Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:21]([C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1)=O>>[F:20][C:17]([F:18])([F:19])[C:14]1[N:12]2[N:13]=[C:8]([N:1]3[CH2:7][CH2:6][CH2:5][N:4]([CH2:21][C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)[CH2:3][CH2:2]3)[CH:9]=[CH:10][C:11]2=[N:16][N:15]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Product: N#Cc1ccc(CN2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-formylbenzonitrile was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1,4-diazepan-1-yl]methyl]benzonitrile.
Reaction SMILES: [CH2:1]([CH:8]([NH2:21])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH2:36][C:37](O)=[O:38])[CH:28]=[CH:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:23]>>[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH2:36][C:37]([NH:21][CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:38])[CH:28]=[CH:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:23]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: NC(Cc1ccccc1)c1ccccc1N1CCCCC1
Product: CCOC(=O)c1ccc(CC(=O)NC(Cc2ccccc2)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
Prepared analogously to Example 19 from α-benzyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Reaction SMILES: [NH2:1][CH:2]1[C:29](=[O:30])[N:4]2[C:5]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[O:18])=[C:6]([CH:9]=[CH:10][C:11]3[S:15][CH:14]=[N:13][C:12]=3[CH3:16])[CH2:7][S:8][C@H:3]12.[C:31]([NH:50][C:51]1[S:52][CH:53]=[C:54]([C:56](=[N:60][O:61][CH3:62])[C:57](O)=[O:58])[N:55]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][O:19][C:17]([C:5]2[N:4]3[C:29](=[O:30])[CH:2]([NH:1][C:57](=[O:58])[C:56](=[N:60][O:61][CH3:62])[C:54]4[N:55]=[C:51]([NH:50][C:31]([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)[S:52][CH:53]=4)[C@H:3]3[S:8][CH2:7][C:6]=2[CH:9]=[CH:10][C:11]2[S:15][CH:14]=[N:13][C:12]=2[CH3:16])=[O:18])=[CH:26][CH:25]=1
Reactant: COc1ccc(COC(=O)C2=C(C=Cc3scnc3C)CS[C@@H]3C(N)C(=O)N23)cc1
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(C=Cc3scnc3C)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 72 %

Procedure:
p-Methoxybenzyl 7-amino-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylate (trans-isomer) as prepared by the method of Reference Example 2 as above and 2-(tritylaminothiazol-4-yl)-2-methoxyiminoacetic acid (syn-isomer) were reacted with each other and the reaction product was processed in the same manner as in Example 1 to give the titled compound in a yield of 72%.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.[H-].[Na+]>CS(C)=O.O1CCCC1>[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31](/[CH:32]=[CH:6]/[CH2:5][C:2]([OH:4])=[O:3])=[CH:30][CH:29]=1
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1ccc(/C=C/CC(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
The mixture of (2-carboxyethyl)triphenylphosphonium bromide (20.0 g, 54.0 mmol) and 4-methoxybenzaldehyde (6.5 g, 53.5 mmol) in anhydrous DMSO (64 mL) was added slowly to the suspension of 60% NaH in mineral oil (4.3 g, 107 mmol) in anhydrous tetrahydrofuran (32 mL). The reaction mixture was stirred at 0° C. for 30 minutes then warmed to room temperature over 4 hours. The reaction mixture was quenched with 1N HCl (150 mL) and extracted with ethyl acetate. The organic phase was washed with water, brine, dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (50% EtOAc in hexanes) to provide (E)-4-(4-methoxyphenyl)but-3-enoic acid (557) (5.7 g, 55.0%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH:21]=[CH2:22]>C1COCC1>[C:20]([O:12][C:2]1([CH3:1])[CH:3]2[CH2:11][CH:7]3[CH2:6][CH:5]([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2)(=[O:23])[CH:21]=[CH2:22]
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OC1(C)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
2-methyl-2-adamantanol (33 g, 0.2 mol) and triethylamine (0.22 mol) were dissolved in 300 ml of THF and then acryloyl chloride (19 g, 0.21 mol) was added slowly thereto using a dropping funnel. Then, the reaction was stirred at room temperature for about 12 hours. After completion of the reaction, excess THF was removed using a rotary evaporator and then the resultant product was poured into water. Then, the resultant product was neutralized with dilute sulfuric acid and extracted using diethyl ether and was then dried over magnesium sulfate. The diethyl ether removed crude product was vacuum-distilled to yield the desired product (yield: 80%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21]CC)[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=3)=[CH:5][C:4]=2[N:3]=1.B(Br)(Br)Br.CO>ClCCl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][OH:21])[N:14]([CH2:15][C:16]([CH3:17])([OH:18])[CH3:19])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(-c4ccc(F)c(F)c4)cnc3c2n1CC(C)(C)O
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC(C)(O)Cn1c(CO)nc2c(N)nc3cc(-c4ccc(F)c(F)c4)cnc3c21
Temperature: 0 °C
Reaction time: 22.5 h
Yield: 36.4 %

