Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([O:13][C@H:14]([C@@H:43]([NH:51][C:52](=[O:71])[C@@H:53]([N:58]1[CH2:62][CH2:61][N:60]([CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[C:59]1=[O:70])[C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:15][C@@H:16]([NH:30][C:31](=[O:42])[C@H:32]([C:38]([CH3:41])([CH3:40])[CH3:39])[NH:33][C:34]([O:36][CH3:37])=[O:35])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:20][CH:19]=1)=[O:12])[CH3:10])=O)(C)(C)C.Cl>ClCCl.O1CCOCC1>[NH2:8][C@@H:9]([CH3:10])[C:11]([O:13][C@H:14]([C@@H:43]([NH:51][C:52](=[O:71])[C@@H:53]([N:58]1[CH2:62][CH2:61][N:60]([CH2:63][C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=2)[C:59]1=[O:70])[C:54]([CH3:55])([CH3:57])[CH3:56])[CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[CH2:15][C@@H:16]([NH:30][C:31](=[O:42])[C@@H:32]([NH:33][C:34]([O:36][CH3:37])=[O:35])[C:38]([CH3:39])([CH3:40])[CH3:41])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:22][CH:23]=1)=[O:12]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](OC(=O)[C@H](C)NC(=O)OC(C)(C)C)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](OC(=O)[C@H](C)N)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product of Example 193A (0.098 g, 0.037 mmol) in dichloromethane (1.0 mL) at room temperature was added a solution of HCl in dioxane (0.13 mL, 4 N), and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated to give the title compound as the bis hydrochloride salt (0.089 g). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.88 (s, 9 H), 0.91 (s, 9 H), 1.57 (d, J=7.4 Hz, 1 H), 1.69-1.74 (m, 2 H), 2.27 (q, J=9.6 Hz, 1 H), 2.53-2.56 (m, 2 H), 2.72-2.85 (m, 3 H), 2.94 (q, J=8.8 Hz, 1 H), 3.17-3.24 (m, 1 H), 3.46 (s, 3 ), 3.87 (d, J=9.9 Hz, 1 H), 4.14 (s, 1 H), 4.19-4.37 (m, 4 H), 4.31 (s, 2 H), 4.60-4.70 (m, 1 H), 5.14 (t, J=7.4 Hz, 1 H), 6.66 (d, J=9.6 Hz, 1 H), 7.00-7.08 (m, 3 H), 7.08-7.16 (m, 2 H), 7.26-7.47 (m, 8 H), 7.90-7.99 (m, 6 H), 8.46-8.57 (m, 3 H), 8.67-8.68 (m, 1 H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14](=O)[C:15]([F:18])([F:17])[F:16])[C:10](=O)[C:9]2=[O:21])=[CH:4][CH:3]=1.[Cl-].[C:23]([C:25]1[CH:26]=[C:27]([NH:31][NH2:32])[CH:28]=[CH:29][CH:30]=1)#[N:24]>C(O)(=O)C>[C:23]([C:25]1[CH:26]=[C:27]([N:31]2[C:10]3[C:9](=[O:21])[N:8]([C:5]4[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=4)[CH2:13][CH2:12][C:11]=3[C:14]([C:15]([F:18])([F:17])[F:16])=[N:32]2)[CH:28]=[CH:29][CH:30]=1)#[N:24]
Reactant: N#Cc1cccc(NN)c1
Reactant: O=C1C(=O)N(c2ccc(I)cc2)CCC1C(=O)C(F)(F)F
Agent: [Cl-]
Solvent: CC(=O)O
Product: N#Cc1cccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(I)cc2)CC3)c1
Yield: 61.3 %

