Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:14][C:13](=[O:15])[O:12][CH:11]([CH:16]([CH3:18])[CH3:17])[C:10]=2[CH:19]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([SH:30])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[CH:16]([CH:11]1[C:10]2[CH:19]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][S:30][C:24]3[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=3)[CH:7]=[CH:8][C:9]=2[NH:14][C:13](=[O:15])[O:12]1)([CH3:18])[CH3:17]
Reactant: COc1ccc(S)cc1OC
Reactant: CC(C)C1OC(=O)Nc2ccc(OCCCCl)cc21
Product: COc1ccc(SCCCOc2ccc3c(c2)C(C(C)C)OC(=O)N3)cc1OC

Procedure:
Prepared analogously to Example 1 from 6-(3-chloropropoxy)-4-isopropyl-4H-3,1-benzoxazin-2-one and 3,4-dimethoxy-thiophenol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH2:11][C:12]([CH2:15]O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH2:11][C:12]([CH2:15][Cl:20])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1CC(CO)=NC=C1OCc1ccccc1
Solvent: c1ccccc1
Product: O=C1CC(CCl)=NC=C1OCc1ccccc1
Temperature: 25 °C

Procedure:
To a suspension of 5-benzyloxy-2-hydroxymethyl-4-pyridone (33 g) in benzene (500 ml) was added thionyl chloride (28.4 ml) at ambient temperature under stirring. After being stirred at the same temperature for 30 minutes, the mixture was refluxed for 4 hours. The resulting mixture was cooled to ambient temperature. The precipitate was collected by filtration, washed with benzene and dried under reduced pressure to give 5-benzyloxy-2-chloromethyl-4-pyridone (41.5 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.S(=O)(=O)(O)[OH:12].[OH-].[K+].Cl>O>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:12])[CH:9]=2)[NH:4][N:3]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1n[nH]c2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1n[nH]c2ccc(O)cc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
A mixture consisting of 5 g of 3-aminoindazole and 4.3 g of 95% sulfuric acid was stirred for 3 hours at 80° C. To the mixture was added 13 ml of water, and the pH of the mixture was adjusted to 14 with potassium hydroxide. The mixture was washed twice with 20 ml of chloroform, and water was removed under reduced pressure. The residue thus obtained was added with 12.5 g of potassium hydroxide and 0.6 ml of water, and the mixture was stirred for 8 hours at 250° C. After cooling, to the mixture was added hydrochloric acid to separate crystals. The crystals were obtained by filtration and dried to give 2.86 g of 3-amino-5-hydroxyindazole having the following analytical values.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5](=[O:10])([O:8][CH3:9])OC>>[CH3:9][O:8][C:5]([NH:3][CH2:2][CH2:1][NH:4][C:5]([O:8][CH3:9])=[O:10])=[O:10]
Reactant: COC(=O)OC
Reactant: NCCN
Product: COC(=O)NCCNC(=O)OC
Reaction time: 24 h

Procedure:
Ethylene diamine (6 g) and dimethyl carbonate (18 g) were mixed together in a round bottom flask at 20° C. TBD (0.1 g) was added and the mixture allowed to stand for 24 h. After this time a white solid product was collected and recrystallised from methanol to give bis (methoxycarbonyl) ethylene diamine. NMR and IR spectra were consistent with the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=1>CN(C1C=CN=CC=1)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:20])=[O:21])=[C:15]([F:23])[CH:14]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1F
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1ccc(Cl)cc1F
