Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([CH2:23]O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:20]1[CH2:21][CH2:22][CH:17]([CH2:23][O:15][C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[O:16])[CH2:18][CH2:19]1
Reactant: OCC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)OCC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (66.94 mmol; 15.35 g) in dichloromethane (100 mL) was added cyclohexylmethanol (55.79 mmol; 6.37 g), dimethylaminopyridine (1.12 mmol; 0.14 g) and dicyclohexylcarbodiimide (66.94 mmol; 12.83 g) and the resulting mixture was stirred for 3 hours at room temperature. The resulting solution was evaporated and the residue was dissolved in ethyl acetate (200 mL). The resulting solution was washed with a 1N hydrochloric acid solution (2×50 mL) and brine (50 mL), and dried over magnesium sulfate. After filtration and evaporation, the residue was purified via flash column chromatography ((eluent gradient: 0 to 5% EtOAc in heptane) to yield piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-cyclohexylmethyl ester after evaporation. MS (ESI) m/z 326.29 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][C:10]2=[O:14])[CH2:7]1)=[O:5])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+]>CCO>[CH2:15]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([C:9](=[CH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]2=[O:14])[CH2:7]1)=[O:5])[CH3:16]
Reactant: CCN(CC)C(=O)C1CN2CCC1C(=O)C2
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC)C(=O)C1CN2CCC1C(=O)C2=Cc1ccccc1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A mixture of 13 (34.6 g, 154 mmole), benzaldehyde (17.4 g, 164 mmole) and NaOH (6.5 g, 164 mmole) in EtOH (400 ml) was refluxed for 3 hours. After cooling the reaction mixture to room temperature, the resulting yellow crystal was collected by filtration and washed with cold EtOH and dried in vacuo to give 14 (38.4 g, 128 mmole). The filtrate was concentrated under reduced pressure to give a second crop (3.3 g, 11 mmole) (total 41.7 g, 139 mmole, 90%).
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Br:34][C:35]1[S:36][C:37]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[C:38]([C:40]([OH:42])=O)[N:39]=1.[NH2:51][C:52]1[CH:53]=[N:54][N:55]([CH3:74])[C:56]=1[N:57]1[CH2:63][C:62]([F:65])([F:64])[CH2:61][CH:60]([NH:66][C:67](=[O:73])[O:68][C:69]([CH3:72])([CH3:71])[CH3:70])[CH2:59][CH2:58]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:47]([O:46][C:44]([NH:43][C:37]1[S:36][C:35]([Br:34])=[N:39][C:38]=1[C:40]([NH:51][C:52]1[CH:53]=[N:54][N:55]([CH3:74])[C:56]=1[N:57]1[CH2:63][C:62]([F:65])([F:64])[CH2:61][CH:60]([NH:66][C:67](=[O:73])[O:68][C:69]([CH3:70])([CH3:71])[CH3:72])[CH2:59][CH2:58]1)=[O:42])=[O:45])([CH3:50])([CH3:49])[CH3:48]
Reactant: Cn1ncc(N)c1N1CCC(NC(=O)OC(C)(C)C)CC(F)(F)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CCC(NC(=O)OC(C)(C)C)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 6,6-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate (2.5 g, 6.67 mmol) in ethanol (100 mL) and water (10 mL) was added ammonium chloride (3.5 g, 65.0 mmol) and iron powder (3.0 g, 53.7 mmol). The reaction mixture was heated at 100° C. for 2.5 hr, before being cooled down at room temperature, filtered through Celite®, washed with MeOH and the filtrate concentrated under reduced pressure. The residue was dissolved in DCM (200 mL), quenched with a saturated solution of sodium hydrogencarbonate (300 mL) and a 10% solution of sodium sulfite (100 mL) and the mixture stirred for 30 min. The layers were separated and the aqueous layer extracted with DCM (100 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-30% EtOAc/isohexane) gave tert-butyl 1-(4-amino-1-methyl-1H-pyrazol-5-yl)-6,6-difluoroazepan-4-ylcarbamate as an orange foam (2.12 g). A solution of PyBOP (1.92 g, 3.70 mmol) and 2-bromo-5-(tert-butoxycarbonyl-amino)thiazole-4-carboxylic acid (795 mg, 2.46 mmol) in DCM (50 mL) was stirred at room temperature for 