Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[ClH:51].C(N(CC)CC)C.[NH:59]1[CH2:63][CH2:62][C@@H:61]([OH:64])[CH2:60]1>CN(C=O)C.O>[ClH:51].[OH:64][C@@H:61]1[CH2:62][CH2:63][N:59]([C:25]([C:24]2[CH:28]=[CH:29][C:21]([C:18]3[N:17]=[C:16]4[N:12]([CH2:11][C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)[N:13]=[N:14][C:15]4=[CH:20][CH:19]=3)=[CH:22][CH:23]=2)=[O:26])[CH2:60]1
Reactant: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reactant: O[C@@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1)N1CC[C@@H](O)C1
Reaction time: 12 h
Yield: 8.7 %

Procedure:
To a solution of example 8 (0.150 g, 0.393 mmol) in DMF (1 ml), HOBT (0.063 g, 0.471 mmol), EDC-HCl (0.187 g, 0.983 mmol) and triethylamine (0.16 ml, 1.17 mmol) were added and stirred for 5 min. (R)-pyrrolidin-3-ol (0.030 g, 0.353 mmol) was added at RT and the reaction mixture was stirred for 12 h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the amide as a yellow solid (0.015 g). The amide was dissolved in THF (2 ml), ether saturated with HCl (2 ml) was added at 0° C. and stirred for 15 min. The precipitate formed was washed with ether and dried under vacuum to afford the title compound as a yellow solid (0.017 g, 10%). M.P.: 120-122° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.87 (d, J=2.9 Hz, 1H), 8.68 (d, J=8.7 Hz, 1H), 8.38 (d, J=8.2 Hz, 1H), 8.30 (d, J=8.2 Hz, 2H), 8.17 (d, J=8.8 Hz, 1H), 8.02 (d, J=8.3 Hz, 2H), 7.83 (d, J=8.7 Hz, 1H), 7.69 (m, 2H), 7.52 (dd, J=8.2, 4.1 Hz, 1H), 6.21 (s, 2H), 3.61 (m, 3H), 3.44 (m, 1H), 1.95-1.80 (m, 4H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([NH:16][C:17]1[C:18]([F:43])=[CH:19][C:20]([F:42])=[C:21]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([F:35])=[C:30](F)[C:31]=3[Cl:33])[C:26](=[O:36])[C:25]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:24]2)[CH:22]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CN1CCCC1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([NH:8][C:30]1[C:31]([Cl:33])=[C:32]2[C:27]([C:26](=[O:36])[C:25]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:24][N:23]2[C:21]2[CH:22]=[C:17]([NH:16][C:14]([O:13][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:15])[C:18]([F:43])=[CH:19][C:20]=2[F:42])=[CH:28][C:29]=1[F:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: NCc1ccccc1
Agent: CN1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(NCc3ccccc3)c(F)cc2c1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
Benzylamine (750 mg) and ethyl 1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (4,200 mg) were added to a solution of N-methylpyrrolidine (800 mg) and N,N-dimethylformamide (20 ml), and the mixture was stirred overnight at 80° C. After the reaction mixture was cooled to room temperature, ethyl acetate (100 ml) was added to the reaction mixture, and the resultant mixture was washed 3 times with water (100 ml). After an organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent; chloroform) to obtain the title compound (3,200 mg) as an amorphous substance.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[F:26][CH:27]([F:33])[CH2:28][NH:29][CH2:30][CH2:31][NH2:32]>>[F:26][CH:27]([F:33])[CH2:28][NH:29][CH2:30][CH2:31][NH:32][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCCNCC(F)F
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCNCC(F)F)c2c1