Yield: 81.8 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.69 mmol), 4-chloro-2-fluorobenzenesulfonyl chloride (200 mg, 0.83 mmol) and DMAP (cat.) gave the title compound (190 mg, 82%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:61])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:24]([O:55][CH3:56])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:53][CH3:54])[C@@H:34]([CH3:52])[C:35]([NH:37][C@@H:38]([CH2:42][C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][CH:44]=1)[C:39]([NH2:41])=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[O:95]=[C:96]1[CH:100]=[CH:99][C:98](=[O:101])[N:97]1[CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][C:107]([NH:109][NH2:110])=[O:108]>CN(C=O)C>[O:101]=[C:98]1[CH:99]=[CH:100][C:96](=[O:95])[N:97]1[CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][C:107]([NH:109][NH:110][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:61])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:24]([O:55][CH3:56])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:53][CH3:54])[C@@H:34]([CH3:52])[C:35]([NH:37][C@@H:38]([CH2:42][C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][CH:44]=1)[C:39]([NH2:41])=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:108]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(N)=O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(N)=O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
15 mg (18 μmol) of (N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were dissolved in 3.8 ml of DMF and then admixed with 27 mg (70 μmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 12 μl of N,N-diisopropylethylamine and with 14 mg (53 μmol) of commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide. The reaction mixture was stirred at RT for 1 h. This was followed by concentration under high vacuum and purification of the remaining residue by means of preparative HPLC. Thus, 6.2 mg (33% of theory) of the title compound were obtained as a colourless foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([C:8]2[NH:9][C:10]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[N:16]=3)=[CH:11][C:12]=2[C:13]#[N:14])[CH:7]=1.O.S(=O)(=O)(O)[OH:26].N>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([C:8]2[NH:9][C:10]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[N:16]=3)=[CH:11][C:12]=2[C:13]([NH2:14])=[O:26])[CH:7]=1
Reactant: CNc1nccc(-c2cc(C#N)c(-c3cc(Cl)ccc3C)[nH]2)n1
Reactant: O=S(=O)(O)O
Agent: N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CNc1nccc(-c2cc(C(N)=O)c(-c3cc(Cl)ccc3C)[nH]2)n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 2-(5-chloro-2-methyl-phenyl)-5-(2-methylamino-pyrimidin-4-yl)-1H-pyrrole-3-carbonitrile (1.15 g, 3.55 mmol) in TFA (15.0 mL) were sequentially added water (2.25 mL) and 98% sulfuric acid (4.5 mL) under efficient stirring. The mixture was allowed to stir for 8 h at 70° C. and then was diluted by drop wise addition of water (45 mL). The reaction mixture was made basic (pH 10-12) by adding 30% aqueous ammonia (15 mL) under stirring. The precipitated solid was collected by filtration, washed with water and finally dried in a vacuum oven at 50° C. affording the title compound as an off-white solid (1.07 g, 88%).
Reaction SMILES: Cl.[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[C:16](=[O:19])([O-])O.[Na+]>>[CH2:2]([N:3]([CH2:4][CH2:16][OH:19])[S:12]([C:7]1[C:6]2[CH:5]=[CH:4][N:3]=[CH:2][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:14])=[O:13])[CH2:11][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=C([O-])O
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Agent: Cl
Agent: [Na+]
Product: CCCCCCN(CCO)S(=O)(=O)c1cccc2cnccc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In 100 ml of ice water was dissolved 10.56 g of 5-isoquinolinesulfonyl chloride hydrochloride, and the pH of the solution was adjusted to 6 with a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with 100 ml of dichloromethane. The dichloromethane layer was added dropwise to a 100 ml of dichloromethane solution containing 8.7 g of N-hexylethanolamine and 6.1 g of triethylamine over 20 minutes while cooling with ice. The mixture was stirred at a temperature of 15° C. to 20° C. for 3 hours, washed with water, and dried with anhydrous magnesium sulfate. Then, thedichloromethane was removed under reduced pressure to obtain an oily residue. The thus obtained oily residue was subjected to purification by silica gel column chromatography (Wacogel C-200, 200 g; solvent: a 5% methanol solution in chloroform) to obtain 5.24 g of N-hexyl-N-(2-hydroxyethyl)-5-isoquinolinesulfonamide.