Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]1[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.[CH3:19][NH2:20].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C1COCC1>[F:1][CH:2]1[CH:7]([NH:20][CH3:19])[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1
Reactant: CN
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CNC1CCN(C(=O)OCc2ccccc2)CC1F
Reaction time: 2 h

Procedure:
To a solution of 9.4 g (37.5 mmol) of 2-2 in 150 mL of 1,2-dichloroethane was added 37.5 mL (74.9 mmol) of a 2M solution of methylamine in THF and 11.9 g (56.2 mmol) of Na(OAc)3BH. After stirring for 2 h, the reaction was quenched with saturated aqueous K2CO3, partitioned with EtOAc, separated, and the aqueous phase extracted 3×EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated by rotary evaporation. The residue was loaded onto a silica gel column and eluted with 80:10:10 CHCl3/EtOAc/MeOH to provide both the cis and trans isomers of 2-2a as colorless oils. Data for the trans isomer of 2-2a, first to elute (confirmed by NOE analysis): 1HNMR (600 MHz, CD2Cl2) δ 7.4-7.3 (m, 5H), 5.1 (m, 2H), 4.4-4.1 (m, 2H), 3.9 (m, 1H), 3.15-3.05 (m, 2H), 2.75 (m, 1H), 2.4 (s, 3H), 2.0 (in, 1H), 1.25 (m, 1H) ppm. Data for the cis isomer of 2-2a, second to elute (confirmed by NOE analysis): 1HNMR (600 MHz, CD2Cl2) δ 7.4-7.2 (m, 5H), 5.1 (m, 2H), 4.9-4.7 (m 1H), 4.4 (m, 1H), 4.15 (m, 1H), 3.1-2.9 (m, 2H), 2.6 (m, 1H), 2.4 (s, 3H), 1.8 (m, 1H), 1.6 (m, 1H) ppm. HRMS (ES) calc'd M+H for C14H19F1N2O2: 267.1504. Found: 267.1500.
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[C:19]([NH:23][C:24](=[O:39])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][N:32]2[CH2:37][CH2:36][NH:35][CH2:34][C@H:33]2[CH3:38])[CH:26]=1)([CH3:22])([CH3:21])[CH3:20].[NH2:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][C:42]=1[F:50].C(N(CC)CC)C>ClCCl>[NH2:40][C:41]1[CH:49]=[CH:48][C:44]([C:45]([N:35]2[CH2:36][CH2:37][N:32]([CH2:31][C:27]3[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=3)[C:24]([NH:23][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:39])[C@H:33]([CH3:38])[CH2:34]2)=[O:46])=[CH:43][C:42]=1[F:50]
Reactant: C[C@@H]1CNCCN1Cc1cccc(C(=O)NC(C)(C)C)c1
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)c2ccc(N)c(F)c2)CCN1Cc1cccc(C(=O)NC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
1-Propanephosphonic acid cyclic anhydride (1.967 g, 3 mmol, 1.840 mL, 50% solution in ethyl acetate) was added dropwise to a solution of (R)N-tert-butyl-3-((2-methylpiperazin-1-yl)methyl)benzamide (500 mg, 1.7 mmol), 4-amino-3-fluorobenzoic acid (239.7 mg, 1.5 mmol) and triethylamine (469 mg, 4.5 mmol, 1.84 mL) in dichloromethane. The reaction was stirred at room temperature for 2 hours. The dichloromethane was removed under reduced pressure and the residue was taken up in ethyl acetate, washed with water, sodium hydrogen carbonate and brine. The organic layer was concentrated under vacuum to afford the title compound (476.3 mg).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][N:11]1[CH:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]=O>>[CH2:1]([N:8]([CH3:28])[CH2:9][CH2:10][N:11]1[CH:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: c1ccc(CNCCN2Cc3ccccc3CC2Cc2ccccc2)cc1