Procedure:
A suspension of 1-[4-amino-7-(3,4-difluorophenyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (0.790 g, 1.85 mmol), obtained from the filtrate from the trituration in Example 59, in dichloromethane (20 mL) was cooled to 0° C. Boron tribromide (5.54 mL of a 1 M solution in dichloromethane) was added dropwise, and the reaction was stirred at room temperature for 22.5 hours. An analysis by LC/MS indicated the reaction was incomplete, and additional boron tribromide (2.7 mL) was added. The reaction was stirred for three hours at room temperature, and then methanol (25 mL) was carefully added. The resulting solution was stirred at room temperature for one hour and concentrated under reduced pressure. A solution of ammonia in methanol (30 mL of 2 M) was added, and the mixture was stirred for 30 minutes and then diluted with methanol (50 mL) and dichloromethane (50 mL). Silica gel was added, and the mixture was concentrated under reduced pressure. The residue was purified by chromatography according to the method described in Example 62. The resulting solid was triturated with acetonitrile, isolated by filtration, washed with acetonitrile, and dried in a vacuum oven to provide 269 mg of 1-[4-amino-7-(3,4-difluorophenyl)-2-(hydroxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol as a light yellow solid, mp 256-258° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([N:17]4[C:21]5=[N:22][CH:23]=[CH:24][CH:25]=[C:20]5[NH:19][C:18]4=[O:26])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[N:6][CH:7]=1.I[CH2:28][CH3:29].O>CN(C=O)C>[CH2:28]([N:19]1[C:20]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[N:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)[N:9]=[CH:10]3)[C:18]1=[O:26])[CH3:29]
Reactant: Cc1ccc(-n2ncc3cc(-n4c(=O)[nH]c5cccnc54)ccc32)nc1
Reactant: CCI
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)n(-c2ccc3c(cnn3-c3ccc(C)cn3)c2)c2ncccc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
A mixture of 3-[1-(5-methylpyridin-2-yl)-1H-indazol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (70 mg) and iodoethane (35.1 mg) in DMF (2 mL) was stirred at 50° C. for 3 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with AcOEt/Hexane. The product was crystallized from AcOEt/Hexane to give the title compound as white crystals (25.0 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[N:4][CH:3]=1.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][OH:20]>>[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][O:20][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:7]=1
Reactant: Clc1cncc(N2CCNCC2)n1
Reactant: OCc1ccco1
Product: c1coc(COc2cncc(N3CCNCC3)n2)c1
Temperature: 110 °C
Reaction time: 7.5 h
Yield: 74 %

Procedure:
K-t-BuO (1.55 g, 13.8 mmol) was added to a mixture of the product from step 2 above (1.40 g, 7.05 mmol) and 2-furanmethanol (5.3 g, 54 mmol). After being stirred for 7.5 h at 110° C., the mixture was applied onto a bed of silica (16×6 cm). Elution with CHCl3/MeOH (95:5 followed by 90:10) furnished 1.35 g (74%) of the title compound as an oil. HRMS m/z calcd for C13H16N4O2(M)+ 260.1273, found 260.1276. Anal. (C13H16N4O2) C, H, N.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH-].[Na+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[C:9]=1[OH:15].C(OCC)(=O)C>O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[C:9]=1[O:15][CH2:3][CH2:2][Br:1]
Reactant: Oc1c(Br)cccc1Br
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: BrCCOc1c(Br)cccc1Br
Yield: 55.9 %

