Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:41])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:34])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C@@H:20]([OH:33])[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1.[CH3:42][C:43]1([CH3:50])[CH2:47][C:46](=[O:48])[O:45][C:44]1=[O:49]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[O:41]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[CH:16]([C@:17]4([CH3:34])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C@@H:20]([O:33][C:44](=[O:49])[C:43]([CH3:50])([CH3:42])[CH2:47][C:46]([OH:48])=[O:45])[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)CC(=O)OC1=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC[C@H](OC(=O)C(C)(C)CC(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 150 °C

Procedure:
A mixture of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-ol (100 mg, 0.170 mmol), 3,3-dimethyldihydrofuran-2,5-dione (436 mg, 3.4 mmol) and DMAP (208 mg, 1.7 mmol) in pyridine (1 mL) was heated up at 150° C. for 37 h. The reaction mixture was filtered and purified by prep. HPLC to provide the title compounds 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,13aR,13bR)-3a-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-3,3-dimethyl-4-oxobutanoic acid, example 1, as a white solid (17 mg, 13%). LCMS: m/e 717.51 (M+H)+, 2.39 min (method 1). 1H NMR (500 MHz, Acetic) δ 4.83 (s, 1H), 4.75 (s, 1H), 4.51 (dd, J=10.8, 5.6 Hz, 1H), 3.41-3.11 (m, 11H), 3.10-2.99 (m, 1H), 2.82 (td, J=10.8, 5.5 Hz, 1H), 2.75-2.63 (m, 2H), 2.27-1.04 (m, 24H), 1.76 (s, 3H), 1.31 (s, 6H), 1.19 (s, 3H), 1.13 (s, 3H), 0.95 (s, 3H), 0.92 (s, 3H), 0.92 (s, 3H) and 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,13aR,13bR)-3a-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid, example 2, as a white solid (60 mg, 47%). LCMS: m/e 717.51 (M+H)+, 2.44 min (method 1). 1H NMR (500 MHz, Acetic) δ 4.82 (s, 1H), 4.72 (s, 1H), 4.57 (dd, J=10.2, 6.0 Hz, 1H), 3.44 (d, J=12.5 Hz, 1H), 3.35-3.20 (m, 6H), 3.19-3.09 (m, 3H), 3.05 (d, J=4.6 Hz, 2H), 2.97-2.85 (m, 1H), 2.81-2.58 (m, 2H), 2.32-2.13 (m, 2H), 1.79-1.05 (m, 22H), 1.75 (s, 3H), 1.33 (s, 3H), 1.31 (s, 3H), 1.23 (s, 3H), 1.11 (s, 3H), 0.96 (s, 3H), 0.90 (s, 3H), 0.89 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[N:31]1([CH2:37][CH2:38][OH:39])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:34]5[CH2:35][CH2:36][N:31]([CH2:37][CH2:38][OH:39])[CH2:32][CH2:33]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:29])[F:30])[CH:3]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: OCCN1CCNCC1
Product: O=C1N=C(N2CCN(CCO)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 2-piperazin-1-yl-ethanol following General Procedure C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[C:8]([O:19][CH3:20])[N:7]=[C:6]([C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:5]=1.[C:27]([C:31]1[S:35][C:34]([S:36](Cl)(=[O:38])=[O:37])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>O1CCCC1>[C:27]([C:31]1[S:35][C:34]([S:36]([NH:3][C:4]2[C:9]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[C:8]([O:19][CH3:20])[N:7]=[C:6]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[N:5]=2)(=[O:38])=[O:37])=[CH:33][CH:32]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1ccccc1Oc1c(N)nc(-c2ncccn2)nc1OC
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)s2)nc(-c2ncccn2)nc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
92 mg of NaH (65%) were added at room temperature to a solution of 162.5 mg of 4-amino-6-methoxy-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine in 10 ml of tetrahydrofuran, the solution was stirred at room temperature for 11/2 hours and subsequently 162.5 mg of 5-tert-butyl-thiophene-2-sulphonyl chloride were added at the same temperature. The mixture was stirred at room temperature for a further 2 hours, poured on to ice/water, extracted with ethyl acetate, the aqueous phase was acidified and extracted with methylene chloride. The combined, organic phases were dried over magnesium sulphate and concentrated on a rotary evaporator. The residue was chromatographed over silica gel with methylene chloride/methanol (20/1) as the eluent. 5-tert-Butyl-N-[6-methoxy-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-thiophene-2-sulphonamide was obtained as a yellow powder. MS: 463 (M-SO2).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[OH:43][C@H:44]1[C@H:49]([OH:50])[C@@H:48]([OH:51])[CH:47](O)[O:46][C@@H:45]1[C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54]>>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][C@@H:47]3[O:46][C@H:45]([C:53]([O:55][CH2:56][C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)=[O:54])[C@@H:44]([OH:43])[C@H:49]([OH:50])[C@H:48]3[OH:51])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: O=C(OCc1ccccc1)[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Product: COc1cc(C(=O)O[C@@H]2O[C@H](C(=O)OCc3ccccc3)[C@@H](O)[C@H](O)[C@H]2O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with (2S,3S,4S,5R)-benzyl 3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-carboxylate (prepared according to the procedure reported in Bowkett et al. Tetrahedron 2007, 63, 7596-7605) to give (2S,3S,4S,5R,6S)-benzyl 6-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: C1COCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1
Yield: 54.6 %

