Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]2[S:33][C:32]([C:34]3([O:38][CH2:39][O:40][CH3:41])[CH2:37][CH2:36][CH2:35]3)=[N:31][CH:30]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH:17]=O)[CH:15]=3)[N:8]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:53][NH:54][CH3:55].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([C:29]2[S:33][C:32]([C:34]3([O:38][CH2:39][O:40][CH3:41])[CH2:35][CH2:36][CH2:37]3)=[N:31][CH:30]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH2:17][N:54]([CH3:55])[CH3:53])[CH:15]=3)[N:8]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1
Reactant: CNC
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3cnn(CC=O)c3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3cnn(CCN(C)C)c3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-pyrazol-1-yl)acetaldehyde (14C) (300 mg, 0.490 mmol) in tetrahydrofuran (3.267 mL) was added sequentially acetic acid (0.056 mL, 0.980 mmol), sodium sulfate (139 mg, 0.980 mmol) and dimethylamine (0.368 mL, 0.735 mmol). The reaction was stirred for 0.5 hours at ambient temperature, and sodium triacetoxyborohydride (208 mg, 0.980 mmol) was added in a single portion. The reaction was stirred overnight and then quenched by the addition of saturated aqueous sodium bicarbonate and ethyl acetate. The layers were separated, and the aqueous layer was extracted with addition ethyl acetate (2×). The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. MS ESI(+) m/z 641.2 [M+H]+.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].Br[CH:6]([CH:14]([CH3:16])[CH3:15])[C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)C>[CH3:2][C:1]1[S:3][C:6]([CH:14]([CH3:16])[CH3:15])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:4]=1
Reactant: CC(N)=S
Reactant: CCOC(=O)C(=O)C(Br)C(C)C
Solvent: CCO
Product: CCOC(=O)c1nc(C)sc1C(C)C
Temperature: 80 °C
Yield: 62.4 %

Procedure:
To a solution of thioacetamide (158 mg) in ethanol (20 ml) was added ethyl 3-bromo-4-methyl-2-oxopentanoate (500 mg) in ethanol (0.5 ml). Molecular sieves (100 mg) were added and the mixture was heated at 80° C. for 18 h. The mixture was filtered, washing with ethanol (5 ml) and the solvent removed in vacuo. The residue triturated with DCM and the solid removed by filtration. The filtrate was concentrated to ˜5 ml and purified by column chromatography on silica gel (10 g silica), eluting with a gradient of 0-100% ethyl acetate in cyclohexane to give the title compound as a yellow oil (280 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[N:12]([CH3:15])[C:11](=[O:16])[C:10]([N:17]([CH2:25][CH2:26][CH2:27][OH:28])[CH2:18][CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[N:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].O[C:30]1[CH:31]=[C:32]([CH:42]=[CH:43][CH:44]=1)[O:33][C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:1]([N:8]1[C:13](=[O:14])[N:12]([CH3:15])[C:11](=[O:16])[C:10]([N:17]([CH2:18][CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH2:25][CH2:26][CH2:27][O:28][C:30]2[CH:31]=[C:32]([CH:42]=[CH:43][CH:44]=2)[O:33][C:34]([CH3:40])([CH3:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[N:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCn1nc(N(CCCO)CCCC(F)(F)F)c(=O)n(C)c1=O
Reactant: CCOC(=O)C(C)(C)Oc1cccc(O)c1
Product: CCCCCCCn1nc(N(CCCOc2cccc(OC(C)(C)C(=O)OCC)c2)CCCC(F)(F)F)c(=O)n(C)c1=O

Procedure:
Compound 51 (oil) is prepared from triazine 9m and from intermediate 10b according to synthesis method 3 using Mitsunobu coupling conditions such as those described for example 33.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][NH:9][C:8]=2[C:12]([NH:14][NH2:15])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.Cl[C:26]([O:28][CH3:29])=[O:27]>C(Cl)Cl.O>[C:1]1([C:7]2[CH:11]=[CH:10][NH:9][C:8]=2[C:12]([NH:14][NH:15][C:26]([O:28][CH3:29])=[O:27])=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)Cl
Reactant: NNC(=O)c1[nH]ccc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)NNC(=O)c1[nH]ccc1-c1ccccc1
Reaction time: 0.25 h
Yield: 81.2 %

