33 (1H, m), 5.09 (1H, d, J=4.1 Hz), 4.22-4.32 (1H, m), 3.75 (4H, t, J=4.5 Hz), 3.70 (2H, m, J=6.8, 6.8, 2.5 Hz), 3.61-3.67 (1H, m), 3.00 (2H, t, J=6.8 Hz), 2.82-2.92 (2H, m), 2.57 (3H, s), 2.42 (4H, br. s.), 1.90-2.01 (2H, m). m/z (ESI, +ve) 433.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([O:9][C@H:10]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)[C:6]([CH3:22])=[CH:5][CH:4]=1)#[N:2].C[N:24]1[C:28](=[O:29])CCC1.[NH:30](C(OCC)=O)N>CCOC(C)=O>[CH3:22][C:6]1[C:7]([O:9][C@H:10]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:11]2)=[N:8][C:3]([C:1]2[NH:30][C:28](=[O:29])[NH:24][N:2]=2)=[CH:4][CH:5]=1
Reactant: CCOC(=O)NN
Reactant: Cc1ccc(C#N)nc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2n[nH]c(=O)[nH]2)nc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 175 °C
Yield: 4.4 %

Procedure:
To the reaction mixture containing (S)-tert-butyl 3-((6-cyano-3-methylpyridin-2-yl)oxy)pyrrolidine-1-carboxylate (1.095 g) was added NMP (1.5 mL) and ethyl hydrazinecarboxylate (0.752 g, 7.22 mmol). The mixture was heated at 175° C. for 1.5 days and was subsequently cooled and diluted with EtOAc. The organic phase was washed with aqueous NH4Cl, dried, and concentrated. The crude product was purified by preparative HPLC eluting with a gradient of 35-60% ACN in water (acid mode) to give the title compound (0.042 g, 4.4% over 2 steps).
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([NH:10][NH2:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[C:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:33]=1>C1(C)C=CC=CC=1>[C:7]([C:8]1[N:33]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:26]2=[N:11][N:10]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC1=NCCCCCC1
Reactant: NNC(=O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(C(c2ccccc2)(c2ccccc2)c2nnc3n2CCCCCC3)cc1
Temperature: 25 °C
Yield: 19.8 %

Procedure:
2,2,2-Triphenylacetohydrazide (48.2 mg, 0.159 mmol) was dissolved in anhydrous toluene (3 mL) and stirred at room temperature under nitrogen. 8-Methoxy-2,3,4,5,6,7-hexahydroazocine (24.7 mg, 0.175 mmole) was added and the solution was stirred at 120° C. overnight and 200° C. for two days. After cooling, the toluene was removed by evaporation and crude product was purified by silica gel chromatography (100% ethyl acetate→5% methanol in ethyl acetate→10% methanol in ethyl acetate) to give the product (2-1) as a white solid (12.4 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:42]=[CH:43][CH:44]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:24][CH:23]=[C:22]([C:25]([NH:27][CH:28]([CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:29]([O:31]C)=[O:30])=[O:26])[CH:21]=2)[CH:15]=1)=[O:8].[OH-].[Na+].O.Cl>C1COCC1.CO>[C:38]([O:37][C:35](=[O:36])[CH2:34][CH2:33][CH:28]([NH:27][C:25]([C:22]1[CH:21]=[C:20]([C:16]2[CH:15]=[C:14]([O:13][C:12]3[CH:42]=[CH:43][CH:44]=[C:10]([NH:9][C:7]([C:3]4[O:4][CH:5]=[CH:6][C:2]=4[CH3:1])=[O:8])[CH:11]=3)[CH:19]=[CH:18][N:17]=2)[NH:24][CH:23]=1)=[O:26])[C:29]([OH:31])=[O:30])([CH3:40])([CH3:41])[CH3:39]
Reactant: COC(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c1c[nH]c(-c2cc(Oc3cccc(NC(=O)c4occc4C)c3)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc(-c3cc(C(=O)NC(CCC(=O)OC(C)(C)C)C(=O)O)c[nH]3)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-tert-butyl 1-methyl 2-({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)pentanedioate (170 mg, 0.28 mmol) in a mixture of THF/MeOH (10 ml/10 ml) was added 1M NaOH solution (2 ml, 2 mmol). The mixture was stirred at room temperature for 2 hours and poured into 100 ml of water. 1M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 5-tert-butoxy-2-({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)-5-oxopentanoic acid as white solid. Yield: 145 mg, 87%.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH:16]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:24]12[CH2:31][CH2:30][N:27]([CH2:28][CH2:29]1)[CH2:26][CH2:25]2>CS(C)=O>[Cl-:1].[C:20]([O:19][C:17]([N:14]1[CH2:15][CH:16]=[C:11]([C:9]2[NH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([N+:24]45[CH2:31][CH2:30][N:27]([CH2:28][CH2:29]4)[CH2:26][CH2:25]5)[C:3]=3[CH:10]=2)[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Reactant: C1CN2CCN1CC2
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c([N+]45CCN(CC4)CC5)ncnc3[nH]2)CC1
Product: [Cl-]
Temperature: 25 °C