Procedure:
According to the general procedure B, 4-chloronitrobenzene (80 mg, 0.51 mmol) reacted with morpholine (53 mg, 0.60 mmol) using 1 mol % of Pd(dba)2, 2 mol % of Ph5FcP(t-Bu)2, and K3PO4 (256 mg, 1.21 mmol) in DME at 100° C. to give the title compound (58 mg, 56%) as a yellow solid: 1H-NMR (400 MHz, CDCl3): δ 8.11 (d, 2H, J=9.6 Hz), 6.82 (d, 2H, J=9.6 Hz), 3.85 (t, 4H, J=5.2 Hz), 3.37 (t, 4H, J=5.2 Hz). 13C{1H}-NMR (125 MHz, CDCl3): δ 154.91, 138.80, 125.76, 112.50, 66.26, 47.00. GC/MS(EI): m/z 208 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]3([CH3:17])[O:16][CH2:15][CH2:14][O:13]3)=[CH:8][C:7]=2[C:6]([N+:18]([O-])=O)=[CH:5][CH:4]=1>C(O)C.[Pd]>[NH2:18][C:6]1[C:7]2[CH:8]=[C:9]([C:12]3([CH3:17])[O:13][CH2:14][CH2:15][O:16]3)[O:10][C:11]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c2cc(C3(C)OCCO3)oc12
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)c2cc(C3(C)OCCO3)oc12
Reaction time: 4 h
Yield: 89 %

Procedure:
To a suspension of 10% Pd on activated carbon (200 mg) in ethanol (100 mL), under N2 protection, was added 7-methoxy-2-(2-methyl-(1,3-dioxolan-2-yl))-4-nitrobenzofuran (6.50 g, 23 mmol). The reaction mixture was degassed under vacuum three times. The reaction mixture was stirred vigorously while hydrogen gas was allowed to flow over the reaction mixture. After 4 h the reaction was complete by TLC (5:1 hex:EA). The reaction mixture was filtered through a pad of celite and the celite was rinsed with additional ethanol. The solvent was removed in-vacuo to obtain 5.1 g (88% yield) of the title compound as a yellow oil.
Reaction SMILES: COC(=O)[C@@H:4]([CH:24]([CH3:35])[C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH3:34])[CH:26]=1)[NH:5][C:6](=[O:23])[C@@H:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[NH:8][C:9](OC(C)(C)C)=[O:10]>FC(F)(F)C(O)=O>[CH3:34][N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]([C@H:24]([C@H:4]2[NH:5][C:6](=[O:23])[C@@H:7]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[NH:8][C:9]2=[O:10])[CH3:35])=[CH:26]1
Reactant: COC(=O)[C@H](NC(=O)[C@@H](Cc1ccccn1)NC(=O)OC(C)(C)C)C(C)c1cn(C)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](c1cn(C)c2ccccc12)[C@H]1NC(=O)[C@@H](Cc2ccccn2)NC1=O
Reaction time: 0.5 h