Procedure:
To a stirred solution of 3-phenyl-1H-pyrrole-2-carbohydrazide (3.80 g, 19.0 mmol) in DCM (60 mL) was added DIPEA (9.89 mL, 56.7 mmol) followed by methyl chloroformate (2.19 mL, 28.3 mmol) at room temperature. The above mixture was stirred for 15 min and was diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using CombiFlash (REDISEP®, silica gel, 80 g, 50% EtOAc/hexanes) as an eluent to yield methyl 2-(3-phenyl-1H-pyrrole-2-carbonyl)hydrazinecarboxylate (4.00 g, 75.0%) as an off-white solid. LCMS method B-2: retention time 1.75 min, [M+1]=260.2. 1H NMR (400 MHz, DMSO-d6) δ ppm: 3.61 (s, 3H), 6.27 (d, J=2.8 Hz, 1H), 6.95 (d, J=2.8 Hz, 1H), 7.20-7.34 (m, 3H), 7.51-7.52 (m, 2H), 9.14 (br s, 2H), 11.51 (br s, 1H).
Reaction SMILES: [N:1](OCCC(C)C)=[O:2].[CH3:9][N:10]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[NH:11]1.C[O-].[Na+]>C(O)C>[CH3:9][N:10]1[C:14](=[O:15])[C:13](=[N:1][OH:2])[CH:12]([CH3:16])[NH:11]1
Reactant: Cc1cc(=O)n(C)[nH]1
Reactant: CC(C)CCON=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1NN(C)C(=O)C1=NO
Temperature: 0 °C
Reaction time: 24 h
Yield: 72.5 %

Procedure:
183 g (1.56 mol) of isopentyl nitrite are added dropwise to 175 g (1.56 mol) of 1,3-dimethyl-pyrazolin-5-one and 84.4 g (1.56 mol) of sodium methylate in 1 L of absolute ethanol, while stirring and cooling with ice so that the internal temperature does not rise above 25° C. to 30° C. When the addition has ended, stirring is continued at room temperature for 24 hours and the sodium salt of 1,3-dimethyl-4-hydroximino-pyrazolin-5-one which has precipitated is filtered off with suction. The crystalline product is dissolved in 1 L of water and the solution is acidified with glacial acetic acid. For complete precipitation, the mixture is cooled at 0° C. for several hours, and the product is then filtered off with suction. 162 g (74% of theory) of 1,3-dimethyl-4-hydroximino-pyrazolin-5-one of melting point 93° C. are obtained.
Reaction SMILES: [C:1]([N:4]([CH3:39])[C:5]1[N:10]=[CH:9][C:8]([N:11]([CH3:31])[C:12](=[O:30])[C:13]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)([CH3:15])[CH3:14])=[C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH:6]=1)(=[O:3])[CH3:2].F[C:41](F)(F)[C:42]1C=C(C(C)(C)C(N(C)C2C(C3C=CC=CC=3C)=CC(NC(C3CC3)=O)=NC=2)=O)C=C(C(F)(F)F)C=1>>[F:24][C:22]([F:25])([F:23])[C:20]1[CH:21]=[C:16]([C:13]([CH3:15])([CH3:14])[C:12]([N:11]([CH3:31])[C:8]2[C:7]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])=[CH:6][C:5]([N:4]([CH3:39])[C:1]([CH:2]3[CH2:42][CH2:41]3)=[O:3])=[N:10][CH:9]=2)=[O:30])[CH:17]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:19]=1
Reactant: CC(=O)N(C)c1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reactant: Cc1ccccc1-c1cc(NC(=O)C2CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cc1ccccc1-c1cc(N(C)C(=O)C2CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as a white foam in comparable yield according to the procedure described above for the preparation of N-[6-(acetyl-methyl-amino)-4-o-tolyl-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide using cyclopropanecarboxylic acid (5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-amide instead of N-(6-acetylamino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.CN(C)[CH:26]=[O:27]>CCCCCC.O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH:18]=1)[CH:26]=[O:27]
Reactant: Fc1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1cc(Cl)ccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To a solution of 1.6M butyllithium in hexane (32 ml) was added anhydrous tetrahydrofuran (100 ml), and then added dropwise 2,2,6,6-tetramethylpiperidine (8.4 ml) at −70° C. or less. To the mixture was added dropwise a solution of 1-chloro-4-fluorobenzene (6.5 g) in anhydrous tetrahydrofuran (20 ml), and the mixture was stirred at −70° C. or less for 2 hours. To the mixture was added dropwise a solution of dimethylformamide (6.5 g) in tetrahydrofuran (15 ml), and the mixture was allowed to stand to warm up to 0° C. The reaction solution was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give oil of 5-chloro-2-fluorobenzaldehyde (5.1 g).
Reaction SMILES: C[O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].C([O-])(O)=O.[Na+]>Br>[C:19]1([CH2:18][CH2:17][CH2:16][N:11]2[C@@H:12]3[C@@H:8]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([OH:2])[C:15]=4[CH2:14][CH2:13]3)[CH2:9][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCc1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCc1ccccc1
Temperature: 0 °C
Yield: 76.9 %

