Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:21]([NH:22][CH3:23])=[CH:20][CH:19]=[CH:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1.[CH3:26][S:27]([CH2:30][C:31](Cl)=[O:32])(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:21]([N:22]([CH3:23])[C:31](=[O:32])[CH2:30][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:20][CH:19]=[CH:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:24][CH:25]=1
Reactant: CS(=O)(=O)CC(=O)Cl
Reactant: CNc1cccn2c(=O)c(O)c(C(=O)NCc3ccc(F)cc3)nc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)CS(C)(=O)=O)c1cccn2c(=O)c(O)c(C(=O)NCc3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
N-(4-fluorobenzyl)-3-hydroxy-9-(methylamino)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide was dissolved in dichloromethane. Methylsulfonylacetyl chloride (1.2 eqs.) and triethylamine (2 eqs.) were added and the solution was stirred at room temperature. After 5 hours a further 2 eqs. of methylsulfonylacetyl chloride and 2 eqs. of triethylamine were added. The solvent was removed under vacuum and the residue was suspended in methano/0.1 M NaOH. The suspension was sonicated for 2 minutes and left stirring at room temperature for 30 minutes. The product was purified by preparative RP-HPLC, using water (0.1% TFA) and acetonitrile (0.1% TFA) as eluants (column: C18). The product was obtained after lyophilization of the pooled product fractions as bright yellow fluffy material.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](O)=[O:5].BrC1C=CC(Cl)=CC=1[CH2:20][O:21][CH2:22]OC>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH2:4][O:5][CH2:20][O:21][CH3:22]
Reactant: O=C(O)c1c(F)cccc1Br
Reactant: COCOCc1cc(Cl)ccc1Br
Product: COCOCc1c(F)cccc1Br

Procedure:
This compound was made from 2-bromo-6-fluorobenzoic acid in the same manner as compound 18d: 1H NMR (300 MHz, CDCl3) δ (ppm) 3.43 (s, 3H), 4.74 (s, 2H), 4.76 (d, J=2.1 Hz, 2H), 7.05 (t, J=9.1 Hz, 1H), 7.18 (td, J=8.2, 5.9 Hz, 1H), 7.40 (d, J=8.2 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[CH:17]=2)=[CH:4][N:3]=1)=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=3.[O-:27][CH2:28][CH3:29].[Na+]>C(O)C>[CH2:25]([S:22]([C:18]1[CH:17]=[C:16]([C:5]2[C:6]3[C:14]4[CH:13]=[C:12]([CH3:15])[CH:11]=[N:10][C:9]=4[NH:8][C:7]=3[C:2]([O:27][CH2:28][CH3:29])=[N:3][CH:4]=2)[CH:21]=[CH:20][CH:19]=1)(=[O:24])=[O:23])[CH3:26]
Reactant: CCS(=O)(=O)c1cccc(-c2cnc(Cl)c3[nH]c4ncc(C)cc4c23)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ncc(-c2cccc(S(=O)(=O)CC)c2)c2c1[nH]c1ncc(C)cc12
Yield: 78 %

Procedure:
Compound 32 (4 mg, 0.01 mmol) was heated in a solution of sodium ethoxide in ethanol (21 wt. %, 0.5 mL) at 200° C. in the microwave for 30 min. Purification by prep-HPLC gave 3.2 mg (78%) of the title compound as a pale yellow solid. 1H NMR (400 MHz, MeOD-d4): δ 8.47 (br s, 1H), 8.18 (s, 1H), 8.03 (d, 1H, J=7.6 Hz), 7.96 (d, 1H, J=7.6 Hz), 7.81-7.89 (m, 3H), 4.63 (q, 2H, J=7.2 Hz), 3.26 (q, 2H, J=7.2 Hz), 2.38 (s, 3H), 1.56 (t, 3H, J=7.6 Hz), 1.32 (t, 3H, J=7.6 Hz). MS (ES) [m+H] calc'd for C21H21N3O3S, 396; found 396.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:11])[C:9]([CH3:10])=[CH:14][N:15]([CH3:16])[CH3:17])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)c1cccc(Cl)c1
Reactant: COC(OC)N(C)C
Product: CC(=CN(C)C)C(=O)c1cccc(Cl)c1