Procedure:
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and N-(2,2-difluoroethyl)ethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 461, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (dd, J=7.83, 1.26 Hz, 1 H), 7.83 (d, J=6.82 Hz, 1 H), 7.60 (td, J=7.45, 1.26 Hz, 2 H), 7.46-7.38 (m, 2 H), 7.28 (dd, J=8.59, 1.77 Hz, 1 H), 6.04 (s, 1 H), 5.13 (s, 2 H), 3.58 (t, J=4.80 Hz, 2 H), 3.46 (t, J=6.19 Hz, 2 H), 3.37 (s, 3 H), 3.10-2.97 (m, 4 H), 2.41 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1.[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH:28]([C:32](Cl)=[O:33])[CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1.CCCCCC>[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH:28]([C:32](=[O:33])[NH:15][C:11]2[CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:14]=[CH:13][N:12]=2)[CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: COc1ccccc1-c1cc(N)ncn1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccccc1-c1cc(NC(=O)C2CCCN(C(=O)OCc3ccccc3)C2)ncn1
Reaction time: 2 h

Procedure:
To a solution of 6-(2-methoxy-phenyl)-pyrimidin-4-ylamine (XXIV) (5 g) in 20 ml of dichloromethane was added 4-dimethylaminopyridine (1.2 eq) followed by dropwise addition of 3-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (XXV) (1.1 eq.) at room temperature. The reaction mixture was stirred for 2 hours and then washed with water. The organic layer was separated, dried over sodium sulfate and concentrated. The obtained crude residue was passed through a pad of silica gel eluting with 25% ethyl acetate in hexane to provide 3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XXVI) (5.1 g).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C@H:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[CH:16][C:17]=1[C:23]([F:25])([F:26])[F:24]
Reactant: COc1ccc(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C[C@@H]2CNCCO2)cc1C(F)(F)F

Procedure:
Intermediate (a), N-Boc-(R)-2-(4-methoxy-3-trifluoromethylbenzyl)morpholine (23 mg, 0.06 mmol), was deprotected using trifluoroacetic acid, (20% v/v solution in dichloromethane, 1 mL total) over 2.5 hrs. The reaction mixture was poured onto an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and dichloromethane: methanol (1:1 v/v, 2 mL×2). The column was then washed with ammonia (2N solution in methanol, 2 mL×3) and the ammonia washes were concentrated in vacuo to yield the desired morpholine, example 2 as a white solid (15 mg, 89%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:10]([N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1)(=[O:12])[CH3:11].C(O)(=O)C>CO.[C].[Pd]>[C:10]([N:13]1[CH2:18][CH2:17][CH:16]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)[CH2:15][CH2:14]1)(=[O:12])[CH3:11]
Reactant: c1ccc2c(c1)CCN2
Reactant: CC(=O)N1CCC(=O)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)N1CCC(N2CCc3ccccc32)CC1
Yield: 82.2 %

Procedure:
Indoline (25 ml), 1-acetyl-4-piperidone (25 g) and glacial acetic acid (20 ml) were dissolved in methanol (300 ml). After adding 10% palladium carbon (1.0 g) thereto, catalytic reduction was carried out under atmospheric pressure. After the completion of the reaction, the reaction solution was filtered through celite, washed with methanol and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate and basified with a 5 N aqueous solution of sodium hydroxide followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system) to give the title compound (35.6 g) as a pale yellow wax (yield: 82.2%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].[C:14]([N:17]1[CH2:21][CH2:20][NH:19][C:18]1=[O:22])(=[O:16])[CH3:15].C(Cl)Cl.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[C:14]([N:17]1[CH2:21][CH2:20][N:19]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[C:18]1=[O:22])(=[O:16])[CH3:15]
Reactant: CC(=O)N1CCNC1=O
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(N2CCN(C(C)=O)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
To a mixture of p-(methoxycarbonyl)phenylboronic acid (2.45 g), 1-acetylimidazolidin-2-one (870 mg) and copper(II) acetate (1.23 g) were added methylene chloride (20 mL) and triethylamine (1.9 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the insoluble material was collected by filtration. The filtrate was extracted with chloroform, and the solvent was evaporated from the organic layer. The obtained residue was purified by column chromatography (chloroform) to give the title compound (292 mg).
Reaction SMILES: [CH2:1]([N:8]([CH2:27][CH2:28][CH2:29][CH3:30])[C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:31][CH2:32][CH2:33][NH2:34]>>[CH2:1]([N:8]([CH2:27][CH2:28][CH2:29][CH3:30])[C:9]1[C:14]2[N:15]=[C:16]([NH:34][CH2:33][CH2:32][OH:31])[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: CCCCN(Cc1ccccc1)c1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Product: CCCCN(Cc1ccccc1)c1ncnc2c(N3CCS(=O)CC3)nc(NCCO)nc12