Procedure:
3.45 g (0.0107 mol) of rac-cis-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-(3-phenyl-propyl)-1H-benzo[e]indole were dissolved in 0.1211 of 48% aqueous HBr and boiled under reflux for 5 hours. The mixture was poured into an ice-cold aqueous solution of 42.8 g (1.07 mol) of NaOH. After the addition of solid NaHCO3 the mixture was extracted three times with CH2Cl2. The organic phase was washed with saturated aqueous NaHCO3 and NaCl solutions, dried with Na2SO4, filtered and concentrated. By chromatography over silica gel with cyclohexane/ethyl acetate 1:1 and crystallization in hexane/ethyl acetate there were obtained 2.53 g (77%) of rac-cis-2,3,3a,4,5,9b-hexahydro-3-(3-phenyl-propyl)-1H-benzo[e]indol-6-ol as whitish crystals with m.p. 98°-100°. The mother liquor was concentrated and the residue was chromatographed over silica gel with cyclohexane/ethyl acetate 1:1. There was obtained an additional 0.62 g of oily material (2.12 mmol, 19%); total yield: 96%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@@:8]23[O:16][CH2:15][CH2:14][C@@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:9]3)[CH:7]=1.[C:26]1(=O)[CH2:30][CH2:29][CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1.O>[CH:26]1([NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@@:8]34[O:16][CH2:15][CH2:14][C@@H:13]3[CH2:12][S:11][C:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[N:9]4)[CH:7]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(c3cc(N)ccc3F)OCC[C@@H]2CS1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1=N[C@]2(c3cc(NC4CCCC4)ccc3F)OCC[C@@H]2CS1
Yield: 42.5 %

Procedure:
A solution of tert-butyl ((4aS,7aS)-7a-(5-amino-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (Step D, Preparation 3, 32 mg, 0.087 mmol), cyclopentanone (23.38 μL, 0.261 mmol), sodium triacetoxyborohydride (55.4 mg, 0.261 mmol) and acetic acid (14.96 μL, 0.261 mmol) in THF (435 μL) was stirred at rt for 12 h, and LC/MS showed a very clean reaction. The crude reaction mixture was purified by reverse phase preparative HPLC on a Luna C18 column (10 μM, 30×100 mm) eluting with 0-100% B (A: 95% eater/5% MeCN/10 nM NH4OAc, B: 5% water/95% MeCN/10 mM NH4OAc) over 12 min to give tert-butyl ((4aS,7aS)-7a-(5-(cyclopentylamino)-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (16 mg, 0.037 mmol, 42.2% yield) as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ 6.90 (dd, J=11.1, 8.7 Hz, 1H), 6.74 (dd, J=6.4, 2.9 Hz, 1H), 6.51 (dt, J=8.7, 3.3 Hz, 1H), 4.22-4.14 (m, 1H), 4.04 (q, J=7.9 Hz, 1H), 3.74 (quin, J=6.1 Hz, 1H), 3.31 (dd, J=13.3, 3.1 Hz, 1H), 3.03 (br. s., 1H), 2.84 (dd, J=13.4, 4.3 Hz, 1H), 2.47-2.31 (m, 1H), 2.25-2.15 (m, 1H), 2.09-1.97 (m, 2H), 1.80-1.57 (m, 4H), 1.53-1.43 (m, 2H), and 1.50 (9H, s). MS (M+H)+: 436.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:4][N:3]=1.[CH3:17][NH:18][CH3:19]>>[CH3:17][N:18]([CH3:19])[C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:4][N:3]=1
Reactant: CNC
Reactant: CC1(C)OB(c2ccc(Cl)nc2)OC1(C)C
Product: CN(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
The title compound was prepared according to the procedures of intermediate 8 except using 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and dimethyl amine.
Reaction SMILES: [Br:1][CH2:2][C:3]1[NH:4][C:5](=[O:22])[C:6]2[C:7]([N:21]=1)=[C:8]([OH:20])[C:9]1[C:10](=[O:19])[NH:11][C:12]([CH2:17][Br:18])=[N:13][C:14]=1[C:15]=2[OH:16].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(O)CCC.C(O)(=O)C.O.[K+].[Br-]>CO>[Br:18][CH2:17][C:12]1[NH:11][C:10](=[O:19])[C:9]2[C:8](=[O:20])[C:7]3[N:21]=[C:3]([CH2:2][Br:1])[NH:4][C:5](=[O:22])[C:6]=3[C:15](=[O:16])[C:14]=2[N:13]=1
Reactant: O=c1[nH]c(CBr)nc2c(O)c3c(=O)[nH]c(CBr)nc3c(O)c12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: O=C1c2nc(CBr)[nH]c(=O)c2C(=O)c2nc(CBr)[nH]c(=O)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 105 mg (0.244 mmol) of 18 suspended in 15 mL of dry methanol, was added 61 mg (0.268 mmol) of dichlorodicyanobenzoquinone (DDQ) and the reaction left to stir at room temperature for 1 hour. The solids were filtered off, washed with methanol, and dried to afford pure 19: 95 mg (91%) yield; dec pt 274°-275° C.; TLC (n-butanol/acetic acid/water [5:2:3]), Rf =0.46; IR (KBr pellet) 3062, 3040, 2990, 2933, 1713, 1645, 1576, 1547, 1480, 1142 cm-1 ; 1H NMR (dimethyl-d6 sulfoxide) δ4.45 (4H, s, methylenes); mass spectrum (EI, solids probe), m/z 428, 430, and 432 (P+ for the 79Br, 79Br; 79Br, 81Br, 81Br, 81Br combinations, respectively, in an intensity ratio of 1:2:1). Anal. Calcd for C12H6Br2N4O4 ; C, 33.52; H, 1.41; N, 13.03. Found: C, 33.89; H, 1.31; N, 12.50.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([Br:15])[CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:7]1=[O:27])C.C(OC(=O)CN1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O)C>>[Br:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[C:8]1([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]1=3)[CH2:24][CH2:23][O:22]4)[C:7](=[O:27])[N:6]2[CH2:5][C:4]([OH:28])=[O:3]
Reactant: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2c(Br)cccc21
Agent: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Product: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2c(Br)cccc21