Procedure:
A mixture of 75.0 g of m-chloropropiophenone and 200 ml of N,N-dimethylformamide dimethyl acetal was stirred and heated at reflux for 16 hours. The mixture was evaporated in vacuo to give a black oil. The oil was subjected to Kugelrohr distillation at 0.5 mm of mercury and the fraction that boils at 110° C. was removed. The residue from the distillation was collected to give 35.0 g of 3'-chloro-3-dimethylamino-2-methylacrylophenone as a black oil.
Reaction SMILES: [CH2:1](I)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:10]([NH:17][C:18]1[C:23]([C:24]([N:26]([O:28][CH3:29])[CH3:27])=[O:25])=[CH:22][N:21]=[C:20]2[NH:30][N:31]=[CH:32][C:19]=12)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C)C=O.O>[CH2:10]([NH:17][C:18]1[C:23]([C:24]([N:26]([O:28][CH3:29])[CH3:27])=[O:25])=[CH:22][N:21]=[C:20]2[N:30]([CH2:1][CH3:2])[N:31]=[CH:32][C:19]=12)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CON(C)C(=O)c1cnc2[nH]ncc2c1NCc1ccccc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncc2c(NCc3ccccc3)c(C(=O)N(C)OC)cnc21
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Ethyl iodide (1.52 gm, 9.63 mmol) and potassium carbonate (2.214 gm, 16.05 mmol) were added to the solution 4-(benzylamino)-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (1 gm, 3.21 mmol) (example 6a) in dimethylformamide and the reaction mixture was stirred at 60° C. for about 5 hours. It was cooled, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified over silica gel column.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11]([Cl:13])=[N:10][CH:9]=[N:8][C:7]=2[C:6](Br)=[CH:5]1)[CH:2]=[CH2:3].[Li]CCCC.[F:20][C:21]([F:41])([F:40])[C:22]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[N:28]=[CH:27]2)=[O:23]>C1COCC1.O.[Cl-].[Na+].O>[CH2:1]([N:4]1[C:12]2[C:11]([Cl:13])=[N:10][CH:9]=[N:8][C:7]=2[C:6]([C:22]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[N:29]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[N:28]=[CH:27]3)([OH:23])[C:21]([F:40])([F:20])[F:41])=[CH:5]1)[CH:2]=[CH2:3]
Reactant: O=C(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Reactant: C=CCn1cc(Br)c2ncnc(Cl)c21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ncnc(Cl)c21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 23.2 %

Procedure:
To a chilled (−78° C.) solution of 5-allyl-7-bromo-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (570 mg, 2.1 mmol) in 10 mL of THF was added n-BuLi (2.5 M in THF, 1.5 mL, 2.5 mmol) dropwise. After 5 minutes, a chilled (−78° C.) solution of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanone (708 mg, 2.3 mmol) in 3 mL of THF was added in one portion. After 15 minutes, the mixture was diluted with water and warmed to room temperature, diluted with brine, and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography using EtOAc-hexanes (15-60% gradient) to provide 245 mg (23%) of the title compound as a beige solid. MS m/z 502.23 (MH+).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Br:17][C:18]1[CH:19]=[C:20]([C:25]([C:27]2[O:28][CH:29]=[CH:30][N:31]=2)=O)[CH:21]=[C:22]([F:24])[CH:23]=1.Cl>C1COCC1.O>[CH2:15]([O:14][C:12](=[O:13])/[CH:11]=[C:25](/[C:20]1[CH:21]=[C:22]([F:24])[CH:23]=[C:18]([Br:17])[CH:19]=1)\[C:27]1[O:28][CH:29]=[CH:30][N:31]=1)[CH3:16]
Reactant: O=C(c1cc(F)cc(Br)c1)c1ncco1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C(/c1cc(F)cc(Br)c1)c1ncco1
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a suspension of NaH (60%, 1.6 g, 40 mmol) in dry THF (30 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (9.15 g, 40 mmol) at −78° C. After being stirred at −78° C. for 1 hour, a solution of (3-Bromo-5-fluoro-phenyl)-oxazol-2-yl-methanone (10.8 g, 40 mmol) in 20 ml THF was added drop wise over 30 min. The mixture was stirred at −78° C. for 30 min and then warmed to room temperature followed by stirring overnight. The mixture was cooled to 0° C. and treated with water (50 mL), pH value was adjusted to 6 with HCl (0.5N) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a petroleum ether/EtOAc mixture to afford 9.5 g of the desired product (Yield: 61%)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([Br:11])[C:3]=1[CH:4]=O.Cl.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][NH2:21].C([O-])(=O)C.[Na+]>CO>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][N:21]=[CH:4][C:3]1[C:2]([Br:1])=[CH:9][C:8]([CH3:10])=[CH:7][C:6]=1[Br:11]
Reactant: NNc1ccccc1F
Reactant: Cc1cc(Br)c(C=O)c(Br)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Br)c(C=NNc2ccccc2F)c(Br)c1

