Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][CH:8]1[C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[C:18]([CH3:19])[C:13]=2[O:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C>C1COCC1>[Cl:20][C:16]1[CH:17]=[C:18]([CH3:19])[C:13]2[O:12][CH2:11][CH2:10][CH2:9][CH:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[C:14]=2[CH:15]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Cc1cc(Cl)cc2c1OCCCC2N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCS(=O)(=O)NC1CCCOc2c(C)cc(Cl)cc21
Reaction time: 8 h
Yield: 85.8 %

Procedure:
0.86 g of ethanesulfonyl chloride was added dropwise with ice-cooling to a solution of 1.3 g of 5-amino-7-chloro-9-methyl-2,3,4,5-tetrahydro-1-benzoxepine and 2.4 g of triethylamine in 30 ml of THF. The mixture was allowed to come to room temperature and was stirred overnight, and the solvent was distilled off in vacuo. After stirring the residue with water, the deposited product was filtered off with suction and dried in vacuo. 1.6 g of 7-chloro-9-methyl-5-(N-ethylsulfonylamino)-2,3,4,5-tetrahydro-1-benzoxepine were obtained, m.p. 144-145° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][CH2:11][CH2:12][CH3:13].C([O-])([O-])=O.[Na+].[Na+].[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>C(Cl)Cl>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:20](=[O:23])[CH2:21][CH3:22]
Reactant: CCCNC1Cc2ccccc2C1
Reactant: CCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCN(C(=O)CC)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a solution of N-indan-2-yl-propylamine (9.5 g, 54.3 mmol) in methylene chloride was added aq. Na2CO3 (150 mL, 3%) followed by propionyl chloride (7.5 mL, 86.3 mmol). The mixture was stirred at ambient temperature for 1 h. The layers were separated and the organic layer was washed with water, separated and dried (MgSO4). Evaporation of the solvent yielded 7 g (56%) of N-indan-2-yl-N-propyl-propionamide. MS m/e 231 (1, M+), 116 (100), 117 (23), 57 (11), 146 (9).
Reaction SMILES: O[C:2]1([C:17]2[C:25]([OH:26])=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=2)[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]1=[O:16].C(N(C(C)C)CC)(C)C.S(Cl)(Cl)=O>ClCCl.[Zn]>[OH:26][C:25]1[C:17]([CH:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]2=[O:16])=[CH:18][C:19]2[O:23][CH2:22][O:21][C:20]=2[CH:24]=1
Reactant: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2cccnc21
Agent: [Zn]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2cccnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a solution of 3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (4.00 g, 11.2 mmol) in anhydrous dichloromethane (80.0 mL) was added diisopropylethylamine (6.10 mL) and thionyl chloride (2.77 g, 23.5 mmol) under nitrogen at 0° C. The reaction mixture was stirred at 0° C. for 1 h and concentrated in vacuo to dryness. The residue was dissolved in THF/acetic acid (7:3, 100 mL) followed by the addition of Zn dust (3.08 g, 47.1 mmol) in one portion. The reaction mixture was stirred at ambient temperature for 16 h, filtered and the residue was washed with ethyl acetate (30.0 mL). The filtrate was concentrated in vacuo to dryness. The residue was dissolved in ethyl acetate (200 mL), washed with saturated ammonium chloride (3×50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography to give the title compound (2.92 g, 76%): 1H NMR (300 MHz, CDCl3) δ 8.64 (br, 1H), 8.26 (d, 1H), 7.52 (d, 1H), 7.05 (dd, 1H), 6.53 (s, 1H), 6.25 (s, 1H), 5.84 (d, 2H), 5.02 (s, 1H), 3.86-3.75 (m, 2H), 1.76-1.67 (m, 2H), 1.33-1.28 (m, 4H), 0.85 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 178.5, 157.4, 150.9, 147.8, 147.5, 141.6, 133.2, 121.7, 118.7, 114.1, 106.4, 101.2, 101.1, 46.5, 39.8, 28.9, 27.3, 22.3, 13.9; MS (ES+) m/z 341 (M+1).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:14][N:13]=[C:4]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:1][C:2]1=[O:3]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1Nc2ccccc2C1=NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a suspension of 73.6 g of isatin in 1.2 l of ethanol was added a solution of 64.1 g of hydroxylamine hydrochloride and 64.1 g of sodium acetate in 500 ml of water. The mixture was stirred at room temperature for 30 minutes and concentrated. The residue was washed with water and recrystallized from ethanol to give 51.8 g (64%) of 3-(hydroxyimino)indolin-2-one as yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.[NH:28]1[CH2:31][CH2:30][CH2:29]1.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[N:28]1([C:25]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[O:27])[CH2:31][CH2:30][CH2:29]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Reactant: C1CNC1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.2 %