Procedure:
1,2-Dibromoethane (5.0 ml, 58 mmol) was added to a solution of sodium hydroxide (2.5 g, 63 mmol) and 2,6-dibromophenol (14.5 g, 57.6 mmol) in 45 ml of water. The mixture was stirred under reflux for 20 hours and then extracted with ether. The combined organic layers was dried over Na2SO4, filtered and concentrated to give colorless oil. Silica gel chromatography, using a gradient of ethyl acetate, in hexanes to afforded 1,3-dibromo-2-(2-bromo-ethoxy)-benzene (11.55 g, 57% yield) as a colorless oil.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:17])[CH2:13][CH:14]1[CH2:16][CH2:15]1>>[CH3:10][O:11][C:12](=[O:17])[CH:13]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:14]1[CH2:16][CH2:15]1
Reactant: COC(=O)CC1CC1
Reactant: O=C(Cl)c1ccccc1
Product: COC(=O)C(C(=O)c1ccccc1)C1CC1
Yield: 28 %

Procedure:
Benzoyl chloride (1.0 ml) and 2-cyclopropylacetic acid methyl ester were subjected to reaction and post-treatment in a similar manner to that described in Reference example 8(a) to obtain the title compound (1.05 g, 28%) as a colorless liquid.
Reaction SMILES: [CH:1]1[NH:8][C:6](=[O:7])[NH:5][C:3](=[O:4])[C:2]=1[F:9].C(N(CC)CC)C.[C:17]([O:25][CH2:26]Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1>CC(N(C)C)=O>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([O:25][CH2:26][N:8]2[CH:1]=[C:2]([F:9])[C:3](=[O:4])[NH:5][C:6]2=[O:7])=[O:24])[CH:19]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: O=C(OCCl)c1cccnc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C(OCn1cc(F)c(=O)[nH]c1=O)c1cccnc1
Reaction time: 24 h

Procedure:
5-FU (1.31 g, 0.01 mol) was dissolved in 5 mL of dimethylacetamide and treated with triethylamine (2.78 mL, 0.02 mol). Chloromethyl nicotinate (2.95 g. 0.012 mol) in 5 mL of dimethylacetamide was added in one portion, and the mixture was stirred for 24 hours, filtered, washed with ethyl acetate and evaporated. The residue was chromatographed on a column of silica gel, using as eluent first benzene, then 3:1 benzene/chloroform, then 1:1 benzene/chloroform, then 3:1 chloroform/benzene, then chloroform and finally 99:1 chloroform/methanol. Unreacted nicotinate was eluted initially, followed by the 1,3-bis-isomer and finally the 1-isomer. The 1-isomer (1.3 g, 50%) melted at 190°-192° C. and had the formula ##STR158## as confirmed by NMR analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[Br:21][C:22]1[CH:23]=[CH:24][C:25]([O:32][CH3:33])=[C:26]([S:28](Cl)(=[O:30])=[O:29])[CH:27]=1>>[Br:21][C:22]1[CH:23]=[CH:24][C:25]([O:32][CH3:33])=[C:26]([S:28]([N:8]2[C:9]3[C:5](=[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])[C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)(=[O:29])=[O:30])[CH:27]=1
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1S(=O)(=O)n1ccc2c(CN(C)C)c(OC)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.4 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 5-bromo-2-methoxybenzenesulphonyl chloride (31 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (9 mg, 27%) as a white solid. MS (ESI+) for C19H21BrN2O4S m/z 454 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[NH:18][CH:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.Br[CH2:26][CH:27]1[CH2:30][CH2:29][CH2:28]1>>[CH:27]1([CH2:26][N:18]2[CH:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:8]4[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=4[CH3:12])[C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:24])[CH:14]=3)[C:19]2=[O:23])[CH2:30][CH2:29][CH2:28]1
Reactant: BrCC1CCC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)[nH]ccc2c1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CCC3)ccc2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 123 using the product of Example 11 and (bromomethyl)cyclobutane.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13](=[O:22])[C:14]([N+:19]([O-:21])=[O:20])=[CH:15]OCC.C(OC(=O)C)(=O)C>>[CH3:11][O:12][C:13](=[O:22])[C:14]([N+:19]([O-:21])=[O:20])=[CH:15][C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1
Reactant: CCOC=C(C(=O)OC)[N+](=O)[O-]
Reactant: Clc1ccc2cc[nH]c2c1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(=Cc1c[nH]c2cc(Cl)ccc12)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 45 h
Yield: 51 %