Procedure:
A mixture of Nα -[N-t-butoxycarbonyl-3-(2-pyridyl)-D-alanyl]-1,β-dimethyl-D-tryptophan methyl ester (10.54 g) and trifluoroacetic acid (80 ml) was stirred on an ice bath for 30 minutes. After removal of the solvent, resultant crude residue was dissolved in ethanol (150 ml) and saturated ammonia in ethanol (150 ml) was added to the solution and resultant mixture was stirred for 16 hours at ambient temperature. After evaporation of the solvent, chloroform (200 ml) was added to the mixture. The insoluble material was filtered off and again solvent was evaporated in vacuo to give an oil which was chromatographed on silica gel (250 g, chloroform-methanol 20:1 as eluent) to afford (3R,6R)-3-[(R)-1-(1-methylindol-3-yl)ethyl]-6-(2-pyridylmethyl)piperazine-2,5-dione. Crystallization from ethanol yielded 3.14 g of the crystals.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:33])[CH2:11][N:12]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:15])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:1][O:8][NH:9][C:10](=[O:33])[CH2:11][N:12]([S:22]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)(=[O:24])=[O:23])[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:15]
Reactant: COc1ccc(S(=O)(=O)N(CC(=O)NOCc2ccccc2)CC(=O)N2CCOCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CONC(=O)CN(CC(=O)N1CCOCC1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
To a solution of N-benzyloxy-[(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino]acetamide (0.33 grams, 0.69 mmol) in methanol (35 mL) was added 5% palladium on activated carbon (85 mg). The mixture was agitated under 2 atmospheres hydrogen in a Parr shaker for 1.5 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent was evaporated. The residue was chromatorgraphed on silica gel with 5% methanol in methylene chloride to afford N-methoxy-[(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino]acetamide as a white solid, 65 mg (24%); 1H NMR (CD3OD): δ7.82 (d, J=9.0 Hz, 2H), 7.08 (d, J=9.0 Hz, 2H), 4.24 (s, 2H), 3.88 (s, 3H), 3.84 (s, 2H), 3.68-3.64 (m, 4H), 3.58-3.50 (m, 4H); MS (thermospray): m/z 388 (M+1), 387 (M); HRMS calculated for C16H22N3O7S (M+H): 388.1178, Found 338.1180.
Reaction SMILES: C(Cl)(Cl)Cl.[CH:5]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:35][CH3:36])[CH:31]=3)[C:26]2=[O:37])[CH2:20][CH2:19]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[BH4-].[Na+]>CO>[CH:5]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:35][CH3:36])[CH:31]=3)[CH:26]2[OH:37])[CH2:20][CH2:19]1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc2c(c1)CCC(CN1CCN(C(c3ccccc3)c3ccccc3)CC1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2c(c1)CCC(CN1CCN(C(c3ccccc3)c3ccccc3)CC1)C2O

Procedure:
In a mixture of 50 ml. of chloroform and 100 ml. of methanol is dissolved 3.5 g. of 2-(4-benzhydryl-1-piperazinylmethyl)-6-methoxy-3,4-dihydro-1(2H)-naphthalenone. Following the addition of 3 g. of sodium borohydride, the solution is stirred at room temperature for 30 minutes. The reaction mixture is then diluted with 500 ml. of water and extracted with chloroform. The extract is dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby 3 g. of 2-(4-benzhydryl-1-piperazinylmethyl)-6-methoxy-1,2,3,4-tetrahydro-1-naphthalenol is obtained as oily residue. This residue is dissolved in a mixture of 20 ml. of 20 % ethanolic hydrochloric acid and 30 ml. of ethanol, and the solution is heated at 80°-90°C. for 30 minutes. The reaction mixture is cooled to obtain 2.7 g. of 3-(4-benzhydryl-1-piperazinylmethyl)-7-methoxy-1,2-dihydronaphthalene hydrochloride as colorless needles melting at 220°-235° C. (gradually decomposed).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:12][C:13]([OH:15])=O.C(Cl)(=O)C(Cl)=O.[CH3:22][N:23]([CH3:39])[CH:24]1[CH2:28][CH2:27][N:26]([C:29]2[S:30][C:31]3[CH:37]=[C:36]([NH2:38])[CH:35]=[CH:34][C:32]=3[N:33]=2)[CH2:25]1>>[CH3:22][N:23]([CH3:39])[CH:24]1[CH2:28][CH2:27][N:26]([C:29]2[S:30][C:31]3[CH:37]=[C:36]([NH:38][C:13](=[O:15])[CH:12]=[CH:11][C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=4)[CH:35]=[CH:34][C:32]=3[N:33]=2)[CH2:25]1
Reactant: O=C(O)C=Cc1ccc2ccccc2c1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Agent: O=C(Cl)C(=O)Cl
Product: CN(C)C1CCN(c2nc3ccc(NC(=O)C=Cc4ccc5ccccc5c4)cc3s2)C1
Yield: 95.7 %