Procedure:
Following the procedure as described in EXAMPLE 2, and making non-critical variations using ethyl(4′-bromo-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetate to replace ethyl(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate, the title compound was obtained (98%) as a colorless solid: MS (ES−) m/z 415.2 (M−1).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1>>[OH:28][C:22]1([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=2)[CH2:27][CH2:26][CH2:25][N:24]([C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=2)=[O:7])[CH2:23]1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3cccc(C(F)(F)F)c3)C2)c1

Procedure:
The compound of Example 10 was prepared according to the general preparation protocol A from 3-trifluoromethylbenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([CH3:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[CH3:34][NH:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[CH3:34][NH:35][CH:36]1[CH2:39][N:38]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([CH3:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:37]1
Reactant: Cc1cc(F)c(N)nc1-n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(Cl)c21
Reactant: CNC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: CNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4C)c3c2Cl)C1
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 68.2 %

Procedure:
To 90 mg of N,N-dimethylformamide were added 25 mg of 1-(6-amino-5-fluoro-3-methylpyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 25 mg of 3-(methylamino)azetidine dihydrochloride, and 70 mg of N-methylpyrrolidine, and the mixture was stirred at 85° C. for 45 minutes. After adding 0.2 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 20 mg of the title compound as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].[C:11](Cl)(Cl)=[O:12].C1(C)C=CC=CC=1>C1COCC1>[CH:7]1[C:3]2[CH2:4][CH2:5][O:6][C:11](=[O:12])[NH:1][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1ccccc1CCO
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2CCO1
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To a solution of 2-aminophenethyl alcohol (4.0 g, 29.16 mmol) in THF (200 mL) was added a solution of 2M phosgene in toluene (17 mL, 34 mmol) at room temperature. The reaction was stirred for 15 minutes, concentrated, and purified with flash chromatography using ethyl acetate (5%→20%) in hexanes to yield 8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one (4 g, 84%): 1H NMR (300 MHz, CDCl3) δ 8.02 (bs, 1H), 7.17 (dt, 1H), 7.09 (d, 1H), 6.99 (dt, 1H), 6.90 (d, 1H), 4.51 (t, 2H), 3.21 (t, 2H).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:18]([CH:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)([CH3:21])([CH3:20])[CH3:19].[BH4-].[Na+]>C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:18]([C@H:22]1[CH2:23][CH2:24][C@H:25]([NH:28][CH:2]2[C:10]3[C:5](=[CH:6][C:7]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)[CH2:26][CH2:27]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CCCCOC(=O)c1ccc2c(c1)CCC2=O
Reactant: CC(C)(C)C1CCC(N)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: CCCCOC(=O)c1ccc2c(c1)CCC2N[C@H]1CC[C@H](C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of butyl 1-oxoindane-5-carboxylate (5.0 g, 21.5 mmol), titanium (IV) isopropoxide (7.04 mL, 23.7 mmol), 4-tert-butylcyclohexyl amine (6.68 g, 43.0 mmol) in absolute ethanol (60 mL) was stirred under nitrogen at room temperature for 18 h. Sodium borohydride (1.22 g, 32.2 mmol) was then added and the resulting mixture was stirred for an additional 24 h at room temperature. The reaction was quenched by pouring into aqueous ammonia (2N, 200 mL). The resulting inorganic precipitate was filtered off