Procedure:
A 4-l. battery jar was charged charged with 641 g (4.23 moles) of 6-chloroindole, 926 g (5.3 moles) of crude (ca. 85% pure) alpha-nitro-beta-ethoxy acrylic acid methylester and 475 g (4.65 moles) of acetic anhydride. The mixture was well stirred at room temperature for 45 hours to give a highly viscous suspension of an orange precipitate. 1.5 l of a mixture of benzene-ether-hexane 1:1:3 was added and the mixture stirred vigorously for 30 minutes. The product was collected by filtration, washed with 1:0 l of the same solvent mixture and dried at room temperature and 16 mmHg to constant weight to afford 600 g (51%) of product as orange crystals, m.p. 159°-160°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](O)[CH2:11][OH:12]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:12][CH2:11][CH2:10][O:6]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(F)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1cccc(C2OCCO2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
A solution of 3-fluorobenzaldehyde (3.0 g, 24.2 mmol) in toluene (100 ml) was treated with ethylene glycol (1.8 g, 29.0 mmol) and p-toluenesulfonic acid (0.05 g, 0.24 mmol). The resulting solution was stirred at 80° C. for 3 hours. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed (brine), dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified on silica gel using 10% ethyl acetate/hexane to provide the title compound (3.4 g, 85%).
Reaction SMILES: COC[N:4]1[C:12]2[C:7](=[C:8]([CH3:23])[CH:9]=[CH:10][C:11]=2[N:13]([CH3:22])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:24]([O:26]CC)=[O:25].Cl.O1CCCC1>C(O)C>[CH3:23][C:8]1[CH:9]=[CH:10][C:11]([N:13]([CH3:22])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:16])=[C:12]2[C:7]=1[CH:6]=[C:5]([C:24]([OH:26])=[O:25])[NH:4]2
Reactant: CCOC(=O)c1cc2c(C)ccc(N(C)S(=O)(=O)c3cccs3)c2n1COC
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
A solution of ethyl 1-(methoxymethyl)-4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (4.0 g), 6N hydrochloric acid (20 ml), tetrahydrofuran (20 ml) and ethanol (60 ml) was stirred at 80° C. for 4 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate. The mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was dissolved in a mixed solvent of tetrahydrofuran (40 ml) and methanol (40 ml), an aqueous solution (20 ml) of 85% potassium hydroxide (2.2 g) was added to this solution, and the mixture was stirred at room temperature for 18 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was acidified with aqueous citric acid solution. The precipitated crystals were collected by filtration, washed with water, and dried to give the title compound (3.3 g, yield 99%) as colorless crystals. MS: 351(MH+). melting point 223-225° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[Cl:25].[Li]CCCC.[CH3:31][N:32]1[C:36]([CH:37]=[O:38])=[CH:35][N:34]=[N:33]1>C1COCC1>[Cl:25][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:37]([C:36]3[N:32]([CH3:31])[N:33]=[N:34][CH:35]=3)[OH:38])[CH:3]=2)[N:8]=[C:7]([O:12][CH3:13])[C:6]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cn1nncc1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -20 °C
Reaction time: 0.03 h