Procedure:
Prepare according to Method C (Example 9), using 3-(2-naphthyl)acrylic acid (69 mg, 0.348 mmol), oxalyl chloride (150 μL, 1.72 mmol), and 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (60 mg, 0.229 mmol) to afford the title compound (97 mg, 96%). mass spectrum (m/e): 442.0 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.30 (d, 1H, J=1.3 Hz), 8.14 (s, 1H), 8.00-7.92 (m, 3H), 7.78 (dd, 1H, J=8.5, 1.6 Hz), 7.71 (d, 1H, J=15.6), 7.59-7.54 (m, 2H), 7.45-7.42 (m, 2H), 6.97 (d, 1H, J=15.4 Hz), 3.71 (t, 1H, J=8.1 Hz), 3.62 (t, 1H, J=7.9 Hz), 3.47 (m, 1H), 3.26 (m, 1H), 2.89 (m, 1H), 2.21-2.17 (m, 7H), 1.94-1.86 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.Cl.[Cl:12][C:13]1[C:17]([Cl:18])=[C:16]([CH3:19])[NH:15][C:14]=1[C:20]([NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:21]>CN(C=O)C.O>[Cl:12][C:13]1[C:17]([Cl:18])=[C:16]([CH3:19])[NH:15][C:14]=1[C:20]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([C:2]2[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=2)[CH2:25][CH2:24]1)=[O:21]
Reactant: COc1nc(Cl)nc(Cl)n1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(Cl)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1

Procedure:
A solution of 2,4-dichloro-6-methoxy-1,3,5-triazine (commercially available) (0.05 g, 0.32 mmol) in DMF (0.5 ml) was added to a solution of 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1, 0.1 g, 0.32 mmol) and TEA (0.06 g, 0.64 mmol) in DMF (1.5 ml). The resultant mixture was stirred for 1 h at room temperature, then was diluted with water and extracted with EtOAc. During the aqueous workup, some of the product precipitated and was collected by suction filtration. The organic extract was dried over magnesium sulphate, filtered and concentrated to give the desired product with small amount of impurities.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:24])[C@H:15]([CH2:16][S:17]2=[O:20])[C@:14]2([CH3:21])[C@H:9]([C:10]([CH3:23])([CH3:22])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[CH:4][C:3]=1[C:25]([OH:27])=O.[CH3:28][N:29](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN>C1COCC1.CN(C=O)C.CCOC(C)=O>[OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:24])[C@H:15]([CH2:16][S:17]2=[O:20])[C@:14]2([CH3:21])[C@H:9]([C:10]([CH3:23])([CH3:22])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[CH:4][C:3]=1[C:25]([NH:29][CH3:28])=[O:27]
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)c4cc(O)c(C(=O)O)cc4[C@]3(C)CC[C@@H]12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1cc2c(cc1O)S(=O)C[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.8 %

