Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=O)C.[C:16](#[N:20])[CH2:17][C:18]#[N:19]>>[NH2:19][C:18]1[O:4][C:5]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=2[C:7](=[O:8])[C:17]=1[C:16]#[N:20]
Reactant: COc1cccc(C(=O)Cl)c1OC(C)=O
Reactant: N#CCC#N
Product: COc1cccc2c(=O)c(C#N)c(N)oc12

Procedure:
In the same way as described in Example 3, 2-acetoxy-3-methoxy-benzoyl chloride and malononitrile are reacted to give a crystalline product, mp 300° C.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[C:6]1([P:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+:26]>CC(C)CC(=O)C>[C:19]1([P:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:13]2[CH:14]=[C:15]([S:1]([O-:3])(=[O:5])=[O:2])[CH:16]=[CH:17][CH:18]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1.[Na+:26]
Reactant: O=S(=O)(O)O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Product: O=S(=O)([O-])c1cccc(P(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 300-ml three-necked flask equipped with a thermometer, stirrer, dropping funnel and nitrogen inlet and outlet lines was charged with 110 g (1.12 moles) of concentrated sulfuric acid and 60 g (0.23 mole) of triphenylphosphine, and the air in the flask was replaced with nitrogen. To the contents with stirring 220 g of fuming sulfuric acid (content of sulfur trioxide: 25% by weight; moles of sulfur trioxide: 0.69 mole) was added dropwise over 1 hour, while the inside temperature was maintained at 25° C. After completion of the dropping, stirring was continued for 12 hours at an inside temperature of 25° C. The reaction mixture obtained was added dropwise onto 1.8 kg of ice water under an atmosphere of nitrogen and hydrolyzed and diluted. To the obtained aqueous solution, 1.5 liters of 4-methyl-2-pentanone was added at a room temperature and sufficiently mixed. After the mixture had been allowed to stand still, the 4-methyl-2-pentanone layer was separated. To the 4-methyl-2-pentanone layer thus obtained, 120 ml of a 5% by weight aqueous sodium hydroxide solution was added dropwise under an atmosphere of nitrogen, while the inside temperature was maintained at 25° C., to neutralize it. The aqueous layer was taken out from the reaction mixture, washed with 100 ml of 4-methyl-2-pentanone and again taken out by separation. The layer was condensed at 80° C. to a volume of 80 ml and then allowed to cool, to precipitate crystals. The crystals precipitated were separated by filtration and vacuum-dried at 60° C., 0.67 kPa (5 mmHg) for 2 hours, to yield 35 g of a white crystalline sodium 3-(diphenylphosphino)benzenesulfonate dihydrate.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:43]=[CH:42][C:13]([CH2:14][O:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[NH:22]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:12][CH:11]=1.[ClH:44]>C(O)C>[ClH:44].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:43]=[CH:42][C:13]([CH2:14][O:15][C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[NH2:22])=[CH:12][CH:11]=1
Reactant: c1ccc(C(N[C@H]2CCCC[C@H]2OCc2ccc(-c3nc4ccccc4o3)cc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: N[C@@H]1CCCC[C@@H]1OCc1ccc(-c2nc3ccccc3o2)cc1
Reaction time: 24 h

Procedure:
Cis-1-[4-(benzoxazol-2-yl)benzyloxy]-2-triphenylmethylaminocyclohexane (2.03 g; 3.6 mmol) in 200 ml ethanol is treated with ethanolic HCl to pH 4 and stirred for 24 hrs. at room temperature. The solution is concentrated in vacuo, treated with ether and a white solid which precipitates out is filtered, washed with dry ether and dried in vacuo to obtain cis-2-[(4-benzoxazol-2-yl)benzyloxy]cyclohexylamine hydrochloride (m.p. 280°-281° C. dec).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([C:8]([OH:10])=O)[N:7]=1.[NH2:11][C@@H:12]([CH3:28])[CH2:13][N:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[CH:20]=2)=[N:15]1>C(Cl)Cl>[Cl:27][C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][N:14]([CH2:13][C@@H:12]([NH:11][C:8]([C:6]3[N:7]=[C:3]([CH2:2][Cl:1])[O:4][CH:5]=3)=[O:10])[CH3:28])[N:15]=2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1coc(CCl)n1
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(CCl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
2-(chloromethyl)oxazole-4-carboxylic acid (400 mg, 2.476 mmol) and 1,3-DCC (5110 mg, 2.476 mmol) were dissolved in dry DCM and stirred for 30 min. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (646 mg, 2.476 mmol) in dry DCM was added to the reaction mixture and stirred at RT overnight. The reaction mixture was diluted with DCM and washed twice with water. Organic phase was evaporated to dryness and the product was purified with Flash-chromatography. Yield 36.9%. m/z [404.3+1].
Reaction SMILES: [OH:1][CH:2]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][CH:25]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:7][C@@H:6]1[C:20]([O:22]C)=[O:21].[OH-].[Na+].[ClH:38]>CO.C(OC(C)C)(C)C>[ClH:38].[ClH:38].[OH:1][CH:2]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][CH:25]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:7][C@@H:6]1[C:20]([OH:22])=[O:21]
Reactant: COC(=O)[C@H]1CN(CCSC2CCCCC2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: CO
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CCSC4CCCCC4)C[C@@H]3C(=O)O)c2c1