Product: CN(CCN1Cc2ccccc2CC1Cc1ccccc1)Cc1ccccc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 1-g) using N-benzyl-2-[3-benzyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine obtained in Example 1 as a starting material and using paraformaldehyde to obtain a title compound as a pale yellow oily substance.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[N:5]([CH3:20])[N:4]=1.[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][N:5]1[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:7][C:3]([CH2:2][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([CH2:2][C:3]3[CH:7]=[C:6]([C:8]4[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=4)[N:5]([CH3:20])[N:4]=3)[CH2:23][CH2:22]2)=[N:4]1
Reactant: C1CNCCNC1
Reactant: COc1cc(-c2cc(CCl)nn2C)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)n(C)n4)CC3)nn2C)cc(OC)c1OC

Procedure:
3-Chloromethyl-1-methyl-5-(3,4,5-trimethoxy-phenyl)pyrazole (119 mg) and homopiperazine (20 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([N:12]([CH:16]2[C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][C:19]=3[CH2:18][CH2:17]2)[N:26]=[C:25]([CH3:29])[N:24]([CH2:30][O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:23]4=[O:38])[CH2:13][C:14]#[CH:15])[CH:9]=[CH:8][C:3]=1[CH:4]=C(C)C.[O:39]=[O+][O-]>C(Cl)Cl.C(O)C>[F:1][C:2]1[CH:11]=[C:10]([N:12]([CH:16]2[C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][C:19]=3[CH2:18][CH2:17]2)[N:26]=[C:25]([CH3:29])[N:24]([CH2:30][O:31][C:32](=[O:37])[C:33]([CH3:35])([CH3:36])[CH3:34])[C:23]4=[O:38])[CH2:13][C:14]#[CH:15])[CH:9]=[CH:8][C:3]=1[CH:4]=[O:39]
Reactant: O=[O+][O-]
Reactant: C#CCN(c1ccc(C=C(C)C)c(F)c1)C1CCc2cc3nc(C)n(COC(=O)C(C)(C)C)c(=O)c3cc21
Solvent: ClCCl
Solvent: CCO
Product: C#CCN(c1ccc(C=O)c(F)c1)C1CCc2cc3nc(C)n(COC(=O)C(C)(C)C)c(=O)c3cc21
Temperature: -70 °C

Procedure:
o-Fluoro-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]-β,β-dimethylstyrene (0.626 g) was dissolved in a mixture of methylene chloride (2 ml) and ethanol (250 ml). The mixture was cooled to -70° C. and ozone gas was passed into the solution for 7.5 minutes. Argon gas was bubbled into the solution for 5 minutes. Dimethyl sulphide (4 ml) was added and the mixture was allowed to warm to ambient temperature. The mixture was evaporated and the residue was purified by column chromatography using a 1:1 mixture of hexane and ethyl acetate as eluant. There was thus obtained o-fluoro-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzaldehyde (0.47 g);
Reaction SMILES: C([NH:4][C:5]1[N:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([C:15]#[N:16])=[C:8]2Cl)(=O)C.[Br:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].Cl.N1C=CC=CC=1>C(OC(O)C)C>[NH2:4][C:5]1[N:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([C:15]#[N:16])=[C:8]2[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([Br:18])[CH:20]=1
Reactant: CC(=O)Nc1ccc2ncc(C#N)c(Cl)c2n1
Reactant: Nc1cccc(Br)c1
Agent: CCOC(C)O
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1cnc2ccc(N)nc2c1Nc1cccc(Br)c1
Yield: 56 %

Procedure:
A solution of 6-acetamido-4-chloro-[1.5]naphthyridine-3-carbonitrile (200 mg, 0.81 mmol), 3-bromoaniline (0.5 ml) and pyridine HCl (188 mg) in ethoxyethanol (20 ml) was heated at reflux for 3 hrs. After cooling, the solvent was removed by rotary evaporation, and the residue was cooled and made basic with NH4OH. The aqueous layer was extracted with ethyl acetate. The combined extracts were washed (brine), dried (Na2SO4), and concentrated. The residue was chromatographed (flash column, silica gel, CH2Cl2:ether:MeOH=5:2:0.5) giving the title compound as a yellow solid (229 mg, 56%). mass spectrum (electrospray, m/e): 341.8 (M+H); IR cm-1: 2215, 1628; H-NMR δ(DMSO-d6): 6.816 (2H, bs, NH2), 7.093 (1H, d, C7-H), 7.35-7.43 (3H, m), 7.567 (1H, s), 7.931 (1H, d, C8-H), 8.333 (1H, s, C2-H), 9.236 (1H, s, NH).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[F:24].C([O-])([O-])=O.[Na+].[Na+].Cl>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([C:2]2[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[N:6][CH:5]=[C:4]([CH:3]=2)[C:14]([OH:16])=[O:15])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(F)c(Cl)c2)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 62.9 %