Procedure:
To a stirred solution of 1M tert-butyl 4-(4-chloro-7H-pyrrolo[2,3-d]-pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.6 mmol) in anhydrous DMSO (0.6 mL), was added 1,4-Diaza-bicyclo[2.2.2]octane (370 mg, 3.3 mmol). The mixture was stirred under argon at rt until TLC analysis showed no starting material was present. The resulting solution containing the title compound was used directly in the next step.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Zn:21].[OH-]>C(O)C>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Zn+2:21].[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: [Zn]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]
Product: [Zn+2]
Temperature: 20 °C

Procedure:
To a mixture obtained by adding 1,145 parts of stearic acid to 5,000 parts of ethanol and mixing these at 75° C., 200 parts of zinc. hydroxide is gradually added and mixed for 1 hour from the completion of addition. After mixing, the mixture is cooled to 20° C., the product is separated by filtration, ethanol and the reaction residue are removed, and the produced solid taken out is dried at 150° C. for 3 hours in a heating-type vacuum dryer, taken out from the dryer and then allowed to cool to obtain solid zinc stearate.
Reaction SMILES: [N:1]1([C:7]2[S:8][CH:9]=[C:10]([Sn](C)(C)C)[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]C1SC=C(Br)N=1.O>N1CCCCC1>[N:1]1([C:7]2[S:8][CH:9]=[C:10]([Br:16])[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Brc1csc(Br)n1
Reactant: C[Sn](C)(C)c1csc(N2CCCCC2)n1
Solvent: O
Solvent: C1CCNCC1
Product: Brc1csc(N2CCCCC2)n1
Temperature: 50 °C
Yield: 100 %

Procedure:
Synthesis of 2-Piperidinyl(trimethylstannyl)thiazole 373 as illustrated in FIG. 53. 2,4-Dibromothiazole (358; 1.0 equiv) was dissolved in piperidine (0.5 M) and the reaction was warmed to 50° C. for 8 h, upon which completion of the reaction was indicated by TLC. The mixture was poured into water and extracted with ether (2×). Drying (MgSO4) and evaporation of the solvents gave 2-piperidinyl-4-bromothiazole 372, which was isolated after flash column chromatography (silica gel, 5% EtOAc in hexanes) in 100% yield.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:40][CH2:39][C:38](=[O:41])[NH:37][CH2:36][CH2:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:40][CH2:39][C:38](=[O:41])[NH:37][CH2:36][CH2:35]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: O=C1CCNCCN1
Product: O=C1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCN1

Procedure:
1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-[1,4]diazepan-5-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and [1,4]diazepan-5-one following General Procedure B.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.[ClH:31].[H][H]>CO.[PdH2]>[ClH:31].[C:27]([Si:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[O:13][C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](O[C@@H]1CCN(Cc2ccccc2)C1)(c1ccccc1)c1ccccc1
Agent: [PdH2]
Agent: Cl
Solvent: CO
Product: CC(C)(C)[Si](O[C@@H]1CCNC1)(c1ccccc1)c1ccccc1