15 min. tert-Butyl 1-(4-amino-1-methyl-1H-pyrazol-5-yl)-6,6-difluoroazepan-4-ylcarbamate (850 mg, 2.46 mmol) and DIPEA (2.0 mL, 11.4 mmol) were added and the mixture stirred at room temperature for 18 hr. The reaction mixture was diluted with DCM (50 mL) and washed with a saturated solution of sodium hydrogencarbonate (100 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification of the residue via silica gel column chromatography (0-100% EtOAc/isohexane) gave tert-butyl 1-(4-(5-(tert-butoxycabonyl-amino)-2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6,6-difluoroazepan-4-ylcarbamate as a pale yellow foam (1.35 g, 77% over two steps). 1H NMR (400 MHz, CDCl3) δ 10.24 (s, 1H), 8.37 (s, 1H), 7.65 (s, 1H), 4.88 (s, 1H), 4.04 (s, 1H), 3.77 (s, 3H), 3.63-3.43 (m, 2H), 3.38-3.24 (m, 2H), 2.52-2.40 (m, 2H), 2.13-2.05 (m, 1H), 1.99 (s, 1H), 1.53 (s, 9H), 1.43 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][CH:10]([CH3:18])[C:11]([O:16]C)=[CH:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1.Cl(O)(=O)(=O)=O.[CH2:34](Cl)Cl>>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][CH:10]([CH3:18])[C:11](=[O:16])[CH2:12][C:13]([O:15][CH3:34])=[O:14])=[CH:7][CH:6]=1
Reactant: COC(=CC(=O)O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Reactant: ClCCl
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)CC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of the methyl ester of 4-[4-(2-chloro-4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoic acid (0.5 g), 35% aqueous perchloric acid (5 ml.) and methylene dichloride (5 ml.) is stirred at RT for 4 days. Then the solution is extracted with methylene dichloride. The combined extracts are washed, dried and evaporated. The residue is purified by prep. thin layer chromatography using 20% ethyl acetate/hexane to yield methyl 4-[4-(2-chloro-4-trifluoromethylphenoxy)phenoxy]-3-oxopentanoate.
Reaction SMILES: [NH2:1][C:2]1[C:22]([Br:23])=[CH:21][C:5]2[C:6]([C:17]([NH:19][CH3:20])=[O:18])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl.N1C=CC=CC=1>[Br:23][C:22]1[C:2]([NH:1][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:3][C:4]2[O:8][C:7]([C:9]3[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[CH:13][CH:14]=3)=[C:6]([C:17]([NH:19][CH3:20])=[O:18])[C:5]=2[CH:21]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)c1c(-c2ccc(C#N)cc2)oc2cc(N)c(Br)cc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(C#N)cc2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A mixture of 6-amino-5-bromo-2-(4-cyanophenyl)-N-methylbenzofuran-3-carboxamide (300 mg, 0.80 mmol) in DCM (2 mL) and pyridine (2 mL) was stirred at room temperature and MsCl (278 mg, 2.4 mmol) was added dropwise. The reaction was stirred at room temperature for 8 h. The reaction was washed with 1N HCl and extracted with DCM, dried with Na2SO4 and concentrated to give 5-bromo-2-(4-cyanophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (260 mg, yield: 72%). MS (M+H)+: 448/450.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:25])[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:25])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1cccc(Cn2c3cccc(O)c3c3c(C(N)=O)cccc32)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(C#N)c1
Reaction time: 0.02 h
Yield: 112.1 %

Procedure:
40% Methanolic Triton B (0.06 mL, 0.13 mM) was added to a solution of the 9-[(3-cyanophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (34.1 mg, 0.1 mM) in 5 mL DMF at room temperature. After 1 minute, tert-butyl bromoacetate (40 mg, 0.2 mM) was added and the resultant mixture stirred at room temperature for 24 h. The mixture was diluted with ethyl acetate, washed four times with H2O, 1 N HCl, H2O, sat. NaHCO3, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was triturated with hexane to afford 51 mg (100%) of the {9-[(3-cyanophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester as a white solid. 1H NMR (CDCl3) δ 7.55 (d, 1H, J=8 Hz), 7.5-7.2 (m, 7H), 6.95 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.3 (br s, 1H), 6.1 (br s, 1H), 5.5 (s, 2H), 4.8 (s, 2H), and 1.5 (s, 9H). IR (KBr, cm−1) 2228, 1748, and 1669. MS (ES) m/e 455, 456.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([OH:22])[CH:11]=[N+:12]([O-])[C:13]=3[C:17]([O:19][CH3:20])=[O:18])[C:8]2=[O:23])=[CH:4][CH:3]=1.C(OC(=O)C)(=[O:28])C.C[O-].[Na+]>>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([OH:22])[C:11](=[O:28])[NH:12][C:13]=3[C:17]([O:19][CH3:20])=[O:18])[C:8]2=[O:23])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c2c(c(O)c[n+]1[O-])C(=O)N(Cc1ccc(F)cc1)CC2