Procedure:
A mixture of 1-methyl-5-(2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 223 μmol), azetidine (60.2 μl, 893 μmol), propylphosphonic anhydride (50% in ethyl acetate, 329 μl, 558 μmol) and N,N-diisopropylethylamine (114 μl, 669 μmol) in tetrahydrofurane (7 ml) is stirred for 18 hours at room temperature. The solvent is evaporated and the residue triturated with sat. aqueous sodium bicarbonate solution. The solid is collected by filtration, washed with water and dried affording 4-(azetidine-1-carbonyl)-1-methyl-N-(2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (28 mg, 31.2%) as a light brown solid. mp.: 253-4° C. MS: m/z=403.4 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH2:7])=[C:5]([C:8]([O:10][CH3:11])=[O:9])[S:4][C:3]=1[CH3:12].C1N=CN([C:18](N2C=NC=C2)=[S:19])C=1.O>CN(C=O)C>[CH3:12][C:3]1[S:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[C:6]2[C:2]=1[NH:1][C:18](=[S:19])[NH:7]2
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1sc(C)c(N)c1N
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C)c2[nH]c(=S)[nH]c12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 3,4-diamino-2-methylthiophene-5-carboxylate (1.0 g) and N,N'-thiocarbonyldiimidazole (1.1 g) in DMF (5 ml) was stirred at 50° C. for one hour. To the reaction mixture was added water to give crystals. Recrystallization from DMF-water afforded colorless prisms (1.2 g, quantitatively), m.p. 285°-288° C. (dec.)
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[Cl:8].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1.ClCCl>[Cl:8][C:7]1[N:6]=[C:5]([CH3:9])[N:4]=[C:3]2[C:2]=1[N:1]=[C:19]([C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[Cl:16])[N:10]2[CH2:11][C:12]([CH3:15])([OH:14])[CH3:13]
Reactant: Cc1nc(Cl)c(N)c(NCC(C)(C)O)n1
Reactant: O=Cc1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1nc(Cl)c2nc(-c3ccccc3Cl)n(CC(C)(C)O)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
Heat a mixture of 1-(5-amino-6-chloro-2-methylpyrimidin-4-ylamino)-2-methylpropan-2-ol (0.5 g, 0.002 mol), 2-chlorobenzaldehyde (0.6 g, 0.004 mol), p-toluene sulfonic acid (0.1 g) and molecular sieves (1.0 g) in toluene (25 mL) to 130° C. for 16 h. Remove the molecular sieves by filtration through diatomaceous earth, and concentrate the filtrate under reduced pressure to give a residue. Dissolve the residue in dry dichloromethane (5 mL) and add DDQ (0.47 g, 0.002 mol) at 0° C. Stir the reaction mixture at room temperature for 2 h. Dilute the reaction mixture with dichloromethane, wash with 1 N sodium hydroxide solution, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give a residue. Purify the residue on a silica gel column eluting with methanol:dichloromethane (2:98) to give the title compound (0.4 g). ES/MS m/z 351 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:12]O.C([O-])=O.[Na+]>C(O)=O>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:10])[C:2]=1[OH:1])#[N:12]
Reactant: Cc1cccc(C=O)c1O
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Product: Cc1cccc(C#N)c1O
Yield: 82.5 %

Procedure:
A solution of 2-hydroxy-3-methylbenzaldehyde (18.6 g), hydroxylamine hydrochloride (14.2 g) and sodium formate (19.2 g) in formic acid (200 mL) was heated at reflux for 18 h, then cooled and partitioned between DEE/water. The organic layer was washed with water, saturated aqueous sodium bicarbonate and brine, then dried over sodium sulfate and concentrated in vacuo to afford a solid. Recrystallization from diethyl ether/petroleum ether afforded the title compound as colorless crystals (15.0 g).
Reaction SMILES: [O:1]=[C:2]1[CH:8](C)[O:7][CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2Cl)[C:5]2[CH:17]=[C:18](Cl)[CH:19]=[CH:20][C:4]=2[NH:3]1.C(=O)([O-])O.[Na+].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.O>O1CCCC1>[O:1]=[C:2]1[CH2:8][O:7][CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1
Reactant: CC1OC(c2ccccc2Cl)c2cc(Cl)ccc2NC1=O
Agent: O=C([O-])O
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1COC(c2ccccc2)c2ccccc2N1