Procedure:
A mixture of (1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8-oxo-8λ4-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-4-carboxylic acid (71) (0.40 g, 1.1 mmol), HATU (0.49 g, 1.3 mmol), Hunig's base (0.24 mL, 1.4 mmol), methylamine (2 M in diethyl ether, 2.7 mL, 5.4 mmol) in anhydrous THF (10 mL) and DMF (2 mL) was placed in a sealed vessel. The reaction was stirred at room temperature for 18 h. The reaction was diluted with EtOAc and washed with water and brine. The organic layer was separated and concentrated to dryness. The crude product was purified by flash chromatography on silica gel (CH2Cl2/EtOAc, 7:3) to yield (1R,10R,11S,16S)-5-hydroxy-N,1,11,15,15-pentamethyl-8-oxo-8λ4-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-4-carboxamide (72) (0.07 g, 16% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCCCCCC>CC(O)COC>[CH3:10][C@@H:7]1[N:6]2[C:5]3[C:14]([C:13]([C:12]([C:17]([OH:19])=[O:18])=[CH:11]2)=[O:16])=[CH:15][C:2]([F:1])=[C:3]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)[C:4]=3[O:9][CH2:8]1
Reactant: CN1CCNCC1
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CCCCCCC
Solvent: COCC(C)O
Product: C[C@H]1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 90 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
3 g (10.67 mmole) of (S)-(−)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4]benzoxazine-6-carboxylic acid was put in suspension in 30 mL of PGME and 4.75 mL (43 mmole) of N-methyl piperazine. The reaction mixture was heated to reflux for 23 hours until completion of the reaction. During that time, the reaction mixture became soluble. The mixture was then cooled to 90° C. and n-Heptane (10 mL) was added at this temperature. The reaction mixture was then cooled to 0° C. and the precipitation occurred around 65° C. The reaction was left at 0° C. for 3 hours, filtrated under vacuum and dried overnight to obtain 2.98 g (77.3%) of levofloxacin.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21]Br)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH2:28]C>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH3:28])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(OCCCCBr)ccc21
Reactant: CCNCCOC
Product: COCCN(C)CCCCOc1ccc2c(c1)CCN2C(=O)OC(C)(C)C

Procedure:
In analogy to example 7.2, 5-(4-Bromo-butoxy)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester and methoxyethyl-ethylamine were converted to yield 5-{4-[(2-Methoxy-ethyl)-methyl-amino]-butoxy}-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as colorless oil, MS: 379 (MH+).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1.[BH4-].[Na+].CCN(C(C)C)C(C)C.O=S(Cl)[Cl:32]>CO.C1COCC1>[Cl:32][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:18])([F:17])[F:1])=[CH:10][CH:11]=1
Reactant: O=Cc1ccc(-c2ccccc2C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccccc1-c1ccc(CCl)cc1
Reaction time: 1 h
Yield: 147.8 %

Procedure:
To a solution of the product of Example 36, Step A (0.15 g, 0.6 mmol) in MeOH (3 m) NaBH4 (0.028 g; 0.74 mmol) was added in portion wise at room temperature. After 1 h of stirring the solvent was evaporated and the residue was diluted to 20 ml with EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue (0.25 g, 0.99 mmol) was dissolved in anhydrous THF (5 ml). To this DIPEA (0.19 ml, 1.1 mmol) was added at 0° C. under N2, with stirring, followed by SOCl2 (0.08 ml, 1.1 mmol). This was stirred overnight at room temperature. The solvent was distilled off and the crude product was diluted to 20 ml with EtOAc and washed with NaHCO3 solution. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was passed through silica gel bead and washed with fresh EtOAc (20 ml). The combined filtrates were evaporated to dryness to give the title compound (0.24 g, 89%) as colourless oil. 1H-NMR (CDCl3) 4.64 (s, 2H); 7.30 (d, 3H, J=8.12 Hz); 7.4-7.58 (m, 4H); 7.73 (d, 2H, J=7.84 Hz).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:21])=O)=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C[N:23](C)S(N)(=O)=O.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.CC(N(C)C)=O>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:23])=[O:21])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Reactant: CN(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: NC(=O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[[4-(methylsulfonyl)-1-piperazinyl]carbonyl] (430 mg, 0.79 mmol), N,N-dimethylsulfamide (390 mg, 3.13 mmol) and DMAP (380 mg, 3.13 mmol) in dimethylacetamide (6 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (450 mg, 2.34 mmol). The reaction solution was stirred at 50° C. for 3 h, concentrated, purified by preparative HPLC (CH3CN/H2O with NH4OAc buffer) to yield 7H-indolo[2,1-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-[[4-(methylsulfonyl)-1-piperazinyl]carbonyl] (135 mg, 0.22 mol, 28%) as a yellow powder. 1HNMR (500 MHz, DMSO-d6) δ 11.65 (s, 1H), 8.41 (br s, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.65 (dd, J=1.5, 8.5 Hz, 1H), 7.63-7.55 (m, 4H), 7.04 (s, 1H), 5.19 (br s, 1H), 4.34 (br s, 1H), 3.66-3.31 (m, 8H), 2.92 (s, 6H), 2.84 (s, 3H), 2.82-2.75 (m, 1H), 2.11-1.06 (m, 10H). LCMS: m/e 652(M−H)1, ret time 1.63 min, column A, 2 minute gradient.