Reactant: CC(=O)OC(C)=O
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)c1[nH]c(=O)c(O)c2c1CCN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To methyl 6-(4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate 2-oxide (0.178 g, 0.514 mmol) was added acetic anhydride (0.157 g, 1.542 mmol) and refluxed. After 1 hour, the reaction mixture was concentrated under vacuum, then sodium methoxide (30 wt. % in methanol, 0.083 g, 1.540 mmol) was added. After stirring at room temperature for 1 hour, the product mixture was concentrated under vacuum. The residue was purified by reverse phase HPLC eluting with 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to afford the title compound as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11])=[O:6].Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(#N)C>[NH2:12][C:10]([C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[NH:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:30]1[CH2:31][CH2:32][CH:27]([C:25](=[O:26])[C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=2)[CH2:28][CH2:29]1)=[O:11]
Reactant: NC(=O)c1ccccc1NC(=O)CCCCl
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC(=O)c1ccccc1NC(=O)CCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 81 %

Procedure:
A mixture of 7.2 parts of 2-[(4-chloro-1-oxobutyl)amino]benzamide, 7.3 parts of (4-fluorophenyl) (4-piperidinyl)methanone hydrochloride, 10.1 parts of N,N-diethylethanamine and 120 parts of acetonitrile is stirred and refluxed for 24 hours. The reaction mixture is evaporated and water is added to the residue. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 10 parts (81%) of N-[2-(aminocarbonyl)phenyl]-4-(4-fluorobenzoyl)-1-piperidinebutanamide as a residue.
Reaction SMILES: CC[O-].[Na+].[N+:5]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)([O-:7])=[O:6].[CH2:16](P(=O)(OCC)OCC)[P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>CO>[CH2:19]([O:18][P:17]([CH:16]=[CH:12][C:11]1[CH:14]=[CH:15][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=1)(=[O:24])[O:21][CH2:22][CH3:23])[CH3:20]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CO
Product: CCOP(=O)(C=Cc1ccc([N+](=O)[O-])cc1)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium ethylate (4.95 g, 72.8 mmol) is added to a solution of 4-nitrobenzaldehyde (10 g, 66.2 mmol) in 200 ml of methanol, and tetraethyl methylenediphosphonate (21 g, 72.8 mmol) is then added dropwise. After 2 h of stirring at room temperature, a further 0.43 g of sodium ethylate and 2 g of tetraethyl methylene diphosphonate are added. After 15 min of stirring at room temperature, the ethanol is evaporated off under vacuum and the residue is bipartitioned in a water/ethyl acetate mixture. The organic phase is washed with water, then dried (MgSO4) and evaporated under vacuum to give the expected product.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:14].O.O.[C:17](O)(=[O:21])[C:18](O)=[O:19]>Cl>[OH:19][C:18]1[C:17]([OH:21])=[N:14][C:3]2[CH:4]=[CH:5][C:6]3[C:7]([C:12]#[N:13])=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[N:1]=1
Reactant: O=C(O)C(=O)O
Reactant: N#Cc1cccc2c(N)c(N)ccc12
Agent: Cl
Solvent: O
Product: N#Cc1cccc2c1ccc1nc(O)c(O)nc12
Temperature: 25 °C
Yield: 44.7 %

Procedure:
A mixture of 0,6 g (3,3 mmol) 1,2-diamino-5-cyanonaphthalene and 1,4 g oxalic acid dihydrate in 35 ml 0,5N hydrochloric acid was refluxed for 3 h. After cooling to 25° C., the precipitate was filtered off and washed with water. The crude product was recrystallized (dimethylsulfoxide-methanol) to give 0,35 g (45%) 2,3-dihydroxy-7-cyano-benzo[f]quinoxaline, m.p. >300° C. IR (KBr): 2190 cm-1 (nitrile function).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([N:17]=[C:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:13](=[O:31])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([NH:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:22][CH2:23]2)[C:13](=[O:31])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=NN2CCN(C(=O)OCc3ccccc3)CC2=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NN2CCN(C(=O)OCc3ccccc3)CC2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The resultant 4-benzyloxycarbonyl-1-{[1-(tert-butoxycarbonyl)-4-piperidinylidene]amino}-2-piperazinone was dissolved in methanol (40 ml), combined with acetic acid (1.2 g) with cooling on ice, followed by sodium cyanoborohydride (943 mg), and then stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and brine, dried, concentrated and purified by a column chromatography (ethyl acetate) to obtain 4-benzyloxycarbonyl-1-[1-(tert-butoxycarbonyl)-4-piperidinylamino]-2-piperazinone (3.7 g) as a colorless amorphous material.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[NH:15]1CCOCC1>ClCCl>[NH2:15][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3]
Reactant: C1COCCN1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Yield: 99.2 %

Procedure:
5-Chlorosulfonyl-2-indolinone (2.3 g) and 2.2 g morpholine in 50 mL of dichloromethane was stirred for 3 hours at room temperature. The precipitate was collected by vacuum filtration, washed with ethyl acetate and hexane and dried to give 2.09 g (74%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].CCCCCC.C([Li])CCC.[F:18][C:19](=[CH2:22])[CH:20]=[O:21]>O1CCCC1>[F:18][C:19]([CH:20]([OH:21])[C:4]#[C:3][C:2]([CH3:6])([CH3:5])[CH3:1])=[CH2:22]
Reactant: C=C(F)C=O
Reactant: C#CC(C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(F)C(O)C#CC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
Ten grams (0.122 mole) of 3,3-dimethyl-1-butyne was dissolved in 100 ml of anhydrous tetrahydrofuran, and the resulting solution was cooled to -40° C. or less in a dry ice-acetone bath. Under a stream of a nitrogen gas, 81.13 ml of a 1.5M hexane solution of n-butyllithium was added dropwise at -40° C. or less with stirring. After aging the reaction solution at -50° C. for 30 minutes, 9.01 g (0.122 mole) of 2-fluoroacrolein was added dropwise at -50° C. or less. After the reaction mixture was allowed to stand overnight at room temperature, it was poured into 200 ml of ice water and extracted with two 100-ml portions of ethyl acetate. The organic layers were combined, washed once with 100 ml of a saturated aqueous sodium chloride solution and concentrated under reduced pressure. The resulting oily product was distilled under reduced pressure to obtain 11 g of 2-fluoro-3-hydroxy-6,6-dimethylhept-1 -ene-4-yne (bp20, 86° C.).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[C:11]2[N:10]=[C:9](Cl)[NH:8][C:7]=2[CH:6]=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1.[F:19][C:20]([F:34])([F:33])[C:21]1[C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:23][CH:24]=[CH:25][CH:26]=1>>[F:1][C:2]([F:18])([F:17])[C:3]1[C:11]2[N:10]=[C:9]([N:30]3[CH2:31][CH2:32][N:27]([C:22]4[C:21]([C:20]([F:34])([F:19])[F:33])=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:28][CH2:29]3)[NH:8][C:7]=2[CH:6]=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: FC(F)(F)c1cc(C(F)(F)F)c2nc(Cl)[nH]c2c1
Product: FC(F)(F)c1cc(C(F)(F)F)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1

Procedure:
The benzoimidazole from step (b) above (115 mg, 0.4 mmol) and 1-(3-trifluoromethylpyridin-2-yl)piperazine (140 mg, 0.6 mmol, Maybridge) reacted under the conditions of Example 3c to give the title compound as a white solid. M.p. 142° C. MS (ESI, pos. ion) m/z: 484 (M+1).