Procedure:
1-(4-iodophenyl)-4-(2,2,2-trifluoroacetyl)-2,3-piperidinedione prepared by the same methods described in WO 00/39131 (5.02 g, 12.2 mmol) and 3-cyanophenylhydrazine chloride (3.44 g, 20.4 mmol) were added together with 75 mL of Acetic acid. The mixture was refluxed for 4 hours. The mixture was cooled and the solvent was removed. The residue was partitioned between EtOAc and H2O. The EtOAc layer was washed with H2O, brine, dried over MgSO4, concentrated, and chromatographed with 1:5 EtOAc:hexane to afford 3.8 g of 1-(3-cyanophenyl)-3-(trifluoromethyl)-6-(4-iodophenyl)-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one as a yellow solid (61.3%). 1H NMR (CDCl3, 300 MHz) δ 7.91-7.90 (m, 1H), 7.87-7.83 (m, 1H), 7.75-7.69 (m, 3H), 7.56 (t, 1H), 7.09-7.04 (m, 2H), 4.15 (t, 2H), 3.19 (t, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]#[C:12][CH:13]([OH:22])[CH2:14][CH2:15][C:16]2[O:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH:6]=[CH:7][CH:8]=1.O.S(=O)(=O)(O)O>C(O)(=O)C>[CH3:21][C:18]1[CH2:19][CH2:20][C:16](=[O:17])[C:15]=1[CH2:14][CH:13]([OH:22])[C:12]#[C:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(CCC#CC(O)CCc2ccc(C)o2)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(CCC#CC(O)CC2=C(C)CCC2=O)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A solution of 10.00 g (33.6 mmol) dl-1-(m-methoxyphenyl)-7-(5-methyl-2-furyl)-3-heptyn-5-ol in 20 ml acetic acid, about 10 ml water and 0.40 ml about 20% sulphuric acid was stirred under nitrogen in an oil-bath at 90° C. for about 24 hours. After cooling, the mixture was poured into 200 ml water and extracted with methylene chloride. The methylene chloride layer was washed with water and evaporated to dryness under reduced pressure. The residue (10.60 g) was dissolved in 500 ml of about 0.1 N ethanolic potassium hydroxide solution and stirred under nitrogen in an oil-bath at about 80° C. for about 1 hour. After cooling, the mixture was poured into 1000 ml water and extracted with methylene chloride. The methylene chloride layer was washed with water and evaporated to dryness under reduced pressure. Yield: 9.85 g.
Reaction SMILES: C(O[C:6]([C:8]1[N:13]=[C:12](O)[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[S:17][C:10]=2[C:9]=1[OH:25])=[O:7])CCC.C([O:30][C:31]([C:33]1C(O)=C2C=C(C3C=CC(F)=CC=3)SC2=C(O)[N:38]=1)=[O:32])CCC>>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[S:17][C:10]3[C:9]([OH:25])=[C:8]([C:6]([NH:38][CH2:33][C:31]([OH:32])=[O:30])=[O:7])[N:13]=[CH:12][C:11]=3[CH:15]=2)=[CH:23][CH:22]=1
Reactant: CCCCOC(=O)c1nc(O)c2sc(-c3ccc(F)cc3)cc2c1O
Reactant: CCCCOC(=O)c1nc(O)c2cc(-c3ccc(F)cc3)sc2c1O
Product: O=C(O)CNC(=O)c1ncc2cc(-c3ccc(F)cc3)sc2c1O