Procedure:
2,6-Dibromo-4-methylbenzaldehyde (600 g, 2.16 mmol), (2-fluorophenyl)hydrazine hydrochloride (351 mg, 2.16 mmol) and sodium acetate (180 mg, 2.19 mmol) were heated in methanol (15 mL) under reflux for 2 hours. The methanol was evaporated and the residue partitioned between dichloromethane (30 mL) and aqueous brine (30 mL). The organic phase was separated, combined with additional dichloromethane extracts (2×15 mL), washed with aqueous sodium bicarbonate (2×15 mL), passed through a hydrophobic frit and evaporated to the title compound (767 mg).
Reaction SMILES: [F:1][C:2]1[C:8]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Br:14]N1C(=O)CCC1=O>CN(C=O)C>[Br:14][C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[C:8]=1[O:9][C:10]([F:11])([F:12])[F:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc(OC(F)(F)F)c1F
Solvent: CN(C)C=O
Product: Nc1ccc(Br)c(OC(F)(F)F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of 2-fluoro-3-(trifluoromethoxy)aniline (1.0 g, 5.13 mmol) dissolved in DMF (2 mL) at 0° C. was slowly added a solution of cold N-bromosuccinimide (0.91 g, 5.13 mmol) dissolved in DMF (6 mL) over 5 min. The reaction mixture was stirred at 0° C. for 1 h, extracted with EtOAc (125 mL) and washed with water (3×25 mL). The combined aqueous layers were extracted with EtOAc (75 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate, filtered, and concentrated to produce the title compound as a dark colored liquid (1.27 g, 90% yield). (m/z): [M+H]+ calcd for C7H4BrF4NO 273.94. found 273.8.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9](=[O:17])[C:10]([CH3:16])([CH3:15])[CH2:11][C:12]([OH:14])=[O:13])=[C:4]([CH3:18])[CH:3]=1.C(N1C=CN=C1)(N1[CH:25]=[CH:24]N=C1)=O.C(O)C>O1CCCC1>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9](=[O:17])[C:10]([CH3:15])([CH3:16])[CH2:11][C:12]([O:14][CH2:24][CH3:25])=[O:13])=[C:4]([CH3:18])[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(C(=O)C(C)(C)CC(=O)O)c(C)cc1Br
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CC(C)(C)C(=O)c1cc(C)c(Br)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.2 g (10 mmol) of 4-(4-bromo-2,5-dimethyl-phenyl)-3,3-dimethyl4-oxo-butanoic acid in tetrahydrofuran is combined with 3.60 g (11 mmol) of carbonyldiimidazole and stirred for 1 hour at ambient temperature. The solvent is replaced by 20 ml of ethanol and the mixture is heated to boiling for 2 hours. Then the solvent is distilled off, the crude product is taken up in methylene chloride, washed with water, dried with sodium sulphate, concentrated and purified by flash chromatography (silica gel; ethyl acetate/petroleum ether=3:97).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([O:38][CH2:39][CH3:40])(=[O:37])[C:35]#[CH:36].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>O1CCCC1>[CH2:1]([O:8][C:9]([C:11]1([N:16]([CH:36]=[CH:35][C:34]([O:38][CH2:39][CH3:40])=[O:37])[S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CC(=O)OCC
Reactant: O=C(OCc1ccccc1)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=CN(C1(C(=O)OCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 25.0 g (53.2 mmol) of 1-[4-(4-fluorophenoxy)benzenesulfonylamino]-cyclopentanecarboxylic acid benzyl ester and 10.8 mL (106 mmol, 2 equivalents) of ethyl propiolate in 200 mL of dry tetrahydrofuran at 1° C. was treated with 53.2 mL (53.2 mmol, 1 equivalent) of a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M) over 45 minutes. The resulting solution was allowed to warm slowly to ambient temperature and stirred overnight. The tetrahydrofuran was displaced with toluene at reduced pressure, and the toluene solution was washed with water and brine, diluted to 600 mL with toluene, stirred with 90 g of silica gel for three hours, filtered, and concentrated to 25.14 g (83%) of 1{(2-ethoxycarbonylvinyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}-cyclopentanecarboxylic acid benzyl ester as an orange oil. 1H NMR (CDCl3) indicated a 1.5:1 trans/cis ratio.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([C:16]3[N:24]4[C:19]([CH:20]=[N:21][C:22](O)=[N:23]4)=[CH:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH:27]=1>>[N:1]1([S:7]([C:10]2[CH:11]=[C:12]([C:16]3[N:24]4[C:19]([CH:20]=[N:21][C:22]([NH:38][C:35]5[CH:34]=[CH:33][C:32]([C:28]6[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=6)=[CH:37][CH:36]=5)=[N:23]4)=[CH:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(-c2cccnc2)cc1
Reactant: O=S(=O)(c1cccc(-c2ccc3cnc(O)nn23)c1)N1CCOCC1
Product: O=S(=O)(c1cccc(-c2ccc3cnc(Nc4ccc(-c5cccnc5)cc4)nn23)c1)N1CCOCC1