Procedure:
To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (1.45 g, 3.37 mmol, Intermediate 5: step d) was added THF (25 mL) and the solution was cooled to −75° C. n-BuLi (2.5 M in hexanes, 1.3 mL, 3.25 mmol) was then added dropwise. After 2 minutes, 1-methyl-1H-1,2,3-triazole-5-carbaldehyde (580 mg, 5.22 mmol, in 3 mL THF) was introduced. The reaction mixture was allowed to warm to −20° C. over 45 minutes at which time the reaction was quenched with aqueous NH4Cl solution. The aqueous portion was extracted with EtOAc (5×40 mL) and the combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel (5% CH3CN-DCM increasing to 30% CH3CN+2% MeOH) provided the title compound as an off white amorphous solid.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:21][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:18])[C:11]([CH3:19])=[C:10]3[CH3:20])=[N+]=[N-].[H][H]>O1CCCC1.CO.[Pd]>[NH2:1][CH2:4][CH:5]1[O:21][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:18])[C:11]([CH3:19])=[C:10]3[CH3:20]
Reactant: [H][H]
Reactant: Cc1c(C)c2c3c(cc(C)c2[nH]c1=O)CC(CN=[N+]=[N-])O3
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C)c2c3c(cc(C)c2[nH]c1=O)CC(CN)O3
Yield: 69 %

Procedure:
The compound obtained in Example 255 (1.05 g, 3.69 mmol) was dissolved in a solvent mixture of tetrahydrofuran (50 ml) and methanol (20 ml). To the solution, 10% palladium-on-carbon (1 g) was added, followed by stirring at 50° C. for 4 hours in the atmosphere of hydrogen. The catalyst was removed by filtration, and the catalyst was evaporated under reduced pressure. As a result, 658 mg of the title compound was obtained as colorless powder (69.1%). The obtained powder was dissolved in methanol (20 ml), to which 4N-HCl in 1,4-dioxane (0.7 ml) was added. Recrystallization from chloroform--methanol--ether yielded 536 mg of the title compound as pale yellow powder (49.3%).
Reaction SMILES: [P:1]([O-:13])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:14][CH2:15]I>>[P:1]([O:13][CH2:15][Cl:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:2]
Reactant: ClCI
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Product: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Yield: 343.6 %

Procedure:
The tetrabutylammonium salt of bis-tert butyl phosphate (57 g, 0.126 mol, Digital Specialty Chemicals) and chloroiodomethane (221 g, 1.26 mol) were stirred at room temperature for four hours and then the volatiles were removed in vacuo. 500 ml of ethyl ether was added to the residue and insoluble solid was filtered away. Concentration of the filtrate and final removal of volatiles using a vacuum pump provided di-tert-butyl chloromethyl phosphate (112 g), typically as a light yellow or brown oil, which was utilized in the next step without any further purification.
Reaction SMILES: [CH3:1][N:2]([N:4]=[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH:13]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[O:23])[C:12]2=[O:32])=[CH:7][CH2:6]1)[CH3:3].N1CC[CH2:35][CH2:34]1.CC(O)=O>>[N:2]1([N:4]=[C:5]2[CH:6]=[CH:7][C:8]([N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][CH:13]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)=[O:23])[C:12]3=[O:32])=[CH:9][CH2:10]2)[CH2:1][CH2:35][CH2:34][CH2:3]1
Reactant: CN(C)N=C1C=CC(N2C(=O)C(NC(=O)Nc3ccc(Cl)cc3)Cc3ccccc32)=CC1
Reactant: C1CCNC1
Solvent: CC(=O)O
Product: O=C(Nc1ccc(Cl)cc1)NC1Cc2ccccc2N(C2=CCC(=NN3CCCC3)C=C2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To the thioimidate solution in MeOH (4 mL, 0.063 mmol) from Example 134, a pre-mixed pyrrolidine (0.037 mL, 0.44 mmol) and HOAc (0.040 mL, 0.70 mmol) were added. The mixture was heated to reflux for 1 h, then was stirred at room temperature overnight. After being concentrated in vacuo, the residue was purified by HPLC to give a white powder (15 mg). MS 488.3 and 490.3 (M+H, Cl pattern).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH3:15]O>O>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([O:5][CH3:15])=[O:4]
Reactant: CCCCC(C)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCC(C)C(=O)OC
Temperature: 50 °C
Yield: 93 %

Procedure:
A solution of 2-methylhexanoic acid (20 g, 153 mmol) in methanol (500 mL) was treated with concentrated sulfuric acid (8.0 mL) and heated to 50° C. for 16 h. The reaction was diluted with water and extracted with ether. The combined organic layers were dried and concentrated to afford 20.57 g (93%) of methyl 2-methylhexanoate as a colorless liquid.