Procedure:
The title compound was prepared from 2-(4-fluoro-phenyl)-4,7-dihydroxy-thieno[3,2-c]pyridine-6-carboxylic acid butyl ester and 2-(4-fluoro-phenyl)-4,7-dihydroxy-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester, example 34-b, under conditions analogous to experimental example 30-g. MS: (+) m/z 424.0, 425.9 (M+1, 79Br/81Br).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH3:24][O:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1>CN(C=O)C>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:31]5[C:26]([O:25][CH3:24])=[N:27][CH:28]=[CH:29][CH:30]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: COc1ncccc1B(O)O
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Solvent: CN(C)C=O
Product: COc1ncccc1-c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)sc1CCO2
Yield: 60 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 2-methoxypyridin-3-ylboronic acid were reacted. The crude material was dissolved in DMF and purified by reverse phase HPLC to provide 129 (200 mg, 60%). 1H NMR (400 MHz, DMSO) δ 8.66 (d, J=2.2, 1H), 8.19 (dd, J=4.9, 1.7, 1H), 8.10 (s, 1H), 7.79 (dd, J=7.3, 1.8, 1H), 7.50 (dd, J=8.4, 2.3, 1H), 7.21-7.09 (m, 2H), 5.75 (dt, J=13.3, 6.7, 1H), 4.42 (t, J=4.9, 2H), 3.91 (s, 3H), 3.47 (t, J=4.9, 2H), 1.52 (d, J=6.6, 6H). MS (ESI(+)): m/z 420.1 (M+H).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25]O)[C:5]1=[O:29])[CH:2]=[CH2:3].[CH:31]1([S:35]([NH2:38])(=[O:37])=[O:36])[CH2:34][CH2:33][CH2:32]1>>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][NH:38][S:35]([CH:31]2[CH2:34][CH2:33][CH2:32]2)(=[O:37])=[O:36])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: NS(=O)(=O)C1CCC1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)C2CCC2)C1=O
Temperature: 40 °C

Procedure:
The title compound was prepared from (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B, 250 mg, 0.560 mmol) and cyclobutanesulfonamide (Example 271G, 256 mg, 1.894 mmol) using the general procedure described in Step A of Example 272, albeit with an oil bath heated at 40° C. The crude product was purified by silica gel chromatography eluting with a gradient of EtOAc in hexanes. The product was obtained as a white powder (220 mg, 70%). LCMS (ESI): m/z=563.2 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:23][C:8]23[CH2:9][CH2:10][CH:11]4[CH:20]([CH:7]2[CH2:6][CH2:5][CH:4]3[CH:3]1[CH3:24])[CH2:19][CH:18]=[C:17]1[C:12]4([CH3:22])[CH2:13][CH2:14][CH:15]([OH:21])[CH2:16]1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>ClCCl>[CH3:1][N:2]1[CH2:23][C:8]23[CH2:9][CH2:10][CH:11]4[CH:20]([CH:7]2[CH2:6][CH2:5][CH:4]3[CH:3]1[CH3:24])[CH2:19][CH:18]=[C:17]1[C:12]4([CH3:22])[CH2:13][CH2:14][CH:15]([O:21][C:32](=[O:34])[CH3:33])[CH2:16]1
Reactant: CC(=O)Cl
Reactant: CC1C2CCC3C4CC=C5CC(O)CCC5(C)C4CCC32CN1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 137.6 %

Procedure:
Compound 130A (15 mg, 0.045 mmol) was dissolved in 1 mL anhydrous dichloromethane. Triethylamine (32 μL, 0.228 mmol) was added followed by acetyl chloride (6.5 μL, 0.09 mmol). The mixture was stirred at room temperature overnight. The crude product was purified on silica gel column eluted with 0.3% ammonium hydroxide and 3% methanol in dichloromethane to give the desired product (23 mg, 68% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[CH2:8][CH2:7][CH2:6]2.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([OH:15])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(cc1OC)C(O)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a stirred solution of 6,7-dimethoxy-3,4-dihydronaphthalen-1(2H)-one (3.09 g, mmol) in MeOH (50 mL) was added NaBH4 (680 mg, 18 mmol) portion wise over 0.5 hour. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with 1N HCl, diluted with water and extracted with DCM. The combined organic phase was washed with brine, dried over sodium sulfate and the solvent was removed under reduced pressure to afford 6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-ol as a yellow oil (2.9 g, 93%). LC-MS (ES-API); rt 7.96 min; m/z calculated for C12H16O3 [M+Na]+ 231.1, found 231.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20]>ClCCl>[C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1)([O:21][CH2:22][CH:23]=[CH2:24])=[O:20]
Reactant: C=CCOC(=O)Cl
Reactant: Nc1ccc(CCCO)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)Nc1ccc(CCCO)cc1
Temperature: 0 °C
Yield: 87.5 %