Procedure:
To a solution of Compound 4 prepared in Example 1-(1) (3.45 g) and sodium hydrogencarbonate (5.5 g) in tetrahydrofuran (50 ml) is added phosphorus pentasulfide (5.5 g) at 50° C., and the mixture is refluxed for 1 hour, poured into water, and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium salfate, and concentrated under reduced pressure. The residue is purified on column chromatography (silica gel/methylene chloride). The resulting light yellow crystals are washed with n-hexane to give crystalline Compound 5 (3.1 g), which is recrystallized from ethyl acetate-n-hexane to give the title compound as pure crystals, mp. 193°-195° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:12](#[N:15])[CH:13]=[CH2:14].Cl>CO.O1CCOCC1>[C:12]([CH2:13][CH2:14][C:2]([CH2:14][CH2:13][C:12]#[N:15])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])#[N:15]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=CC#N
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)C(CCC#N)(CCC#N)C(=O)OCC
Temperature: 60 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of diethyl malonate (1 g, 6.2 mmol) and Triton B (40% in MeOH, 0.13 g, 0.31 mmol) in dioxane (1.2 cm3) was added dropwise acrylonitrile (0.658 g, 12.4 mmol) and the mixture was stirred at 60° C. overnight. The mixture was then cooled to room temperature and neutralized with 0.1M HCl (3 cm3) and poured to ice-water (10 cm3). Crystals precipitated during 30 min. These were collected by filtration and recrystallised from EtOH (cooling in freezer before filtering off) to give diethyl 2,2-bis(2-cyanoethyl)malonate (1.25 g, 75.8%) as a white solid, mp 62.2-63.5° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:14]=[O:15])C1C=CC=CC=1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].O.C([O-])(=O)C.[Na+]>ClCCCl.O>[CH:14]([C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:16][C:17]=1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:15]
Reactant: CN(C=O)c1ccccc1
Reactant: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(C(=O)OCc2ccccc2)[nH]c2ccccc12
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A mixture of 6.5 ml (70 mmol) of phosphorus oxychloride and 9.3 ml (70 mmol) of N-methylformanilide was stirred at ambient temperature. The resulting mixture was diluted with 90 ml of 1,2-dichloroethane, treated with 15.0 g (59.8 mmol) of benzyl indole-2-carboxylate, and heated at reflux for 1 h. After being allowed to cool for 5 min, the warm solution was poured into an ice-cold solution of 60 g of sodium acetate hydrate in 200 ml of water. The resulting mixture was stirred for 1 h, filtered, and the yellow solid was washed twice with water and twice with ether, and air-dried. The filtrate was treated with 400 ml of hexane and filtered. The combined solids were digested with hot ethyl acetate, cooled to 0° C., and filtered to give 13.41 g (80%) of the desired compound as an off-white solid. 1H NMR (CDCl3 /CD3OD) δ 5.50 (s,2H), 7.3-7.55 (m, 8H), 8.38 (d,J=9 Hz,1H). Mass spectrum: (M+H)+ =280.
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Cl:14])[N:3]=1.[NH:15]1[CH2:19][CH2:18][C@H:17]([CH2:20][OH:21])[CH2:16]1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:14][C:4]1[N:3]=[C:2]([N:15]2[CH2:19][CH2:18][C@H:17]([CH2:20][OH:21])[CH2:16]2)[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=1
Reactant: OC[C@H]1CCNC1
Reactant: Cn1cnc2cc(Cl)nc(Cl)c2c1=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnc2cc(Cl)nc(N3CC[C@H](CO)C3)c2c1=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 5,7-dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (270 mg, 1.17 mmol), (S)-pyrrolidin-3-ylmethanol (1.40 mmol), Hunig's base (1.02 mL, 5.85 mmol) and dioxane (4 mL) was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and worked-up. The residue was purified using slilica gel flash column chromatography (eluent: 0-10% methanol in dichloromethane) to afford (S)-7-chloro-5-(3-(hydroxymethyl)pyrrolidin-1-yl)-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][N:32]=1)[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=[O:17].[C:33]([O:37][C:38]([C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43](O)=[O:44])=[O:39])([CH3:36])([CH3:35])[CH3:34].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH2:9]([N:8]([CH2:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:43]([C:42]2[CH:41]=[C:40]([CH:48]=[CH:47][CH:46]=2)[C:38]([O:37][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:39])=[O:44])=[C:3]([C:13]2[CH:14]=[C:15]([C:16](=[O:17])[NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)[CH:30]=[CH:31][N:32]=2)[CH:4]=1)[CH3:10]
Reactant: CC(C)(C)OC(=O)c1cccc(C(=O)O)c1
Reactant: CCN(CC)c1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a mixture of 2-(2-amino-5-(diethylamino)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide (25a, 6.33 mmol, 2.8 g), 3-(tert-butoxycarbonyl)benzoic acid (7.60 mmol, 1.69 g) and DIEA (31.65 mmol, 4.09 g) in DMF (15 mL) was added HATU (7.6 mmol, 2.89 g). The mixture was stirred at 60° C. for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water (2×), sat. aqueous NaHCO3 (1×), brine (1×), dried and concentrated. The residue was purified by column to give a yellow solid (3.9 g, 95%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](OC)=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[CH:13](=O)[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].Cl.[CH3:26]O>O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:26])=[CH:4][C:3]=1[C:10](=[O:12])[CH:11]=[CH:13][CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CO
Reactant: O=CC=Cc1ccccc1
Reactant: COc1ccc(O)c(C(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(O)c(C(=O)C=CC=Cc2ccccc2)c1
Reaction time: 8 h