Procedure:
This compound was prepared analogous to Example 2 from 8-(N-benzyl-butylamino)-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido[5,4-d]pyrimidine (melting point: 153°-155° C.) and 2-hydroxyethyl-amine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[C:28]([Cl:53])=[C:29]([N:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:37]([C:48](=[O:52])[N:49]([CH3:51])[CH3:50])[CH2:36]2)[CH:30]=[C:31]([C:33]#[N:34])[CH:32]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O1CCOCC1>[Cl:53][C:28]1[C:27]([NH:26][C:2]2[N:7]=[C:6]([N:8]([CH:18]3[CH2:20][CH2:19]3)[CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:5]3=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]3[N:3]=2)=[CH:32][C:31]([C:33]#[N:34])=[CH:30][C:29]=1[N:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH:37]([C:48](=[O:52])[N:49]([CH3:50])[CH3:51])[CH2:36]1
Reactant: CN(C)C(=O)C1CN(c2cc(C#N)cc(N)c2Cl)CCN1C(=O)OC(C)(C)C
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(C(=O)OC(C)(C)C)C(C(=O)N(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 100 °C
Yield: 79.6 %

Procedure:
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (197 mg, 0.555 mmol), tert-butyl 4-(3-amino-2-chloro-5-cyanophenyl)-2-(dimethylcarbamoyl)piperazine-1-carboxylate (227 mg, 0.557 mmol), palladium (II) acetate (37.4 mg, 0.167 mmol), DPPF (30.8 mg, 0.056 mmol), Xantphos (32.1 mg, 0.056 mmol), and cesium carbonate (271 mg, 0.833 mmol) were combined in a 100 ml round bottom flask and dioxane (5 mL) was added. The flask was evacuated and backfilled with N2 3×, then heated at 100° C. for 1 h. Some SM remaining by LCMS. The reaction was cooled to room temperature and an additional 0.15 eq. catalyst and 0.05 eq of each ligand was added. The flask was purged with N2 and heated for an additional 30 min. The reaction was cooled to room temperature and filtered through celite, rinsing with EtOAc. The solvent was removed in vacuo to leave a brown solid. The crude material was purified by flash column chromatography (0-40% EtOAc/DCM; 40 g column). Tert-butyl 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-2-(dimethylcarbamoyl)piperazine-1-carboxylate (321 mg) was obtained as a yellow solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.[NH2:9][C@H:10]([C:12]([N:14]1[C:20](=[O:21])[CH:19]([CH3:22])[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[C:16]2[C:27]([NH2:31])=[CH:28][CH:29]=[CH:30][C:15]1=2)=[O:13])[CH3:11]>>[O:1]1[CH2:5][CH2:4][CH:3]([C:6]([NH:9][C@H:10]([C:12]([N:14]2[C:20](=[O:21])[CH:19]([CH3:22])[C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=3[C:16]3[C:27]([NH2:31])=[CH:28][CH:29]=[CH:30][C:15]2=3)=[O:13])[CH3:11])=[O:8])[CH2:2]1
Reactant: O=C(O)C1CCOC1
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Product: CC1C(=O)N(C(=O)[C@H](C)NC(=O)C2CCOC2)c2cccc(N)c2-c2ccccc21