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6](=[O:18])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[C:9]([N+:15]([O-])=O)[CH:8]=1>[Fe].C(O)(=O)C>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([C:6]([O:5][CH3:4])=[O:18])=[CH:8][C:9]=1[NH2:15])=[O:14]
Reactant: COC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1ccc(C=O)c(N)c1
Reaction time: 1 h
Yield: 85 %

Procedure:
To a 1:1 mixture of ethanol and acetic acid was added methyl4-formyl-3-nitrobenzoate (1 eq) and Fe dust (3 eq) was added in portions. The reduction was complete in 1 h. The reaction mixture was filtered and then concentrated and partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate and dried and concentrated to give methyl 4-formyl-3-aminobenzoate in 85% yield. ES/MS m/z 180 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C)=[CH:6][C:5]([I:10])=[CH:4][C:3]=1[O:11]C.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([I:10])=[CH:4][C:3]=1[OH:11]
Reactant: COc1cc(I)cc(OC)c1Cl
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1cc(I)cc(O)c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.5 %

Procedure:
A solution of 2-chloro-5-iodo-1,3-dimethoxybenzene (3) (7.15 g, 23.9 mmol) in DCM (20 mL) was cooled to 0° C. Boron tribromide (11.3 mL, 120 mmol) was added dropwise over 30 min and the reaction mixture was allowed to slowly warm to RT and stirred for 20 h. The reaction mixture was cautiously added to iced water (30 mL) with stirring. The phases were separated and the organic solution was washed with brine (3×30 mL). The solvent was removed in vacuo to afford 2-chloro-5-iodobenzene-1,3-diol (4) (4.17 g, 64% yield) as a white solid: m/z 269 [M−H]− (ES−).
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([CH2:21][C:22](O)=[O:23])[C:6](=[O:25])[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:4]=1[CH3:36])#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:61][CH2:62][CH2:63][OH:64].C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:18])=[O:19])[N:7]([CH2:21][C:22]([NH:61][CH2:62][CH2:63][OH:64])=[O:23])[C:6](=[O:25])[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=2)[C:4]=1[CH3:36])#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)NCCO)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 81.9 %

Procedure:
The reaction was carried out under argon. 2-[(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]acetic acid (45 mg, 87 μmol; Example 21) was initially charged in DMF (1.5 ml), HATU (165 mg, 434 μmol, 5 eq.) was added at 0° C. and the mixture was stirred for 20 min. 2-Aminoethanol (26.5 mg, 434 μmol, 5 eq.) and N,N-diisopropylethylamine (56 mg, 434 μmol, 5 eq.) were then added, and the mixture was stirred at RT for 16 h until complete conversion had been achieved (HPLC control). The reaction mixture was then concentrated under reduced pressure, and the crude product was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a colorless solid (40 mg, 82% of theory).
Reaction SMILES: [Li]CCCC.I[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1.C(O[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)(C)C>C1COCC1>[CH3:32][C:27]1([CH3:33])[C:28]([CH3:31])([CH3:30])[O:29][B:25]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=2)[O:26]1
Reactant: CCCCCCCCc1ccc(I)cc1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-BuLi (16.6 mL, 1.6 M in hexanes) was added over 10 minutes to a solution of 1-iodo-4-octylbenzene from Part A (6.9 g, 21.8 mmol) in dry THF (100 mL) at −78° C. under a nitrogen atmosphere. The mixture was stirred for another 10 minutes at −78° C. 2-Isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (6.21 mL, 30.4 mmol) was subsequently added dropwise to the mixture and stirring was continued at room temperature overnight. The reaction was then quenched with distilled water, and THF was removed under vacuum. The product was then extracted into diethyl ether and the organic layer was washed with brine, dried over MgSO4, filtered and evaporated in vacuo to give 6.38 g of 4,4,5,5-tetramethyl-2-(4-octylphenyl)-1,3,2-dioxaborolane as a colorless oil. The product was used in the next step without further purification.