Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:19]=[CH:18][C:17]4[N:16]([CH2:20][CH2:21][CH:22]([NH:27]C(=O)OC(C)(C)C)[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15][C@@H:14]5[CH2:35][O:36][CH2:37][CH2:38][N:13]5[C:12]=4[N:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1>C(Cl)Cl.FC(F)(F)C(O)=O>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:19]=[CH:18][C:17]4[N:16]([CH2:20][CH2:21][CH:22]([NH2:27])[C:23]([CH3:26])([CH3:24])[CH3:25])[CH2:15][C@@H:14]5[CH2:35][O:36][CH2:37][CH2:38][N:13]5[C:12]=4[N:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)NC(CCN1C[C@@H]2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc21)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(N)CCN1C[C@@H]2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc21

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 193 using tert-butyl (1-((R)-2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-4,4-dimethylpentan-3-yl)carbamate (PREPARATION x78) in CH2Cl2 (0.5 mL) and trifluoroacetic acid (0.5 mL) (11.7 mg, 76%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (s, 9 H), 1.51-1.75 (m, 1 H), 1.91-2.08 (m, 1 H), 3.02-3.39 (m, 4 H), 3.53-3.65 (m, 6 H), 3.80-3.96 (m, 1 H), 3.97-4.16 (m, 2 H), 4.60-4.76 (m, 1 H), 6.96-7.12 (m, 1 H), 7.20-7.33 (m, 1 H), 7.47-7.88 (m, 4 H), 11.33-11.59 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C24H32N6O, 421.27 found 421.4.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[O:40]1[C:45]2[CH:46]=[CH:47][C:48]([C:50](Cl)=[O:51])=[CH:49][C:44]=2[O:43][CH2:42][CH2:41]1>>[O:40]1[C:45]2[CH:46]=[CH:47][C:48]([C:50]([O:1][CH:2]3[CH2:20][CH:19]4[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]5[C:16]([C:22]([NH:24][S:25]([CH:28]6[CH2:30][CH2:29]6)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]4=[O:21])[CH2:15]5)[CH2:3]3)=[O:51])=[CH:49][C:44]=2[O:43][CH2:42][CH2:41]1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: O=C(Cl)c1ccc2c(c1)OCCO2
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccc4c(c3)OCCO4)CN2C1=O
Yield: 39.1 %

Procedure:
Prepared by way of method II using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 2,3-dihydro-1,4-benzodioxine-6-carbonyl chloride (105 mg, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 50 mg (39%) of 18-(2,3-dihydro-1,4-benzodioxine-6-carbonyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 99.5% pure (HPLC), MS m/z 729 (M−H)−, HRMS: calcd. 748.3228 and found 748.3220 (M+NH4)+, mp 199-201° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]([C:19](=[O:24])C(F)(F)F)=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[OH2:29]>CN(C)C=O.COC(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]([C:19]([OH:24])=[O:29])=[C:10]2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CCn2c(c(C(=O)C(F)(F)F)c3ccccc32)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCn2c(c(C(=O)O)c3ccccc32)C1
Yield: 86.2 %

Procedure:
To a solution of 0.29 g (0.77 mmol) 10-(2,2,2-trifluoro-acetyl)-3,4-dihydro-1H-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester in 7 ml N,N-dimethylformamide were subsequently added 0.22 g (4.6 mmol) sodium hydride (50% in oil) and a solution of 0.070 ml (3.9 mmol) water in 1 ml N,N-dimethylformamide at room temperature. The reaction mixture was diluted with tert-butyl methyl ether after 2 h and extracted with 1 M sodium hydroxide solution (2×30 ml). The combined aqueous layers were acidified (pH 1-2) with 2 M hydrochloric acid at 0° C. and extracted with tert-butyl methyl ether (3×50 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the title compound (0.21 g, 86%) as a light brown solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][O:14][CH2:15][CH2:16][NH2:17]>>[Cl:8][C:6]1[CH:5]=[C:4]([NH:17][CH2:16][CH2:15][O:14][CH3:13])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:17][CH2:16][CH2:15][O:14][CH3:13])[CH:7]=1
Reactant: COCCN
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1Cl
Product: COCCNc1cc(Cl)cc(NCCOC)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
0.2 mole (45.3 g) of 2,4,6-trichloronitrobenzene is added in portions to 180 ml of 2-methoxyethylamine heated to 80° C., with stirring. Heating is continued for 2 hours 30 minutes after the addition is complete. The reaction medium is diluted with 180 ml of ice-cold water. The product expected precipitates. It is drained, washed with water and dried under vacuum at 60° C. in the presence of phosphorous pentoxide. Recrystallized from 96° ethanol, it melts at 90° C.
Reaction SMILES: Cl.[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([CH:12]([OH:20])[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:8][CH2:7]2)OCC1.[OH-].[Na+]>O1CCCC1>[OH:20][CH:12]([CH:9]1[CH2:8][CH2:7][C:6](=[O:2])[CH2:11][CH2:10]1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC(Cc1ccccc1)C1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1CCC(C(O)Cc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
2 M hydrochloric acid (30 ml) was added to a solution of 1-(1,4-dioxaspiro[4.5]dec-8-yl)-2-phenylethanol (2.98 g, 11.3 mmol) in tetrahydrofuran (30 ml). The solution was stirred at 50° C. overnight. The mixture was rendered alkaline with 4 M sodium hydroxide solution, the phases were separated and the aqueous phase was extracted with methylene chloride (3×20 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:20]([NH2:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:20]([NH:26][C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: CCCCCCN
Product: CCCCCCNC1=C(c2ccccc2)S(=O)(=O)N(CCOC)C1=O