Procedure:
5-Bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1211586-75-2; 1.5 g; 5.0 mmol) was dissolved in toluene (35 mL) an DMF (2 mL). To this solution was added 1,1′-bis(diphenylphosphino)-ferrocene-palladium(II)dichloride dichloromethane complex (204 mg, 250 μmol), followed by 3-chloro-4-fluorophenylboronic acid (CAN 144432-85-9; 959 mg, 5.5 mmol) and 2M-Na2CO3 (20.0 mL 40.0 mmol). The reaction mixture was heated to 90° C. and stirred for 4 h, cooled and poured into 100 mL ice water, acidified with 45 mL 2N—HCl and extracted ethyl acetate. The organic layers were combined, dried with Na2SO4 and concentrated in vacuo. The crude material was crystallized from heptane:ethyl acetate (5:1) to yield 1.1 g (63%) of the title compound as light grey solid; LC-MS (UV peak area/ESI): 97%, 348.0066 (M−H)−.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].C(N(CC)CC)C>C(OCC)(=O)C>[N+:18]([C:12]1[CH:13]=[C:14]([NH:15][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:16]=[CH:17][C:11]=1[F:10])([O-:20])=[O:19]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccccc1
Reaction time: 2 h
Yield: 81.1 %

Procedure:
Benzoyl chloride (12 mL, 103 mmol) was added dropwise to 4-fluoro-3-nitroaniline (15.64 g, 100 mmol) and triethylamine (17 mL, 122 mmol) in ethyl acetate (400 mL) at room temperature. The reaction mixture was stirred for 2 hours and then allowed to stand overnight. The reaction mixture was washed with 10% aqueous citric acid solution (200 mL), saturated aqueous sodium bicarbonate solution (200 mL), and brine (100 mL); dried (magnesium sulfate), filtered, and concentrated to about 100 mL at which point a solid began to precipitate. The mixture was cooled to zero degrees and the straw-colored solid collected by filtration to afford the product (21.1 g) in two crops.
Reaction SMILES: [Na].[F:2][C:3]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:4]=1[NH:5][C:6](=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[SH:7].[C:25]([O:28][CH2:29][C:30]([CH2:32]Cl)=[O:31])(=[O:27])[CH3:26]>CN(C)C=O>[F:2][C:3]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:4]=1[NH:5][C:6](=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[S:7][CH2:32][C:30](=[O:31])[CH2:29][O:28][C:25](=[O:27])[CH3:26]
Reactant: CCOC(=O)C(C(=O)OCC)=C(S)Nc1ccc(F)c(F)c1F
Reactant: CC(=O)OCC(=O)CCl
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)=C(Nc1ccc(F)c(F)c1F)SCC(=O)COC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Diethyl [(2,3,4-trifluoroanilino)(mercapto)methylene]malonate sodium salt (5.3 g) was dissolved in N,N-dimethylformamide (70 ml) and thereto 1-acetoxy-3-chloroacetone (2.2 g) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered to remove insoluble materials. After the filtrate was evaporated to dryness under reduced pressure, water was added to the residue and the mixture was extracted with chloroform. The extract was washed with a NaCl solution and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure to give the title compound (6.0 g) as pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.S1C=CC=C1>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1nccc(-c2cccc([N+](=O)[O-])c2)n1
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: Nc1cccc(-c2ccnc(N)n2)c1

Procedure:
4-(3-amino-phenyl)-pyrimidin-2-ylamine was prepared in an analogous manner: A solution of 4-(3-nitro-phenyl)-pyrimidin-2-ylamine (0.046 mol) in MeOH (250 ml) was hydrogenated at 50° C. with Pd/C 10% (2 g) as a catalyst in the presence of a solution of thiophene in DIPE (4% v/v, 1 ml). After uptake of H2 (3 equiv.), the catalyst was filtered off and the filtrate was concentrated and dried (vacuum 60° C.). Yield: 8.64g of 4-(3-amino-phenyl)-pyrimidin-2-ylamine (87%) (m.p.; 190-194° C.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].Cl.N1C=CC=CC=1.[OH:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH2:27]>C(OCCO)C>[OH:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Reactant: Cc1ccc(N)cc1O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cccc2c(Nc3ccc(C)c(O)c3)c(C#N)cnc12
Temperature: 100 °C
Yield: 89 %

Procedure:
Using an analogous procedure to that described in Example 274. A reaction mixture of 328.0 mg (1.5 mmol) of 4-chloro-8-methoxy -3-quinolinecarbonitrile, 173.3 mg (1.5 mmol) of pyridine hydrochloride and 203.2 mg (1.7 mmol) of 3-hydroxy-4-methyl-aniline in 15 mL of 2-ethoxyethanol was heated at 100° C. for 1.5 hr. After the work up, 407.7 mg (89.4%) of the product was obtained as a yellow solid, m.p. 148-150° C., mass spectrum (electrospray, m/e): M+H 306.9.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[CH2:18][CH3:19])=[C:8]([CH2:10][OH:11])[CH:9]=1.[CH3:20]I>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[CH2:18][CH3:19])=[C:8]([CH2:10][O:11][CH3:20])[CH:9]=1
Reactant: CI
Reactant: CCC1CCCCN1c1ccc(Br)cc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1CCCCN1c1ccc(Br)cc1COC
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of sodium hydride (2.3 g, 93 mmol) in anhydrous DMF (130 mL) was added a solution of [5-bromo-2-(2-ethylpiperidin-1-yl)phenyl]methanol (15 g, 48.3 mmol) in DMF (20 mL) drop wise at 0° C. After 30 minutes, methyl iodide was added drop wise at 0° C. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl (30 mL), then diluted with water (100 mL) and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a yellow oil (15.2 g, 97%). 1H NMR (CDCl3, 400 MHz) δ 7.59 (1H, s), 7.35 (1H, d), 7.02 (1H, d), 4.49-4.59 (2H, m), 3.43 (3H, s), 2.88 (1H, d), 2.75 (1H, bs), 2.51 (1H, bs), 1.79-1.86 (2H, m), 1.62 (3H, d), 1.40 (2H, m), 0.88 (2H, m), 0.70 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]([NH2:27])[CH2:15][N:16]3[C:20]([CH3:21])=[C:19]([Cl:22])[C:18]([C:23]([F:26])([F:25])[F:24])=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:28][CH3:29].[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]([NH:27][C:30](=[O:32])[CH3:31])[CH2:15][N:16]3[C:20]([CH3:21])=[C:19]([Cl:22])[C:18]([C:23]([F:25])([F:26])[F:24])=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:28][CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(N2CCC(C(N)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)ccc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(N2CCC(C(Cn3nc(C(F)(F)F)c(Cl)c3C)NC(C)=O)CC2)ccc1Cl
Yield: 91.1 %

Procedure:
A solution of 1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)-2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethanamine (49 mg, 0.109 mmol) in anhydrous DCM (1.5 mL) was treated with acetic anhydride (0.012 mL, 0.130 mmol) and DMAP (1.3 mg, 11 μmol), and the resultant mixture was stirred at RT for 1.5 h. After this time, the mixture was diluted with DCM (5 mL) and then washed sequentially with saturated NaHCO3 and brine. The organic extract was dried (MgSO4) and concentrated in vacuo to give N-(1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)-2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)acetamide (49 mg), which was used without further purification in the reaction below. LC-MS: 493.25, [M+H]+; tR=3.08 min (method b).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1.[NH2:14][CH2:15][CH2:16][OH:17].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9]([NH:14][CH2:15][CH2:16][OH:17])(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCCO)c1cc(F)c(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