Procedure:
To a round bottomed flask was added the 3-(4-aminophenyl)propanol (1.3 g, 8.6 mmol), pyridine (1.0 mL, 12 mmol) and dichloromethane (25 mL). The solution was cooled to 0° C. and treated with allyl chloroformate (1.0 mL, 9.4 mmol). After allowing to warm to 22° C. over 1 hour, the reaction mixture was diluted with dichloromethane and washed twice with 1N HCl, followed by sat. NaHCO3, water and sat. aq. NaCl. The organic extract was dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (50% EtOAc in hexane), provided 1.77 g (88%) of 3-(4-(N-carboallyloxy)aminophenyl)propanol as a clear oil which solidified on standing.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[N:12]2[N:13]=[C:14]([CH2:16][O:17][CH3:18])[N:15]=[C:11]2[N:10]=[C:9]([CH3:19])[CH:8]=1>CN(C)C1C=CC=CC=1>[Cl:3][C:7]1[N:12]2[N:13]=[C:14]([CH2:16][O:17][CH3:18])[N:15]=[C:11]2[N:10]=[C:9]([CH3:19])[CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1nc2nc(C)cc(O)n2n1
Solvent: CN(C)c1ccccc1
Product: COCc1nc2nc(C)cc(Cl)n2n1
Reaction time: 1 h

Procedure:
To a mixed solution of 300 ml of phosphorus oxychloride and 50 ml of N,N-dimethylaniline was added 38.8 g of 7-hydroxy-2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidine, and the mixture was stirred at 50° to 60° C. for one hour. After removing phosphorus oxychloride, the residue was dissolved in 500 ml of chloroform and stirred by adding ice. The chloroform layer was separated and washed with water, and then dried over anhydrous magnesium sulfate and distilled the solvent to obtain crystals. The crystals were collected by filtration and washed with water, and then dried to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:10]([C:13]1[CH:18]=[C:17]([F:19])[C:16]([CH:20]2[CH2:22][O:21]2)=[C:15]([F:23])[CH:14]=1)(=[O:12])=[O:11].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:10]([C:13]1[CH:18]=[C:17]([F:19])[C:16]([CH:20]([OH:21])[CH2:22][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[C:15]([F:23])[CH:14]=1)(=[O:12])=[O:11]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2cc(F)c(C3CO3)c(F)c2)c(C)c1
Reactant: C1COCCN1
Solvent: CCO
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2cc(F)c(C(O)CN3CCOCC3)c(F)c2)c(C)c1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a solution of N-(2,4-dimethylphenyl)-3,5-difluoro-N-isobutyl-4-(oxiran-2-yl)benzenesulfonamide (150 mg, 0.379 mmol) in ethanol (1.5 mL) at 25° C. was added morpholine (0.033 ml, 0.379 mmol) and the reaction mixture stirred at 50° C. for 6 hours. The mixture was concentrated in vacuo and purified by mass directed autoprep (ammonium carbonate modifier). The appropriate fractions were combined and evaporated in vacuo to give the required product, 9 mg, as a colourless oil. LCMS [LCMS2] Rt 1.33 min, m/z (ES+) 483 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:6][O:5][C:4]([C:7]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=2[C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([Si](C(C)C)(C(C)C)C(C)C)[CH:19]=[CH:18]3)=[N:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][C:2]1([CH3:34])[CH2:6][O:5][C:4]([C:7]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=2[C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH:19]=[CH:18]3)=[N:3]1
Reactant: COc1cccc(-c2ccc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c2)c1C1=NC(C)(C)CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc3[nH]ccc3c2)c1C1=NC(C)(C)CO1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 99.9 %