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[NH:6]1[CH2:11][CH2:10][CH:9]([O:12][C@@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]2)[CH2:8][CH2:7]1.CN1CCOCC1>C(#N)C>[C:1]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C@@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]2)[CH2:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COC(=O)[C@H]1C[C@H](OC2CCNCC2)CC[C@@H]1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COC(=O)[C@H]1C[C@H](OC2CCN(C(C)=O)CC2)CC[C@@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of acetyl chloride (24 uL, 0.00033 mol) in 0.5 ml of ACN was added to a solution of 1-tert-butyl 2-methyl (1S,2S,4R)-4-(piperidin-4-yloxy)cyclohexane-1,2-dicarboxylate hydrochloride made above (50 mg, 0.0001 mol) and 4-methylmorpholine (44 uL, 0.00040 mol) in acetonitrile (1.5 mL, 0.029 mol) at 22 Celsius. It was stirred at rt for 30 min, then quenched with Water, extracted with EA, and concentrated to give 1-tert-butyl 2-methyl (1S,2S,4R)-4-[(1-acetylpiperidin-4-yl)oxy]cyclohexane-1,2-dicarboxylate. 2 ml of TFA was added in 1-tert-butyl 2-methyl (1S,2S,4R)-4-[(1-acetylpiperidin-4-yl)oxy]cyclohexane-1,2-dicarboxylate (0.1 mmol, 0.0001 mol) in dichloromethane (2 ml). It was stirred at rt overnight and concentrated to give the corresponding TFA salt for next step. Benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (49 mg, 0.00011 mol) was added to a solution of (1S,2S,4R)-4-[(1-acetylpiperidin-4-yl)oxy]-2-(methoxycarbonyl)cyclohexanecarboxylic acid made above (0.1 mmol, 0.0001 mol) and 1-phenylpiperazine (17 uL, 0.00011 mol) in N,N-dimethylformamide (0.5 mL, 0.006 mol) at rt. After 5 min, N,N-diisopropylethylamine (52 uL, 0.00030 mol) was added at 0 Celsius. It was stirred at rt overnight. The reaction was chromatographed by combiflash (ethyl acetate in hexanes: 100%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([F:13])[C:10]([Br:14])=[CH:9][C:8]=1[F:15].[CH2:16]([O:18]CC)C>O>[Br:14][C:10]1[C:11]([F:13])=[CH:12][C:7]([CH:16]=[O:18])=[C:8]([F:15])[CH:9]=1
Reactant: Fc1cc(Br)c(F)cc1Br
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: O
Product: O=Cc1cc(F)c(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (1.95M in hexanes, 10.2 ml)) was added dropwise to a stirred solution of 1,4-dibromo-2,5-difluorobenzene (5 g, 18.4 mmol) in diethyl ether (60 ml) at −70° C. After 1 h, the solution was warmed to 0° C. over 1 h, diluted with water, the layers separated and the ether layer dried over sodium sulphate and evaporated. Purification by column chromatography (Biotage), eluting with 5% ethyl acetate/hexane, gave a yellow oil (1.82 g).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:19][C:20]([CH3:25])([CH3:24])[C:21](Cl)=[O:22]>ClCCl>[C:21]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)(=[O:22])[C:20]([CH3:25])([CH3:24])[CH3:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C(=O)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
Ethyl isonipecotate (20 mL, 130 mmol) was dissolved in 130 mL of dichloromethane and cooled to 0° C. and triethyl amine (19.9 mL, 143 mmol) was added. Trimethylacetyl chloride (16.8 mL, 136 mmol) was added dropwise and the reaction was allowed to warm to rt and stirred for 16 h. The reaction mixture was washed with hydrochloric acid solution (1.0 M, aq), sodium bicarbonate (sat., aq.) and sodium chloride (sat., aq.). The organic layer dried over magnesium sulfate, filtered and the solvent removed to provide 29.5 g (94%) of 20a as a pale orange liquid. LC-MS m/z, 242 [M+H]+.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[OH:8][C:9]1[C:19]([CH:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][C@H:30]3[CH2:34][CH2:33][CH2:32][O:31]3)[C:21]2=[O:35])=[CH:18][C:12]2[N:13]([CH3:17])[CH2:14][CH2:15][O:16][C:11]=2[CH:10]=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH3:17][N:13]1[C:12]2[CH:18]=[C:19]3[C:20]4([C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]([CH2:29][C@H:30]5[CH2:34][CH2:33][CH2:32][O:31]5)[C:21]4=[O:35])[CH2:2][O:8][C:9]3=[CH:10][C:11]=2[O:16][CH2:15][CH2:14]1