A solution of 4-bromo-2,5-difluorobenzenesulfonyl chloride (1.17 g, 4 mmol) in CH2Cl2 (3 mL) was added to a solution of 2-aminoethanol (0.36 mL, 6 mmol) and triethylamine (1.67 mL, 12 mmol) in CH2Cl2 (12 mL) at ambient temperature. The mixture was stirred at ambient temperature for 1 h and concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 10% MeOH/CH2Cl2 to give 884 mg (70%) of 4-bromo-2,5-difluoro-N-(2-hydroxyethyl)benzenesulfonamide as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.67 (dd, 1H, Ja=7.2 Hz, Jb=6.0 Hz), 7.47 (dd, 1H, Ja=8.7 Hz, Jb=5.1 Hz), 5.39-5.14 (m, 1H), 3.78-3.64 (m, 2H), 3.26-3.10 (m, 2H), 1.73 (bs, 1H); LRMS (ESI), m/z 314/316 (M−H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[N:3]=1.[NH2:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][NH:24]2)=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[N:3]=[C:2]([NH:17][C:18]2[CH:26]=[C:25]3[C:21]([CH:22]=[N:23][NH:24]3)=[CH:20][CH:19]=2)[N:7]=1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Nc2ccc3cn[nH]c3c2)n1
Reaction time: 1 h
Yield: 44.9 %

Procedure:
A mixture of 2,4-dichloro-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazine (1 g, 3.6 mmol), 6-aminoindazole (0.5 g, 3.7 mmol), tetrahydrofuran (10 ml), and diisopropylethylamine (0.65 ml, 3.7 mmol) was stirred for 1 hour. After concentrating under reduced pressure, the residue was treated with water (25 ml) and stirred for 10 minutes. The solid was filtered, treated with hydrochloric acid (1 M, 10 ml), stirred vigorously for 10 minutes, and filtered. The solid was purified by flash chromatography on silica eluting with 5% methanol-dichloromethane to yield the title compound (600 mg, 45% yield). 1H NMR (DMSO-d6) 13.04 (br s, 1H), 10.90-10.97 (m, 1H), 8.12 (s, 1H), 8.02 (s, 1H), 7.71 (m, 2H), 7.53 (m, 1H), 7.41 (m, 1H), 7.34 (m, 1H), 2.50-2.54 (m, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:29])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:20](=[O:27])[NH:19][C:18]2=[O:28])=[CH:13][CH:12]=1)[CH3:8].Cl[CH2:31][C:32]([NH:34][C:35]1[C:40]([CH:41]([CH3:43])[CH3:42])=[CH:39][CH:38]=[CH:37][C:36]=1[CH:44]([CH3:46])[CH3:45])=[O:33].O>CN(C)C=O>[CH2:7]([O:9][C:10](=[O:29])[C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:21]3([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:20](=[O:27])[N:19]([CH2:31][C:32](=[O:33])[NH:34][C:35]3[C:36]([CH:44]([CH3:46])[CH3:45])=[CH:37][CH:38]=[CH:39][C:40]=3[CH:41]([CH3:43])[CH3:42])[C:18]2=[O:28])=[CH:15][CH:16]=1)[CH3:8]
Reactant: CCOC(=O)c1ccc(N2C(=O)NC(=O)C23CCCCC3)cc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(N2C(=O)N(CC(=O)Nc3c(C(C)C)cccc3C(C)C)C(=O)C23CCCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