through Celite and washed with CH2Cl2 (300 mL). The organic layer was separated and the remaining aqueous layer was extracted once with CH2Cl2 (150 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. Chromatography (8% to 15% EtOAc in Hexane) afforded butyl 1-[(trans-4-tert-butylcyclohexyl)amino]indane-5-carboxylate and the corresponding cis product (less polar than the trans amine). HPLC/MS: m/z=372.3 (M+1), Rt=2.14 min. 1H NMR (CDCl3): δ 7.93 (1H, d, J=8.0 Hz), 7.92 (1H, s), 7.43 (1H, d, J=8.0 Hz), 4.41 (1H, t, J=6.5 Hz), 4.35 (2H, t, J=6.5 Hz), 3.05 (1H, ddd, J=4.0 Hz, 8.0 Hz, 16.0 Hz), 2.86 (1H, dt, J=8.0 Hz, 16.0 Hz), 2.65 (1H, m), 2.51 (1H, m), 2.10 (1H, m), 2.02 (1H, m), 1.88-1.76 (5H, m), 1.56-1.48 (2H, m), 1.22-1.01 (8H, m), 0.90 (9H, s).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[OH-].[Na+].[C:7]1(=[O:12])[CH2:11][CH2:10][CH2:9][CH2:8]1.C(O)(=O)C>O>[CH3:1][C:2](=[C:8]1[CH2:9][CH2:10][CH2:11][C:7]1=[O:12])[CH3:4]
Reactant: CC(C)=O
Reactant: O=C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)=C1CCCC1=O

Procedure:
A mixture of 190 ml of acetone and 36.0 g of sodium hydroxide in 600 ml of water was treated with 60.0 g of cyclopentanone under stirring. After stirring for about 12 hours at about room temperature, the mixture was neutralized with 36% acetic acid and extracted with three 60 ml portions of ether. The combined extracts were dried over anhydrous magnesium sulfate and evaporated to give a residue. The residue was distilled to obtain 62.6 g of 2-(1-methylethylidene) cyclopentanone as a colorless liquid. The boiling point of this intermediate compound was determined to be 85°-88° C. at a pressure of 10 mm Hg. A subsequent Mannich reaction yielded the 2-Dimethylaminomethyl-5-(1-methylethylidene) cyclopentanone hydrochloride. The melting point of the product was determined to be 173°-175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[CH2:13]([O:15][CH:16]([O:25][CH2:26][CH3:27])[C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:14].N1CCCCC1.C(OCC)(=O)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[C:18]([C:17]([CH:16]([O:15][CH2:13][CH3:14])[O:25][CH2:26][CH3:27])=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1cc([N+](=O)[O-])ccc1Cl)C(=O)C(OCC)OCC
Yield: 102 %

Procedure:
A mixture of 2-chloro-5-nitrobenzaldehyde (3.73 g), ethyl 4,4-diethoxyacetoacetate (4.365 g) and piperidine (272.5 mg) in benzene (10 ml) was refluxed under azeotropic dehydration for 1.5 hours. To the mixture was added ethyl acetate, and the resultant mixture was washed three times with water and then with an aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent was removed under reduced pressure to give a reddish brown oil (7.87 g) of ethyl 2-(2-chloro-5-nitrobenzylidene)-4,4-diethoxyacetoacetate. The mixture of thus obtained reddish brown oil and ethyl 3-aminocrotonate (3.48 g) was heated with stirring at 105° to 107° C. in an oil bath for 4.5 hours. The resultant mixture was extracted with ethyl acetate, and the extract was washed with water three times and then with an aqueous solution of sodium chloride, and dried over magnesium sulfate. After removal of the solvent from the extract, the obtained residue (10.87 g) was subjected to column chromatography on silica gel with an eluent (a mixture of 20 parts of chloroform and one part of ethyl acetate by volume). The fractions were checked with thin-layer chromatography and crystals (6.02 g) were obtained by removing the solvent from the fraction containing the designated substance. The crystals were recrystallized from a mixture of diethyl ether and n-hexane to give crystals and diethyl 2-methyl-4-(2-chloro-5-nitrophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 117° to 118° C.