Procedure:
{7-[3-(Morpholine-4-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl}-(4-pyridin-3-yl-phenyl)-amine was prepared from 7-[3-(morpholine-4-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 4-pyridin-3-yl-phenylamine in an analogous manner to Example 1052a. Product isolated as a yellow foam (16 mg, 10%). LCMS (m/e) 513 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.88 (s, 1H), 8.79 (s, 1H), 8.61-8.52 (m, 1H), 8.49 (s, 1H), 8.41 (d, 1H, J=7.6 Hz), 7.91 (d, 1H, J=7.8 Hz), 7.80-7.60 (m, 6H), 7.40-7.31 (m, 1H), 7.08 (d, 1H, J=4.6 Hz), 7.02 (s, 1H), 6.90 (d, 1H, J=4.5 Hz), 3.75-3.66 (m, 4H), 3.09-3.00 (m, 4H).
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:42])[CH2:14][O:15][C:16]1[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[C:18]([O:26][CH2:27][C:28]([N:30]2[CH2:34][CH2:33][CH2:32][C@@H:31]2[C:35]([O:37]C(C)(C)C)=[O:36])=[O:29])[CH:17]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:35]([C@H:31]1[CH2:32][CH2:33][CH2:34][N:30]1[C:28](=[O:29])[CH2:27][O:26][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=1)[O:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:42])([OH:37])=[O:36]
Reactant: COC(=O)c1cc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)cc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(OCC(=O)N2CCC[C@@H]2C(=O)O)cc(OCC(=O)N2CCC[C@@H]2C(=O)O)c1
Reaction time: 8 h
Yield: 94.1 %

Procedure:
A solution of 710 mg (1.2 mmol) (R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-methoxycarbonyl-phenoxy]-acetyl]-pyrrolidine- 2-carboxylic acid tert-butyl ester in 10 ml trifluoroacetic acid was stirred for 3 h at room temperature. The solvent was removed in vacuo and the residue suspended in 20 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 540 mg (94%) of the title compound as a white powder. MS m/e (%): 477 (M-H-, 100).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Cl:6].[C:8]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]>>[Cl:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:13][CH:14]=1
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: OC(CCl)CCCl
Product: CC(C)(C)c1ccc(OCC(O)CCCl)cc1