Procedure:
2'-Hydroxy-5'-methoxyacetophenone (4.1 g, 22 mmole) and cinnamaldehyde (3.35 g, 25 mmole) were dissolved in minimum methanol (2.5 mL). Concentrated sodium hydroxide (12.5 mL, 50%) was added, and the mixture was kept on ice for 8 hr. The resultant solid was suspended in water and acidified using HCl (4N). The oil that separated was dissolved in ethanol and crystallized from ethanol/water to give 1-(2-hydroxy-5-methylphenyl)-5-phenylpenta-2,4-dien-1-one (1.2 g) as red-brown powder. Mass (CI--NH3) m/z 281 (M++1, base). 1H NMR (CDCl3).3.9(s, 3H, CH3),6.95-7.8(m, 12H). The above compound (170 mg, 0.6 mmole) was dissolved in a mixture of ethanol (3.5 mL) and acetone (4 mL). Sodium hydroxide 1N (1 mL) and hydrogen peroxide (1 mL, 35%) were added, and the solution was stirred 6 hr. at room temperature. The mixture was precipitated by adding water and HCl and purified on preparative TLC (petroleum ether-ethyl acetate) to give compound 15, mp 160-163° C. mass (CI NH3) m/z 297(M++1,base). 1H NMR (CDCl3) 3.9(s,3H,CH3), 4.45(d,J=12 Hz,1H), 4.8(m,1H), 6.55(dd,1H), 6.9-7.6(m,9H).
Reaction SMILES: Cl.[CH:2]1([CH:7]([C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([N:16]3[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[N:17]3)=[C:11]([CH3:25])[CH:10]=2)[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].F[C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][N:34]=1>CN(C)C=O.O>[CH:2]1([CH:7]([NH:8][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][N:34]=2)[C:9]2[CH:10]=[C:11]([CH3:25])[C:12]([N:16]3[CH:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:18]=[N:17]3)=[C:13]([CH3:15])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1cc(C(N)C2CCCC2)cc(C)c1-n1cc(C(F)(F)F)cn1
Reactant: COC(=O)c1ccc(F)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(c2cc(C)c(-n3cc(C(F)(F)F)cn3)c(C)c2)C2CCCC2)nc1
Temperature: 85 °C
Reaction time: 15 h