Procedure:
Following General Procedure C-P above using tetrahydro-3-furoic acid and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 408 (M+H).
Reaction SMILES: C(OC([N:8]1[CH:13]([CH:14]([OH:27])[CH:15]([NH:23][C:24](=[O:26])[CH3:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]2[CH:28]([CH2:29][O:30][CH3:31])[CH:9]1[CH2:10][CH2:11]2)=O)(C)(C)C.[ClH:32]>O1CCCC1>[ClH:32].[CH2:16]([CH:15]([NH:23][C:24](=[O:26])[CH3:25])[CH:14]([OH:27])[CH:13]1[CH:12]2[CH:28]([CH2:29][O:30][CH3:31])[CH:9]([CH2:10][CH2:11]2)[NH:8]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1.[ClH:32]
Reactant: COCC1C2CCC1N(C(=O)OC(C)(C)C)C2C(O)C(Cc1ccccc1)NC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: COCC1C2CCC1C(C(O)C(Cc1ccccc1)NC(C)=O)N2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Cool a solution of 3-(2-acetylamino-1-hydroxy-3-phenylpropyl)-7-methoxymethyl-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (Isomer 1) (0.044 g, 0.102 mmol) in tetrahydrofuran (1 mL) and add a solution of hydrochloric acid (2.0 mL, 4 M in 1,4-dioxane). Stir the mixture for 5 h at room temperature, concentrate and purify (silica gel chromatography, eluting with 2 M ammonia in 5:95 to 10:90 methanol:dichloromethane) to give the title compound after treatment with the same equivalent of hydrochloric acid in diethyl ether (16 mg, 43%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[CH:31](=O)[CH:32]([CH3:34])[CH3:33].C([BH3-])#N.[Na+]>CO>[CH2:31]([NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)C=O
Reactant: NCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)CNCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 159 from (Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone-hydrochloride, isobutyraldehyde and sodium cyanoborohydride in methanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[N:18]2[C:13]([CH:14]=[N:15][C:16](S(C)=O)=[N:17]2)=[CH:12][CH:11]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][C:36]([NH2:38])=[O:37])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[N:18]2[C:13]([CH:14]=[N:15][C:16]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:30][CH2:31][N:32]([CH2:35][C:36]([NH2:38])=[O:37])[CH2:33][CH2:34]4)=[CH:25][CH:24]=3)=[N:17]2)=[CH:12][CH:11]=1
Reactant: NC(=O)CN1CCC(c2ccc(N)cc2)CC1
Reactant: COc1cccc(F)c1-c1ccc2cnc(S(C)=O)nn12
Product: COc1cccc(F)c1-c1ccc2cnc(Nc3ccc(C4CCN(CC(N)=O)CC4)cc3)nn12
Reaction time: 6 h

Procedure:
Following the synthetic and purification procedures of Example 1291c, 7-(2-Fluoro-6-methoxy-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (79 mg, 0.26 mmol) was coupled to 2-[4-(4-amino-phenyl)-piperidin-1-yl]-acetamide (91 mg, 0.39 mmol) in a sealed vial at 125° C. for 96 h followed by 6 h in a microwave reactor at 170° C. Yield of
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10]C)=[O:9])=[O:4].O.[OH-].[Li+].Cl>CO.O>[CH3:1][N:2]([CH3:15])[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9])=[O:4]
Reactant: COC(=O)c1cccc(C(=O)N(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)C(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
Methyl 3-(N,N-dimethylcarbamoyl)benzoate (2.30 g, 11.1 mmol) obtained in Step 1 was dissolved in a mixed solvent (1:1) (50 mL) of methanol and water, and lithium hydroxide monohydrate (932 mg, 22.2 mmol) was added thereto, followed by stirring at room temperature for 1 hour. 3 mol/L hydrochloric acid was added to the reaction mixture to adjust the pH to 3, and the precipitated solid was collected by filtration to afford 3-(N,N-dimethylcarbamoyl)benzoic acid (2.12 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10](/[CH:13]=[N:14]/[S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])=[N:9]2)=[CH:4][CH:3]=1.[CH3:21][Mg]Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C@H:13]([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH3:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccn(-c2ccc(Cl)cc2)n1
Solvent: ClCCl
Product: C[C@@H](N[S@](=O)C(C)(C)C)c1ccn(-c2ccc(Cl)cc2)n1
Temperature: -40 °C
Reaction time: 3 h
Yield: 49.8 %