Reactant: CN1CCOc2cc(O)c(C3C(=O)N(C[C@H]4CCCO4)c4ccccc43)cc21
Reactant: O=C(O)C(F)(F)F
Agent: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: CN1CCOc2cc3c(cc21)C1(CO3)C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-one trifluoroacetate to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one was obtained (72%) as a colorless solid. Following the procedure described in EXAMPLE 2.28 and making non-critical variations using 1-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydro-1H-spiro[furo-[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one to replace 1-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one, 1-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydro-1H-spiro[furo-[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one hydrochloride was obtained (83%) as a colorless solid: mp>135° C. (dec.) (hexanes); 1H NMR (300 MHz, DMSO-d6) (diastereomers) δ7.83 (br s, 1H), 7.36-7.29 (m, 1H), 7.22 (d, J=8.1 Hz, 1H), 7.15 (d, J=7.5 Hz, 1H), 7.07-7.00 (m, 1H), 6.51 (br s, 1H), 6.44, 6.40 (br s, 1H), 4.82-4.59 (m, 2H), 4.38-4.26 (m, 2H), 4.25-4.14 (m, 1H), 3.87-3.69 (m, 3H), 3.66-3.59 (m, 1H), 3.36-3.24 (m, 2H), 2.78, 2.75 (br s, 3H), 2.02-1.72 (m, 3H), 1.68-1.55 (m, 1H); 13C NMR (75 MHz, DMSO-d6) (diastereomers) δ 176.8, 158.2, 157.8, 148.3, 143.1, 142.9, 131.5, 131.2, 128.9, 128.8, 123.6, 123.5, 122.9, 122.3, 114.0, 113.3, 109.9, 109.8, 98.9, 79.9, 79.8, 75.7, 75.6, 67.3, 62.3, 57.0, 48.9, 43.9, 43.7, 42.3, 42.1, 28.7, 28.5, 25.2, 25.1; MS (ES+) m/z 393.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10].[Br:14]Br.O>C(Cl)(Cl)Cl.C(OCC)C>[Br:14][CH2:10][C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:12])([F:13])[F:1])=[O:11]
Reactant: CC(=O)c1ccccc1C(F)(F)F
Reactant: BrBr
Solvent: O
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2′-(Trifluoromethyl)acetophenone (10.0 g) was dissolved in chloroform (30 mL) and diethyl ether (30 mL), a solution of bromine (8.50 g) in chloroform (20 mL) was added dropwise while maintaining the reaction temperature at not higher than 25° C. After the dropwise addition, the mixture was stirred at room temperature for 1 hr, water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, concentration under reduced pressure to give crude 2-bromo-1-(2-trifluoromethylphenyl)ethanone. Potassium carbonate (13.82 g) was added to ethyl cyanoacetate (44.44 g), and the mixture was stirred at 45° C. for 1 hr. A solution of crude 2-bromo-1-(2-trifluoromethylphenyl)ethanone in acetone (100 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hr, and stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→7:1) to give the title compound as an oil (yield 10.43 g, from 2′-(trifluoromethyl)acetophenone, yield 66%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32]O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.CC(C)(O)[C:36]#[N:37].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][C:36]#[N:37])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)(O)C#N
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(CO)cn3)[nH]2)cc1)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CCc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 22.8 %

Procedure:
To a solution of [6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]methanol (0.500 g) in tetrahydrofuran (10 mL) were added acetone cyanohydrin (202 mg), tributylphosphine (466 mg) and 1,1′-(azodicarbonyl)dipiperidine (540 mg), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was suspended in ethyl acetate and filtered to remove the precipitate, and the filtrate, and the suspension was concentrated under reduced pressure. The residue was successively purified by silica gel column chromatography (ethyl acetate:hexane=20:80-100:0, volume ratio) and basic silica gel column chromatography (ethyl acetate:hexane=20:80-100:0, volume ratio), and recrystallized from hexane-ethyl acetate to give the title compound (0.116 g, yield 23%) as colorless crystals. MS: 476 (MH+). melting point 139-141° C.