Procedure:
The title compound was prepared from 4-chloro-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide and hexane-1-amine in a similar manner as described for Example 1. 1H NMR (400 MHz, CD3CN): δ 7.48-7.56 (m, 5H), 5.83-5.99 (m, 1H), 3.83 (t, 2H), 3.67 (t, 2H), 3.35 (s, 3H), 2.84-2.90 (m, 2H), 1.13-1.32 (m, 4H), 0.92-1.09 (m, 4H), 0.82 (t, 3H); Mass Spectrum: M−H+ 365.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[C:21]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:6]1[CH3:32].[OH-].[Li+]>O1CCCC1>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:33])=[O:2])[C:6]([CH3:32])=[C:7]2[CH2:15][C:16]1[C:21]([S:22]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)(=[O:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: COC(=O)Cn1c(C)c(Cc2ncccc2S(=O)(=O)c2ccc(F)cc2)c2cc(F)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2ncccc2S(=O)(=O)c2ccc(F)cc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
A solution of {5-fluoro-3-[3-(4-fluorobenzenesulfonyl)pyridin-2-ylmethyl]-2-methylindol-1-yl}acetic acid methyl ester (0.18 g) in tetrahydrofuran (5.0 mL) was treated with 1.0 M aqueous lithium hydroxide solution (0.45 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, pH adjusted to 4 by the addition of 0.1 M aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined organic extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (1:19 to 49:1 by volume) to afford the title compound as a white solid (0.13 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=[CH:3]1.C(Cl)Cl.ClN1C(=[O:28])CCC1=O>C(OCC)C.C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][C:3]1=[O:28]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1ccc2cccc(C(=O)c3ccccc3)c21
Solvent: ClCCl
Solvent: CCOCC
Product: CN1C(=O)Cc2cccc(C(=O)c3ccccc3)c21
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6.17 g. (26.25 mmoles) of 1-methyl-7-benzoylindole in 62 ml. of methylene chloride was added 3.58 g. (26.25 mmoles) of 98% N-chlorosuccinimide and the mixture allowed to stir for 90 minutes. An additional 720 mg. of N-chlorosuccinimide was added and stirring continued for 2 hours. The reaction mixture was concentrated in vacuo and 52 ml. of acetic acid added. The mixture was heated to 80° C. and 27 ml. of 85% phosphoric acid was added. The temperature was raised to reflux for 90 minutes and the reaction was cooled and poured into 200 ml. of ice and water. The precipitate was filtered, dissolved in methylene chloride and the solution dried with magnesium sulfate. Removal of the solvent gave a residue which was dissolved in 5% diethyl ether-methylene chloride and filtered through silica gel. The fractions were collected, combined and concentrated to give 4.0 g. of the product as a viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:6]([NH:20][C:21]([NH2:23])=[S:22])=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1.C(N(CC)CC)C.Br[CH2:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]1)=O>CCO>[Br:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:6]([NH:20][C:21]2[S:22][CH:37]=[C:38]([CH:40]3[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:44][CH2:45]3)[N:23]=2)=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CBr)CC1
Reactant: COc1cccc(Sc2cnc(NC(N)=S)c(Oc3ccc(F)cc3Br)c2)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cccc(Sc2cnc(Nc3nc(C4CCN(C(=O)OC(C)(C)C)CC4)cs3)c(Oc3ccc(F)cc3Br)c2)c1
Temperature: 70 °C
Yield: 82 %