Procedure:
To a mixture of (+/−)-cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine hydrochloride (1.002 g, 2.680 mmol) and potassium carbonate (1.51 g, 10.7 mmol) in N,N-dimethylformamide (5.36 mL) was added methyl 6-fluoronicotinate (472 mg, 2.95 mmol). The reaction was heated to 85° C. After 15 h, the reaction was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (3×50 mL). The combined organics were dried (Na2SO4) and filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (ethyl acetate/heptane) gave methyl (+/−)-6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methyl)amino)nicotinate. 1H NMR (400 MHz, CDCl3, δ): 8.67 (d, J=1.6 Hz, 1H), 7.99 (dd, J=9.0, 2.0 Hz, 1H), 7.93 (s, 1H), 7.75 (s, 1H), 7.12 (s, 2H), 6.28 (d, J=9.0 Hz, 1H), 4.43-4.33 (m, 1H), 3.87 (s, 3H), 2.36-2.23 (m, 1H), 2.04-1.97 (m, 7H), 1.77-1.41 (m, 6H), 1.37-1.28 (m, 1H). MS (M+1): 473.2.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:19])=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=2)[C:13]#[N:14])[CH:8]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:19][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:31]([C:26]2[NH:27][C:28]3[C:24]([CH:25]=2)=[CH:23][C:22]([O:21][CH3:20])=[CH:30][CH:29]=3)=[O:32])=[CH:8][C:7]=1[O:9][C:10]1[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
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: COc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3)cc2c1
Yield: 37.8 %

Procedure:
N-({4-Chloro-3-[(3-chloro-5-cyanophenyl)oxy]phenyl}methyl)-5-(methyloxy)-1H-indole-2-carboxamide was prepared in a similar manner as described herein from 3-{[5-(aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile (0.025 g, 0.085 mmol), 5-(methyloxy)-1H-indole-2-carboxylic acid, (0.025 g, 0.13 mmol), HATU (0.05 g, 0.13 mmol), DIPEA (0.025 mL, 0.13 mmol) and DMF (1 mL). The crude material was purified by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were neutralized and extracted with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound (0.015 g, 36%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.42 (d, 1H), 8.98 (t, 1H), 7.76 (d, 1H), 7.59 (d, 1H), 7.43 (dd, 1H), 7.35 (d, 1H), 7.25-7.28 (m, 2H), 7.23 (d, 1H), 7.03 (dd, 2H), 6.80 (dd, 1H), 4.48 (d, 2H), 3.72 (s, 3H). MS: m/z 466.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[O-]S(C(F)(F)[F:19])(=O)=O.ClC1C=[N+](F)C=C(Cl)C=1>C(Cl)Cl>[F:19][C:11]1[C:2]([OH:1])=[CH:3][C:4]([O:12][CH3:13])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: COC(=O)c1ccc(O)cc1OC
Agent: F[n+]1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1cc(F)c(O)cc1OC
Temperature: 25 °C

Procedure:
To a stirred solution of the methyl 4-hydroxy-2-methoxybenzoate (1 g, 5 mmol, from Step 3) in CH2Cl2 (20 mL) was added 3,5-dichloro-1-fluoropyridinium triflate (2.25 g, 6 mmol). The solution was refluxed for 48 h and then cooled to ambient temperature and stripped down under reduced pressure. The crude oil was purified by pressurized silica gel column chromatography using 99:1 CH2Cl2 :MeOH. Evaporation of the CH2Cl2 :MeOH mixture gave the desired methyl 5-fluoro-4-hydroxy-2-methoxybenzoate as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.[Li]CCCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C>C1COCC1>[F:9][C:5]1[CH:4]=[CH:3][C:2]([B:15]([OH:20])[OH:16])=[CH:7][C:6]=1[CH3:8]
Reactant: Cc1cc(Br)ccc1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(B(O)O)ccc1F
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 84 %

Procedure:
5-Bromo-2-fluorotoluene (6 g, 31.7 mmol) was dissolved in dry THF (50 mL) and cooled to −78° C. under N2. n-BuLi (14 mL, 2.5M solution in THF) was added slowly using a dry syringe. Cloudiness appeared. The reaction was stirred for 40 minutes at −78° C. Triisopropyl borate (22 mL, 95 mmol) was slowly added while stirring. The reaction was allowed to warm to room temperature. Stirring continued for an additional 2 hours. A pale yellow, cloudy solution formed. (TLC (1:2 ethyl acetate/hexanes)) indicated disappearance of the starting material. The reaction was quenched by adding 10% aqueous NaOH (200 mL). After stirring for 45 minutes, 10% citric acid solution (300 mL) was added until, pH ˜5.0. The product was extracted with ethyl acetate (500 mL). The organic phase was washed with brine and dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide an off white solid (yield: 4.1 g, 84%).