Procedure:
(3R)-1-Benzyl-3-(tert-butyldiphenyl-silyloxy)pyrrolidine (1.18 g) was dissolved in methanol (12 ml), 1N hydrochloric acid (240 μl) and palladium hydride (221 mg) were added, and hydrogen was introduced to conduct catalytic reduction under normal pressure at room temperature for 4.5 hours. The catalyst was removed by filtration, and the filtrate was concentrated to solid under reduced pressure to obtain crude (3R)-3-(tert-butyldiphenyl-silyloxy)pyrrolidine hydrochloride (984 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH3:22][C:23]([O:26][C:27]([NH:29][C@H:30]([C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)[C:31](O)=[O:32])=[O:28])([CH3:25])[CH3:24].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[OH:40][C:37]1[CH:38]=[CH:39][C:34]([C@@H:30]([NH:29][C:27](=[O:28])[O:26][C:23]([CH3:24])([CH3:22])[CH3:25])[C:31](=[O:32])[NH:1][C:2]2[CH:3]=[C:4]3[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]4=[C:7]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:8][C:9]([CH:10]=2)=[C:5]34)=[CH:35][CH:36]=1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)c1ccc(O)cc1
Yield: 67.9 %

Procedure:
Preparation of example 153 from the title compound of Example 7 (hydrochloride) (42 mg, 0.134 mmol), (2R)-({[(1,1-dimethylethyl)oxy]carbonyl}amino)(4-hydroxyphenyl)ethanoic acid (54 mg, 0.202 mmol), triethylamine (0.056 mL, 0.402 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (77 mg, 0.202 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Additional (2R)-({[(1,1-dimethylethyl)oxy]carbonyl}amino)(4-hydroxyphenyl)ethanoic acid (27 mg, 0.10 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (39 mg, 0.10 mmol) were added after 24 hours to drive the reaction to completion. Silica gel chromatography (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the title compound (48 mg, 0.091 mmol) as a yellow powder in 68% yield.
Reaction SMILES: [N-]=[N+]=[N-].[Na+].[Cl-].[NH4+:6].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]23[NH:32][CH2:31][CH2:30][N:16]2[C:17](=[O:29])[C:18]2[N:19]([CH:21]=[C:22]([C:24]4[NH:28][N:27]=[N:26][N:25]=4)[CH:23]=2)[CH2:20]3)=[CH:11][CH:10]=1.CN([CH:36]=[O:37])C>>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]23[N:32]([C:9]([C:10]4[C:11]([CH3:12])=[N:6][O:37][CH:36]=4)=[O:8])[CH2:31][CH2:30][N:16]2[C:17](=[O:29])[C:18]2[N:19]([CH:21]=[C:22]([C:24]4[NH:28][N:27]=[N:26][N:25]=4)[CH:23]=2)[CH2:20]3)=[CH:11][CH:10]=1
Reactant: COc1ccc(C23Cn4cc(-c5nnn[nH]5)cc4C(=O)N2CCN3)cc1
Reactant: CN(C)C=O
Reactant: [NH4+]
Agent: [Cl-]
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: COc1ccc(C23Cn4cc(-c5nnn[nH]5)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Temperature: 120 °C
Yield: 13 %

Procedure:
Sodium azide (33 mg, 0.51 mmol) and ammonium chloride (27 mg, 0.51 mmol) was added to a solution of 10a-(4-methoxyphenyl)-7-(1H-tetrazol-5-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (150 mg, 0.43 mmol) in DMF and heated in a sealed tube at 120° C. for 16 hours. The reaction mixture was concentrated and purified by flash chromatography to give 10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-7-(1H-tetrazol-5-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (75) as a white solid (28 mg, yield 13%). Compounds 145 and 146 were similarly prepared using General Method A: Route (c) as follows.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([F:15])=[C:13](F)[C:12]([CH3:17])=[C:11]2[C:6]=1[C:7](=[O:25])[C:8]([C:22]([OH:24])=[O:23])=[CH:9][N:10]2[C@@H:18]1[CH2:20][C@@H:19]1[F:21])(=[O:3])[CH3:2].[C:26]([O:30][C:31]([NH:33][C:34]1([C@H:37]2[CH2:41][NH:40][CH2:39][C@H:38]2[F:42])[CH2:36][CH2:35]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].CN1CCCCC1>CS(C)=O>[C:1]([NH:4][C:5]1[C:14]([F:15])=[C:13]([N:40]2[CH2:41][C@H:37]([C:34]3([NH:33][C:31]([O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:32])[CH2:35][CH2:36]3)[C@H:38]([F:42])[CH2:39]2)[C:12]([CH3:17])=[C:11]2[C:6]=1[C:7](=[O:25])[C:8]([C:22]([OH:24])=[O:23])=[CH:9][N:10]2[C@@H:18]1[CH2:20][C@@H:19]1[F:21])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1([C@H]2CNC[C@H]2F)CC1
Reactant: CC(=O)Nc1c(F)c(F)c(C)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Solvent: CS(C)=O
Solvent: CN1CCCCC1
Product: CC(=O)Nc1c(F)c(N2C[C@@H](F)[C@@H](C3(NC(=O)OC(C)(C)C)CC3)C2)c(C)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Temperature: 80 °C
Reaction time: 7 h