Procedure:
A 50 mL round-bottomed flask was charged with 1-(3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-yl)thiourea (1.5 g, 3.12 mmol), triethylamine (0.740 mL, 5.31 mmol), tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (1.15 g, 3.75 mmol), and EtOH (25 mL). The reaction was heated to 70° C. for 3 hours. The reaction was cooled to room temperature and partitioned between EtOAc and water. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (10% EtOAc in hexanes) to afford (1.76 g, 82.0% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][NH2:14].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][NH:14][C:23](=[O:24])[O:25][CH2:26][CH3:27]
Reactant: COc1ccc(CCN)c(Cl)c1OC
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCCc1ccc(OC)c(OC)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.5 %

Procedure:
To the solution of 2-(2-chloro-3,4-dimethoxyphenyl)ethanamine (2.8 g, 12.98 mmol) in dichloromethane (DCM) (40 mL) at 0° C. was added triethylamine (1.990 mL, 14.28 mmol) and ethyl chloroformate (1.371 mL, 14.28 mmol). The reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was washed with water, brine, dried over magnesium sulfate and chromatographed to give ethyl 2-chloro-3,4-dimethoxyphenethylcarbamate (1.7 g, 5.91 mmol, 97% yield). LCMS (M+H)+: 288.1
Reaction SMILES: COC(=O)[CH2:4][NH:5][CH2:6][C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([O:14]C(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:6]1[NH:5][CH2:4][C:12](=[O:14])[N:8]2[CH2:9][CH2:10][CH2:11][C@H:7]12
Reactant: COC(=O)CNC[C@H]1CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CNC[C@H]2CCCN12
Yield: 99 %

Procedure:
1,1-Dimethylethyl (2R)-2-({[2-(methyloxy)-2-oxoethyl]amino}methyl)-1-pyrrolidinecarboxylate (D3; 800 mg, 2.94 mmol) was dissolved in methylene chloride (10 ml) and treated with trifluoroacetic acid (2.5 ml) for 2 h. The reaction mixture was loaded as such on a SCX column and the non-basic compounds were washed away with methanol. The ninhydrine-positive fractions eluted with 1M methanolic ammonia were concentrated under vacuum at 40° C. for 30 min, isolating the title compound as a pale yellow oil: 410 mg, 2.92 mmol, 99% yield.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH:20]([C:22]3[CH:23]=[N:24][C:25]([S:28][CH3:29])=[N:26][CH:27]=3)O)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:22]3[CH:23]=[N:24][C:25]([S:28][CH3:29])=[N:26][CH:27]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSc1ncc(C(O)c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CSc1ncc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 64.1 %

Procedure:
To (1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-methylsulfanyl-pyrimidin-5-yl)-methanol (35, 4.70 g, 10.5 mmol) in 120.0 mL of acetonitrile, triethylsilane (22.0 mL, 138 mmol) and trifluoroacetic acid (11.0 mL, 143 mmol) are added. The reaction is stirred at 80° C. for 3 hours, then concentrated under vacuum, mixed with aqueous potassium carbonate and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and solvents removed under vacuum to provide the desired compound (36, 2.90 g).
Reaction SMILES: Cl.[O:2]1[CH2:6][CH2:5][NH:4][C:3]1=[NH:7].Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19])=O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:7]=[C:3]2[N:4]([CH:9]=1)[CH2:5][CH2:6][O:2]2
Reactant: N=C1NCCO1
Reactant: O=C(CBr)c1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cn3c(n2)OCC3)c(F)c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 26.7 %

Procedure:
The oxazolidin-2-imine hydrochloride (TCI, 5.00 g, 40.8 mmol) and 2-bromo-1-(2,4-difluorophenyl)ethanone (7.99 g, 34.0 mmol, Example #8, Step A) were dissolved in DMF (34.7 mL) then Na2CO3 (9.01 g, 85.0 mmol) was added. The mixture was stirred for about 15 min and then it was heated to about 80° C. for about 5 h. The mixture was cooled then filtered and the filtrate was concentrated under reduced pressure. The material was purified by flash chromatography on silica gel using DCM/EtOAc (gradient 1:0 to 0:1) to give the title compound (2.02 g, 26%): LC/MS (Table 1, Method g) Rt=1.94 min; MS m/z: 223.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([OH:21])=O)=[CH:11]2)[C:4]=1[CH3:22].CN1C(=O)CCC1.C(N(CC)CC)C.Cl.[F:38][C:39]([F:45])([F:44])[O:40][CH2:41][CH2:42][NH2:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO>[CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([NH:43][CH2:42][CH2:41][O:40][C:39]([F:45])([F:44])[F:38])=[O:21])=[CH:11]2)[C:4]=1[CH3:22]
Reactant: NCCOC(F)(F)F
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncccc32)c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COc1ncnc(Cn2cc(C(=O)NCCOC(F)(F)F)c3ncccc32)c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 28.2 %