87 mg (0.63 mmol, 1 eq.) of potassium carbonate are added to a solution of 200 mg (0.63 mmol, 1 eq.) of 4-(2,4-dioxo-1,3-diazaspiro[4.5]dec-1-yl)benzoic acid ethyl ester and 160 mg (0.63 mmol, 1 eq.) of 2-chloro-N-(2,6-diisopropylphenyl)acetamide in 30 ml of dimethylformamide. The reaction medium is stirred at room temperature overnight. It is then poured into water and extracted with ethyl acetate. The organic phases are combined and washed with water. They are dried over sodium sulfate. The solvents are evaporated off. The residue is precipitated from dichloromethane and heptane. The product 4-{3-[(2,6-diisopropyl-phenylcarbamoyl)methyl]-2,4-dioxo-1,3-diaza-spiro[4.5]dec-1-yl}benzoic acid ethyl ester is obtained in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH2:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=O)=[CH:11][CH:10]=1)[CH3:8].O=S(Cl)Cl.[OH-].[Na+]>C(Cl)Cl>[CH2:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13]2[O:4][CH2:3][C:2]([CH3:6])([CH3:5])[N:1]=2)=[CH:11][CH:10]=1)[CH3:8]
Reactant: CC(C)(N)CO
Reactant: CCc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCc1ccc(C2=NC(C)(C)CO2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a 3-neck, 2 L round bottom flask was added 173.71 g (1.0 mol, 97%) of 2-amino-2-methyl-1-propanol in 300 mL of dry methylene chloride. The flask was equipped with a magnetic stir bar and thermometer and was placed into a dry ice/acetone bath and cooled to 0° C. From a separatory funnel, a solution of 4-ethylbenzoyl chloride (168.5 g, 1.0 mol), dissolved in about 300 mL of methylene chloride was slowly added, while maintaining the reaction temperature below 5° C. The mixture was allowed to stir at room temperature overnight. Solid propanol amine-HCl was filtered off and the filter cake was washed with methylene chloride. The combined methylene chloride extracts were concentrated partially on a rotary evaporator and used directly in the next step. The intermediate amide solution generated in the first step was cooled in an ice bath and DMF (0.5 mL) was added. 125 g (1.04 mol) of SOCl2 in 50 mL of methylene chloride from a separatory funnel was added drop-wise at a controlled rate, keeping the reaction temperature at 0-5° C. The reaction was stirred at room temperature for an additional 2-3 hours. The reaction mixture was cooled in an ice bath and 25% NaOH was added to make the aqueous layer basic (pH=11-12). The mixture was transferred to a large separatory funnel, the methylene chloride layer was separated, and the aqueous layer was extracted twice with chloroform. The combined organic phases were dried an evaporated to yield 201 g of 2-(4-ethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole as a yellow viscous oil. 1H NMR(CDCl3, 300 MHz), δ (ppm): 7.8 (d, 2H), 7.2 (d, 2H), 4.088 (s, 2H), 2.68 (q, 2H), 1.375 (s, 6H), 1.24 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(O)(=O)C.[Na].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Br:1][C:2]1[C:3]([F:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[CH2:6][CH2:5]2
Reactant: O=C1CCc2c(ccc(Br)c2F)C1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Fc1c(Br)ccc2c1CCC(N1CCOCC1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To 6-bromo-5-fluoro-tetralin-2-one (1 g, 4.11 mmol) and morpholine (0.36 mL, 4.11 mmol) in dichlormethane is added glacial acetic acid (0.52 mL, 9.05 mmol). The reaction mixture is cooled with an ice bath and sodium triacetoxyborhydride (1.74 g, 8.23 mmol) is added. The reaction mixture is stirred at r.t. overnight. Morpholine (0.2 mL) is added and stirred again at r.t. overnight. The reaction mixture is basified with potassium carbonate solution (20%) and stirred for 15 min. The organic layer is separated and the aq. layer is washed two times with dichlormethane. The organic layers are dried and concentrated. The crude product is purified by reversed phase HPLC Yield 57%, m/z 314/316 [M+H]+, rt 0.68 min, LC-MS Method X011_S03.