Procedure:
To a solution of (R,E)-N-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)methylene)-2-methylpropane-2-sulfinamide (2.12 g, 6.84 mmol) in DCM (40 ml) at −40° C. was added methylmagnesium bromide (9.12 ml, 27.4 mmol). The reaction was stirred at −40° C. for 3 hours. The reaction mixture was then quenched with saturated NH4Cl solution (20 mL). The aqueous layer was adjusted to pH=8 with HCl (1M) and extracted with DCM (2×200 mL). The combined organic was dried (Na2SO4) and concentrated. The residue was then purified via silica gel chromatography (EtOAC/heptane) to give (R)—N—((R)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.11 g). LCMS (B) m/z 326.3 (M+H)+
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:11]1([C:14]2[N:15]=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(C(F)(F)F)cnn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cnnc(N2CCNCC2)c1
Reaction time: 0.5 h

Procedure:
4-(5-Trifluoromethyl-pyridazin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (45 mg) was dissolved in dichloromethane (0.5 mL), and trifluoroacetic acid was added (0.5 mL). The reaction mixture was stirred for 30 minutes before being concentrated in vacuo to afford the crude title compound which was used directly in the next step without further purification or analysis.
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].C(N(CC)CC)C.Cl.[C:21]([N:24]1[CH2:29][CH2:28][CH:27]([C:30](Cl)=O)[CH2:26][CH2:25]1)(=[O:23])[CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.C1(C)C=CC=CC=1.O>[C:21]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[O:12][C:11]3[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=3)[N:2]=2)[CH2:26][CH2:25]1)(=[O:23])[CH3:22]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Nc1c(O)cccc1C(=O)O
Agent: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1CCC(c2nc3c(C(=O)O)cccc3o2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 21.4 %

Procedure:
To a suspension of 2-amino-3-hydroxybenzoic acid hydrobromide (2.0 g, 8.5 mmol) in dichloromethane (25 mL) was added triethylamine (4.77 mL, 34.2 mmol) followed by 1-acetylpiperidine-4-carbonyl chloride hydrochloride (1.93 g, 8.55 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 17 h. The reaction was quenched with aqueous 2 N HCl (50 mL). The reaction mixture was extracted with dichloromethane (3×250 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated to afford a light yellow solid. The crude solid was dissolved in toluene (20 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (2.08 g, 10.9 mmol). The reaction mixture was then heated to reflux under nitrogen for 10 h. The reaction was cooled to room temperature, poured into water (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic phase was washed with water (2×100 mL), brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel, 9:1 to 7:3 ethyl acetate/methanol) to afford 2-(1-acetylpiperidin-4-yl)benzoxazole-4-carboxylic acid (524 mg, 21%) as a brown solid: 1H NMR (300 MHz, DMSO-d6) δ 10.81 (br s, 1H), 7.48 (dd, J=7.7, 1.6 Hz, 1H), 6.94 (t, J=7.8 Hz, 1H), 6.89 (dd, J=7.7, 1.6 Hz, 1H), 4.45-4.34 (m, 2H), 3.92-3.82 (m, 2H), 3.18-3.05 (m, 1H), 2.07-2.02 (m, 2H), 2.02 (s, 3H), 1.92-1.82 (m, 2H); MS (ESI+) m/z 289 (M+H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][C:20]2[N:21]=[C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]3[C:29]=2[CH3:30])[CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)C1C=CC=CC=1.[H][H]>[Pd].CO.O1CCCC1>[NH2:15][C:14]1[CH:13]=[CH:12][C:11]([CH2:18][CH2:19][C:20]2[N:21]=[C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]3[C:29]=2[CH3:30])=[CH:10][C:9]=1[OH:8]
Reactant: [H][H]
Reactant: Cc1ccn2c(C)c(C=Cc3ccc([N+](=O)[O-])c(OCc4ccccc4)c3)nc2c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccn2c(C)c(CCc3ccc(N)c(O)c3)nc2c1

Procedure:
10% Palladium on carbon (10 g) was added to a mixture of 2-[2-(3-benzyloxy-4-nitrophenyl)vinyl]-3,7-dimethylimidazo[1,2-a]pyridine (27.3 g) in methanol (200 ml) and tetrahydrofuran (200 ml) and the mixture was stirred at ambient temperature under atmospheric pressure of hydrogen gas. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was triturated with ethyl acetate and the precipitate was collected by filtration to give 2-[2-(4-amino-3-hydroxyphenyl)ethyl]-3,7-dimethylimidazo[1,2-a]pyridine (13.8 ).