Procedure:
See FIG. 21(c). 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (40 mg, 0.13 mmol) was taken in a 50 ml single necked flask equipped with an air condenser connected to nitrogen source. NMP (3 ml, 31.17 mmol) was added to get a solution. Triethyl amine (0.056 ml, 0.40 mmol) was added followed by the addition of 2-(trifluoromethoxy)ethanamine hydrochloride (44.4 mg, 0.27 mmol). The reaction mass was stirred at RT for 5 minutes. HATU (61.2 mg, 0.16 mmol) was added and stirred at RT for 30 min. After the completion of the reaction, few drops of methanol was added and clear solution was subjected for reverse phase HPLC purification to get 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-N-(2-(trifluoromethoxy)ethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (15.00 mg, 27.3%). ES+MS m/z: 410 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.25 (s, 3 H ) 3.68-3.80 (m, 2 H ) 3.93 (s, 3 H ) 4.24 (t, J=5.27 Hz, 2 H ) 5.69 (s, 2 H ) 7.26 (dd, J=8.29, 4.71 Hz, 1 H ) 7.94 (d, J=7.35 Hz, 1 H ) 8.28 (s, 1 H ) 8.38-8.54 (m, 2 H ) 8.96 (s, 1 H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:12][C:11]=1[F:31])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 84.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (50 mg, 0.0815 mmol) prepared in Example 42a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (32 mg, 85%) as a colorless solid.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.C(Cl)(Cl)Cl.C(O)(=O)C>[CH2:13]([N:15]([CH2:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[CH2:16][CH3:17])[CH3:14]
Reactant: CCNCC
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CCN(CC)Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
To a solution of methyl 4-formylbenzoate (300 mg) in 1,2-dichloroethane (6 mL) is added diethylamine (113 μL), and thereto is added sodium triacetoxyborohydride (581 mg) and acetic acid (261 μL) under ice-cooling. The mixture is stirred at room temperature for 18 hours. The reaction mixture is diluted with chloroform (5 mL) and thereto is added a saturated sodium hydrogencarbonate solution (10 mL). After stirring, the organic layer is separated and concentrated. The resultant crude product is purified by column chromatography on NH-silica gel (Solvent; n-hexane:ethyl acetate=70:30→40:60) to give methyl 4-(diethylaminomethyl)benzoate (144 mg, yield; 60%) as an oil. MS (APCI) m/z: 222 [M+H]+
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[C:5]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:6]([Br:12])[NH:7][C:8]=2[CH:9]=[CH:10][CH:11]=1.[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:12][C:6]1[N:7]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:8]2[C:4]([C:5]=1[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1)=[C:3]([S:2][CH3:1])[CH:11]=[CH:10][CH:9]=2
Reactant: CSc1cccc2[nH]c(Br)c(Cc3ccc(Cl)cc3)c12
Reactant: CCOC(=O)CCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1c(Br)c(Cc2ccc(Cl)cc2)c2c(SC)cccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
To a solution of the indole of Step 7 (800 mg, 2.4 mmol) in DMF (15 mL) was added NaH (136 mg, 3.4 mmol, 60% in oil) at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes and tetra-n-butylammonium iodide (300 mg) was added, followed by the addition of ethyl 4-bromobutyrate (663 mg, 3.3 mmol). The resulting mixture was stirred for 2 h at r.t., quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 20% EtOAc in Hexanes to provide 690 mg of the title compound as a brown oil.
Reaction SMILES: [CH:1]1[C:12]2=[C:13]3[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7][CH2:6][CH2:5][C:4]3=[CH:3][C:2]=1[NH2:14].I[C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:1]1[C:12]2=[C:13]3[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7][CH2:6][CH2:5][C:4]3=[CH:3][C:2]=1[NH:14][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1
Reactant: Nc1cc2c3c(c1)CCCC3CCC2
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(Nc2cc3c4c(c2)CCCC4CCC3)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
5,6,6a,7,8,9-Hexahydro-4H-2-phenalenylamine (0.250 g) and ethyl 4-iodobenzoate (0.360 g) were dissolved in anhydrous toluene (5 ml), the solution was added with tris(dibenzylideneacetone)dipalladium (0.024 g), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.036 g), and cesium carbonate (0.455 g), and the mixture was stirred overnight at 80° C. under an argon flow. The reaction mixture was left to cool, and then poured into ice water, and the mixture was extracted with diethyl ether. The organic layer was washed successively with 2 N aqueous hydrochloric acid, water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:50) to obtain the title compound (0.160 g, yield: 36%). The compound was recrystallized from chloroform-n-hexane to obtain colorless needles (melting point: 154-155° C.).