Procedure:
4,4-dimethyl-2-[2-(1-triisopropylsilylindol-5-yl)-6-methoxyphenyl]-2-oxazoline (8.5 g, 17.8 mmoles) was dissolved in 300 ml of THF. The solution was cooled to 0° C. Tetrabutylammonium fluoride (17.8 mmoles, 178 ml of 1M in THF) was added dropwise. The reaction was stirred at 0°-5° C. for 40 minutes, poured into ice water, and extracted into ether. The organic phase was dried over sodium sulfate, and the solvent was removed. The reaction produced 5.7 g of 4,4-dimethyl-2-[2-(indol-5-yl)-6methoxyphenyl]-2-oxazoline. (MS)
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[CH:11][CH:12]=2)[CH2:7][NH:6]1)=[O:4].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=2)=[O:4]
Reactant: COC(=O)C1Cc2ccc([N+](=O)[O-])cc2CN1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COC(=O)c1cc2ccc([N+](=O)[O-])cc2cn1
Yield: 71 %

Procedure:
To a solution of the above ester in 1,4-dioxane (100 mL) was added 2.8 g (12.7 mmol) of DDQ, and the reaction mixture was refluxed for 6 h. After removal of solvents, the residue was dissolved with ethyl acetate (250 mL) and washed with aq. NaHSO3 solution (1M solution, 100 mL), water and brine. The ethyl acetate layer was dried over sodium sulfate, evaporated under reduced pressure and purified by column chromatography (eluting with ethyl acetate then EtOAc/methanol v/v=100:5) to provide 1.0 g (71%) of the 7-nitro-isoquinoline-3-carboxylic acid methyl ester. LCMS: 233 (M+1)+. The methyl ester was hydrolyzed according to the general procedure B to give 0.9 of 7-nitro-isoquinoline-3-carboxylic acid. LCMS: 219 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1)#[N:2].[NH2:15][C:16]1[CH:30]=[CH:29][C:19]([O:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:18][CH:17]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[CH:29][CH:30]=3)=[O:13])=[CH:8][C:7]=2[CH:14]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(N)cc1
Reactant: N#Cc1ccc2oc(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc(NC(=O)c2cc3cc(C#N)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.5 %

Procedure:
5-Cyano-2-benzofurancarboxylic acid (300 mg, 1.60 mmol) and t-butyl 4-aminophenoxyacetate (395 mg, 1.76 mmol) were dissolved in N,N-dimethylformamide (40 ml), and 1-hydroxy-1H-benzotriazole (238 mg, 1.76 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (342 mg, 1.76 mmol) were added. The mixture was stirred at room temperature for 18 hours. Water (100 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to give 512 mg of t-butyl 4-[(5-cyano-2-benzofuranyl)carbonylamino]phenoxyacetate as a pale-yellow solid (82%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(OC([NH:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([O-])=[O:26])=[N:23][CH:24]=1)=O)(C)(C)C.[Li+].CCN(C(C)C)C(C)C>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:25]([C:22]2[CH:21]=[CH:20][C:19]([CH2:18][NH2:17])=[CH:24][N:23]=2)=[O:26])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)[O-])nc1
Reactant: NCc1ccc(F)cc1
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Product: NCc1ccc(C(=O)NCc2ccc(F)cc2)nc1
Yield: 26.3 %

Procedure:
Use the General Procedure 6-2, using 4-fluoro-benzylamine (551 mg, 4.4 mmol), lithium 5-(tert-butoxycarbonylamino-methyl)-pyridine-2-carboxylate (740 mg, 2.93 mmol) and DIEA (2.6 mL) as cosolvent, to give the title compound as a white solid (200 mg, 26%). MS (ES+) m/z: 260 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:8]=1.[CH:21](OCC)=[O:22]>CCO>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH:17][CH:21]=[O:22])[N:8]=1
Reactant: NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: CCOC=O
Solvent: CCO
Product: NC(=NCC(F)(F)F)Nc1ccnc(SCCCNC=O)n1