Procedure:
A mixture consisting of 5-acetylamino-6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (54.4 mg, 0.154 mmol), (3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidine (54.5 mg, 0.223 mmol), 1-methylpiperidine (51.3 mg, 0.517 mmol) and dimethyl sulfoxide (0.25 ml) was stirred at an outer temperature of 80° C. for 7 hours. When analysis was carried out by a high performance liquid chromatography after completion of the reaction, formed ratio of the compound of interest 5-acetylamino-7-[(3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid was 49%. Also, residual ratio of the material was 34%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:23][OH:24])[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:26][CH2:27][O:28][Si](C(C)(C)C)(C)C>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:23][O:24][CH2:26][CH2:27][OH:28])[O:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)(C)OC(=O)N1CCO[C@](CO)(c2ccc(Cl)c(Cl)c2)CC1
Product: Cl
Product: OCCOC[C@@]1(c2ccc(Cl)c(Cl)c2)CCNCCO1

Procedure:
Using tert-butyl (7S)-7-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate and (2-bromoethoxy)(tert-butyl)dimethylsilane, and by a method similar to that of Example 363, step B and Example 39, step B, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3](S(O)(=O)=O)=[CH:4][CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](S(O)(=O)=O)[CH:14]=1.N[C:24]1C=CC=CC=1.C=O>>[CH:15]1[C:16]([CH2:24][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)=[CH:17][CH:18]=[C:13]([NH2:12])[CH:14]=1
Reactant: Nc1ccccc1S(=O)(=O)O
Reactant: Nc1ccccc1
Reactant: Nc1cccc(S(=O)(=O)O)c1
Agent: C=O
Product: Nc1ccc(Cc2ccc(N)cc2)cc1

Procedure:
An 2-anilinesulfonic acid derivative (e.g. sodium 2-anilinesulfonate) or an 3-anilinesulfonic acid derivative (e.g. sodium 3-anilinesulfonate) and aniline are treated with formalin under acidic conditions, to give the corresponding 4,4′-diaminodiphenylmethane derivative. This is diazotized using sodium nitrite under acidic conditions in the presence of hydrochloric acid, followed by reaction with sodium azide, to give the desired product.
Reaction SMILES: C1([OH:7])C=CC=CC=1.[CH:8]1([N:14]=[C:15]=[N:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.N1C2C(=CC=CC=2)C(CCCC(O)=O)=C1>O1CCCC1>[C:15]([NH:14][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)([NH:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:7]
Reactant: Oc1ccccc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)CCCc1c[nH]c2ccccc12
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C
Yield: 17 %

Procedure:
Phenol (0.46 g., 0.005 mole), dicyclohexylcarbodiimide (1.01 g, 0.005 mole) and indole-3-butyric acid (1.00 gm. 0.005 mole) were dissolved in minimal amounts of tetrahydrofuran in individual glass-stoppered Erlenmeyer flasks. Indole-3-butyric acid and dicyclohexylcarbodiimde solutions were mixed together and allowed to react for 15 minutes. The phenol solution was then added and the mixture allowed to react for 48 hours at room temperature. The mixture was then cooled in a refrigerator (0° C.). Dicyclohexylurea crystals which formed were filtered, washed with cold tetrahydrofuran, and the filtrate reduced in volume. Filtration, washing, and volume reduction were repeated four times.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[CH2:17]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)[CH3:18]>>[CH2:17]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:21][CH:20]=1)[CH3:18]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CCc1ccc(C=O)cc1
Product: CCc1ccc(C2NC(C(=O)OC)Cc3c2[nH]c2ccccc32)cc1

Procedure:
The same method but starting from racemic tryptophan methyl ester and 4-ethylbenzaldehyde gave the cis and trans isomer of the title compound.