Procedure:
Utilizing the procedure of Preparation 16, 1,4-dichloro-2-butanol was reacted with 4-t-butylphenol to give white title compound, m.p. 45°-47° C. Petroleum ether (30°-60° C.) was the recrystallizing solvent.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl.Cl[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]Cl.C(N(CC)CC)C>C(O)CCC>[N:1]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: ClCCNCCCl
Reactant: Nc1ccc2[nH]ccc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: c1cc2cc(N3CCNCC3)ccc2[nH]1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 5-aminoindole (6.23 g, 47 mmol), bis(2-chloroethyl)amine hydrochloride (16.8 g, 96 mmol) and triethylamine (19 mL, 141 mmol) in butanol is heated at 100° C. for 8 hours, cooled to room temperature and concentrated in vacuo to give 9.46 g of 5-piperazin-1-yl-1H-indole.
Reaction SMILES: FC1C(C(O)=O)=C([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)C(C)=CC=1.[F:17][C:18]1[C:19](I)=[C:20]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[C:21]([OH:23])=[O:22]>>[F:17][C:18]1[C:19]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:20]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[C:21]([OH:23])=[O:22]
Reactant: Cc1cc(F)c(I)c(C(=O)O)c1
Reactant: Cc1ccc(F)c(C(=O)O)c1-n1nccn1
Product: Cc1cc(F)c(-n2nccn2)c(C(=O)O)c1

Procedure:
The title compound was prepared following the same general protocol as described for 6-fluoro-3-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A352 using 3-fluoro-2-iodo-5-methylbenzoic acid. MS (ESI) 222 (M+H).
Reaction SMILES: [S:1]=[C:2]1[NH:6][C:5]2=[C:7]([C:11]([O:13]C)=[O:12])[CH:8]=[CH:9][CH:10]=[C:4]2[O:3]1.O.[OH-].[Li+:17]>C1COCC1.O>[S:1]=[C:2]1[NH:6][C:5]2=[C:7]([C:11]([O-:13])=[O:12])[CH:8]=[CH:9][CH:10]=[C:4]2[O:3]1.[Li+:17]
Reactant: COC(=O)c1cccc2oc(=S)[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])c1cccc2oc(=S)[nH]c12
Temperature: 75 °C
Reaction time: 72 h
Yield: 93.2 %

Procedure:
To a solution of methyl 2-thioxo-2,3-dihydrobenzoxazole-4-carboxylate (150 mg, 0.72 mmol) in THF (6 mL) was added a solution of lithium hydroxide monohydrate (45.1 mg, 1.08 mmol) in H2O (3 mL). The reaction mixture was heated to 75° C. with stirring for 3 days, cooled down to room temperature and concentrated under reduced pressure to afford the lithium 2-thioxo-2,3-dihydrobenzoxazole-4-carboxylate (135 mg, 96.5%) as a yellow solid. MS consistent
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:14][CH2:13]1)[CH:7]=O)([O-:3])=[O:2].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:13][CH2:14][CH:15]([CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:16][CH2:17]1)[CH2:7][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)([O-:3])=[O:2]
Reactant: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)c([N+](=O)[O-])c1
Reactant: C1COCCN1
Product: O=[N+]([O-])c1cc(CN2CCOCC2)ccc1N1CCC(CN2CCCC2)CC1

Procedure:
Prepared from the product of Example 64 and morpholine.
Reaction SMILES: Cl.C1(C(=[N:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH:24]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:23]3)=[CH:18][CH:17]=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CCO>[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]2[CH2:27][CH2:26][CH2:25][CH:24]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:23]2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)CC1CCCC(c2ccc(N=C(c3ccccc3)c3ccccc3)cc2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CC1CCCC(c2ccc(N)cc2)C1
Yield: 47.8 %