Reaction SMILES: [Al].[CH2:2](Br)[C:3]#[CH:4].[O:6]1[CH2:11][CH2:10][CH2:9][O:8][CH:7]1[C:12]1[CH:13]=[C:14]([C:18]([CH3:27])([CH3:26])[CH2:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH:15]=[CH:16][CH:17]=1>C1COCC1.C(OCC)C>[O:6]1[CH2:11][CH2:10][CH2:9][O:8][CH:7]1[C:12]1[CH:13]=[C:14]([C:18]([CH3:27])([CH3:26])[CH2:19][C:20]([C:21]([F:23])([F:24])[F:22])([OH:25])[CH2:4][C:3]#[CH:2])[CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cccc(C2OCCCO2)c1
Reactant: C#CCBr
Agent: [Al]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CCC(O)(CC(C)(C)c1cccc(C2OCCCO2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
Aluminum amalgam was prepared from aluminum foil (1.16 g, 14.4 mmol) and mercuric chloride (12 mg, catalytic amount) in 20 mL of anhydrous THF by vigorously stirring the mixture at room temperature for 1 hour under an argon atmosphere. A solution of propargyl bromide (4.80 mL, 80 wt. % in toluene, 43.1 mmol) in 25 mL of anhydrous THF was slowly added to a stirred suspension maintaining a temperature of 30° C.-40° C., and after addition, stirring at 40° C. was continued until a dark gray solution was obtained (ca. 1 hour). The propargyl aluminum sesquibromide solution was added to a solution of 4-(3-[1,3]dioxan-2-ylphenyl)-1,1,1-trifluoro-4-methylpentan-2-one (5.6 g, 14.2 mmol) in 100 mL of anhydrous diethyl ether at −78° C. The reaction mixture was stirred at this temperature for 3 hours, and then was allowed to warm to room temperature, at which time it was stirred for 12 hours. The reaction mixture was then poured into 20 mL of ice-water and extracted with four 30 mL portions of diethyl ether. The combined extracts were washed with 20 mL of brine, dried over magnesium sulfate, and concentrated in vacuo. Chromatography on silica gel (100% hexanes to 40% ethyl acetate in hexanes, gradient) afforded 2.5 g of the title compound as an oil (50% yield).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.Cl.[NH+]1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(C)(C)C#N)c1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: CC(C)(C#N)c1cccc(O)c1
Temperature: 210 °C

Procedure:
A mixture of the title product of Example 106 Step 1 (520 mg, 2.97 mmoles) and pyridinium hydrochloride (2 g, 17.3 mmol) was stirred in an oil bath at 200-220 ° C. under a drying tube and so maintained for 3 h. After cooling, the mixture was partitioned between DCM and water, further extracted, and the combined organic extracts dried over Na2SO4, filtered, and evaporated to give the title compound, 416 mg, as a brownish oil.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([N:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)N=C2CCC(=O)CC2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(=O)C>[CH:8]1[CH:9]=[CH:10][CH:11]=[C:6]2[NH:12][C:24]3[C:25](=[CH:26][C:21]4[NH:12][C:6]5[C:7]([C:22]=4[CH:23]=3)=[CH:8][CH:9]=[CH:10][CH:11]=5)[C:7]=12
Reactant: O=C1CCC(=NN(c2ccccc2)c2ccccc2)CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: c1ccc2c(c1)[nH]c1cc3c(cc12)[nH]c1ccccc13
Temperature: 10 °C
Reaction time: 18 h
Yield: 71.1 %

Procedure:
In a 1.5 liter flask equipped with a mechanical stirrer and a condenser were added glacial acetic acid (100 milliliters) and concentrated sulfuric acid (20 milliliters). Into this mixture, which was maintained at 10° C. with an ice bath, was added powdered cyclohexane-1,4-dione bisphenylhydrazone (22.0 grams) in small portions with stirring. After the aforementioned addition, the ice bath was removed and the mixture was allowed to warm to 23° C., and stirred for a further 10 minutes. Subsequently, the mixture was heated to about 65° C. (Centigrade throughout) until an exothermic reaction occurred. The reaction mixture was cooled with an ice bath, and within 5 minutes a light brown solid was formed. The reaction mixture was allowed to remain at room temperature, about 25° C., for about 18 hours, and filtered. The filtered cake was then washed with acetic acid, water, and then stirred in boiling methanol for 30 minutes before filtering and drying in vacuo for about 2 to 5 hours to provide 7.2 grams of pure 5,11-dihydroindolo[3,2-b]carbazole as pale yellow crystals.