Procedure:
A mixture of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(3-aminopropylthio)pyrimidine (0.3 g.), ethyl formate (5 ml.) and EtOH (2 ml.) was heated under reflux for 48 hours, then evaporated to dryness. The residue was dissolved in N aqueous HCl and the solution washed with EtOAc. The aqueous phase was basified with 10N aqueous NaOH, extracted with EtOAc and the extract dried and evaporated to dryness. The residue was recrystallised from EtOAc to give N-[3-(4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimid-2-ylthio)propyl]formamide (0.2 g.), m.p. 165°-166°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Br:15][CH2:16][C:17]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[NH:8][CH:9]=1)=[O:18]
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=C(Cl)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CBr)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
5-Bromo-1H-pyrrolo[2,3-b]pyridine (5 g, 25.2 mmol) was added to aluminum chloride (16.8 g, 126.2 mmol) in dichloromethane (200 ml) under nitrogen. The mixture was allowed to stir at room temperature for 1 hour. Then bromoacetyl chloride (11 ml, 126.2 mmol) in dichloromethane was added drop wise and the reaction was allowed to proceed at room temperature overnight. The next day the reaction was cooled to 0° C. and was quenched with methanol (˜30 ml) until the reaction turned clear. The reaction was concentrated under vacuum and resuspended in water (300 ml). The pH was adjusted to 7 with 7N sodium hydroxide solution and then extracted with ethyl acetate (300 ml×3). The combined organic layers were extracted with saturated sodium potassium tartrate, brine, dried with Na2SO4. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded 2-bromo-1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone (7.4 g, 92% yield). 1H NMR (500 MHz, DMSO-d6) δ 4.76 (s, 2H), 8.45 (s, 1H), 8.61 (s, 1H), 8.75 (s, 1H), 12.98 (s, 1H). MS: m/z 318.8 (M+H+).
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:5]=[C:6]([C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][C:9]=1[CH3:10]>C(Cl)(Cl)Cl>[Br:1][CH2:12][C:11]([C:6]1[CH:7]=[CH:8][C:9]([CH3:10])=[C:4]([Br:3])[CH:5]=1)=[O:13]
Reactant: CC(=O)c1ccc(C)c(Br)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=O)CBr)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.8 %

Procedure:
A solution of bromine (0.68 mL, 13.3 mmol) in chloroform (13 mL) was added dropwise over a 35 minute period to a stirred solution of 1-(3-bromo-4-methylphenyl)ethanone (2.96 g, 13.9 mmol) in chloroform (40 mL) at 0° C. After the addition, the ice-bath was removed and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give an oil which crystallized to give the title compound (4.11 g, 95%) as an orange solid.
Reaction SMILES: [C:1]([OH:5])(=O)[C:2]#[CH:3].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:18]([C:20]1[N:21]=[C:22]([CH2:27][C:28]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])=[O:29])[NH:23][C:24]=1[CH2:25][CH3:26])[CH3:19]>>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[C:28]([C:27]1[CH:3]=[CH:2][C:1](=[O:5])[N:23]2[C:24]([CH2:25][CH3:26])=[C:20]([CH2:18][CH3:19])[NH:21][C:22]=12)=[O:29]
Reactant: C#CC(=O)O
Reactant: CCc1nc(CC(=O)c2ccc(F)cc2F)[nH]c1CC
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCc1[nH]c2c(C(=O)c3ccc(F)cc3F)ccc(=O)n2c1CC

Procedure:
The compound is prepared as described in example 6 with 98.3 mg (1.35 mmol) of propiolic acid, 262.2 mg (1.62 mmol) of 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole and 250 mg (0.90 mmol) of 2-(4,5-Diethyl-1H-imidazol-2-yl)-1-(2,4-difluorophenyl)ethanone (example XXVII).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[C:23]([F:35])=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25](O)=O>>[Cl:21][C:22]1[C:23]([F:35])=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:30]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(Cl)c1F
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cc(C(F)(F)F)cc(Cl)c3F)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 65 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-chloro-2-fluoro-5-(trifluoromethyl)benzoic acid: MS (ESI): m/z 487 (M−1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)=[N:3][CH:4]=1
Reactant: CN1CCNCC1
Reactant: Brc1ccc(Br)nc1
Product: CN1CCN(c2ccc(Br)cn2)CC1

Procedure:
Prepared from 2,5-dibromopyridine and 4-methylpiperazine in a similar manner to Example 9(d).