Procedure:
Aqueous HCl (1 mL of a 1M solution) was added to ethyl (3-{4-[(diphenylmethylene)amino]phenyl}cyclohexyl)acetate (137 mg, 0.32 mmol) in EtOH (10 mL) with stirring. After 1 h the reaction mixture was basified with aqueous potassium carbonate (10 mL of a saturated solution and the mixture was extracted with Et2O (2×15 mL), washed with water (15 mL) and dried. Volatile material was removed by evaporation and the residue was purified by chromatography eluting with 0-35% EtOAc/isohexane to give the title compound (Intermediate 89) (40 mg, 48%) as a gum; MS m/e MH+ 262.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([NH:9][NH2:10])=[O:8].[C:15](Cl)(Cl)=[O:16]>>[Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]1[O:8][C:15](=[O:16])[NH:10][N:9]=1
Reactant: NNC(=O)c1sc2ccccc2c1Cl
Reactant: O=C(Cl)Cl
Product: O=c1[nH]nc(-c2sc3ccccc3c2Cl)o1

Procedure:
In the same way as above, 3-chlorobenzo(b)thiophene 2-carboxylic acid hydrazide was reacted with phosgene to give 3-chloro-2-(2-oxo-3H-1,3,4-oxadiazole-5-yl)-benzo(b)thiophene, mp. 218°-220°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:9]=1)[CH2:7][OH:8].[H-].[Na+].C([Li])CCC.[F:18][CH:19]([F:30])[CH:20]=[N:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH:19]([F:30])[F:18])=[C:6]([CH2:7][OH:8])[CH:9]=1
Reactant: OCc1cc(Cl)ccc1I
Reactant: COc1ccc(N=CC(F)F)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(NC(c2ccc(Cl)cc2CO)C(F)F)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 37.9 %

Procedure:
A solution of 5-chloro-2-iodobenzylalcohol (0.948 g, 3.53 mmol) in dry THF (27 mL) was added, rinsing with dry THF, to a stirred suspension of NaH (0.155 g, 3.89 mmol) in dry THF (9 mL) at 0° C. After 5 min the mixture was cooled to −78° C. and n-butyl-lithium (2.5 M in hexanes, 2.97 mL, 7 mmol) was added dropwise over 5 minutes. After a further 10 min, a solution of N-(2,2-difluoroethylidene)-N-(4-methoxyphenyl)amine (0.654 g, 3.53 mmol) in dry THF (9 mL) was added. After 1 h the mixture was quenched with excess saturated aqueous NH4Cl at −78° C. then was stirred at ambient temperature for 15 min. The solution was partitioned between EtOAc and brine. The EtOAc layer was dried (Na2SO4) and evaporated in vacuo and the residue was purified by flash column chromatography on silica (eluting with 5% methylene chloride, 5-30% ethyl acetate/hexanes gradient) to give (5-chloro-2-{2,2-difluoro-1-[(4-methoxyphenyl)amino]ethyl}phenyl)methanol (0.439 g) as an oil: MS 328.4 (M+1); 1H NMR (CDCl3, 400 MHz) δ 2.00 (br s, 1H), 3.70 (s, 3H), 4.14 (br s, 1H), 4.82 (m, 2H), 5.02 (m, 1H), 6.08 (dt, J=3.0 Hz, 56.0 Hz, 1H), 6.57 (d, J=9.0 Hz, 2H), 6.71 (d, J=9.0 Hz), 2H), 7.29 (dd, J=2.2 and 8.4 Hz, 1H), 7.40 (d, J=2.2 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][OH:14])[CH:11]=2)[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[CH:3]=1.[OH-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]([Cl:28])([Cl:27])[Cl:26])=[O:22]>CCOC(C)=O>[Cl:26][C:25]([Cl:28])([Cl:27])[CH2:24][O:23][C:21](=[O:22])[NH:1][C:2]1[N:6]([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][OH:14])[CH:11]=2)[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[CH:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)c1cc(N)n(-c2cnn(CCO)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cnn(CCO)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
A solution of Intermediate Ab (250 mg, 1.06 mmol) in EtOAc (3 mL) was treated with aqueous NaOH (1M, 1.9 mmol), followed by 2,2,2-trichloroethyl chloroformate (154 μL, 1.16 mmol) and the reaction mixture was stirred at RT for 1 h. The mixture was partitioned between EtOAc (10 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with a further 10 mL EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by FCC, using 0-40% EtOAc in DCM to afford the title compound as a colorless oil (300 mg, 70%). LCMS (Method 3): Rt 3.42 min, m/z 410, 412 [MH+].