Procedure:
0.4 gof methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclohexylthio)ethyl]piperidine-3-carboxylate was heated in 3 cm3 of methanol to which had been added 0.48 cm3 of 5N aqueous sodium hydroxide solution under an inert atmosphere for 16 hours. After concentrating the reaction mass under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained was taken up in 5 cm3 of 6N hydrochloric acid and then 2.5 cm3 of methanol. The brown solution obtained was evaporated under the same conditions as above. The residue which resulted therefrom was taken up in 5 cm3 of diisopropylether, filtered off, and washed with 2 times 3 cm3 of the same solvent. The solid obtained was dried under reduced pressure (13 Pa) at a temperature in the region of 60° C. 0.37 g of (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclohexylthio)ethyl]piperidine-3-carboxylic acid dihydrochloride was obtained in the form of a solid with a brown color melting while softening in the region of 170° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[Si:14]([O:21][CH2:22][CH:23]=O)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C([BH3-])#N.C(O)(=O)C>CN(C=O)C>[Si:14]([O:21][CH2:22][CH2:23][NH:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Agent: [BH3-]C#N
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OCCNCc1nc2c(c(=O)[nH]1)COCC2
Temperature: 150 °C
Yield: 10.5 %

Procedure:
To a mixture of 2-(aminomethyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (50 mg, 0.28 mmol) and 2-(tert-butyldimethylsilyloxy)acetaldehyde (53 uL, 0.28 mmol) in DMF (1 mL) was added siliabond cyanoborohydride (300 mg, 0.30 mmol, 1 mmol/g) and acetic acid (0.158 mL, 2.8 mmol). The mixture was heated via microwave at 150° C. for 5 minutes, concentrated in vacuo and the resulting material was purified via HPLC to provide the title compound (10 mg, 11% yield). 1H NMR (400 MHz, CDCl3) δ 4.51 (s, 2 H), 3.87 (t, J=5.5 Hz, 2H), 3.71 (s, 2H), 3.58-3.68 (m, 2H), 2.62 (ddd, J=14.7, 5.3, 5.1 Hz, 4H), 0.82 (s, 9H), 0.00 (s, 6H). Retention time=1.52 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH3:29])[CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:17][CH:16]=3)=[O:13])=[CH:7][C:6]=2[CH:30]=1.[CH3:31][O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)=[O:34]>C(=O)([O-])[O-].[K+].[K+].C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:31][O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([C:2]2[CH:30]=[CH:6][C:5]3[CH2:11][CH2:10][CH2:9][C:8]([C:12]([NH:14][C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH3:29])[CH:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[CH:17][CH:16]=4)=[O:13])=[CH:7][C:4]=3[CH:3]=2)=[CH:37][CH:36]=1)=[O:34]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3CCC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
A mixture of 2-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-6,7-dihydro-5H-benzocyclohepten-8-carboxamide (0.95 g) and 4-methoxycarbonylphenylboronic acid (0.4 g) in 1M potassium carbonate (6 ml), ethanol (6 ml) and toluene (75 ml) was stirred for 30 minutes at room temperature under argon. Tetrakis(triphenylphosphine)palladium(0.12 g) was added to the mixture, and the mixture was refluxed for 6 hours under argon. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over MgSO4. The solvent was evaporated in vacuo. The residue was subjected to a silica gel column chromatography (ethyl acetate/methanol/triethylamine) to give 2-(4-methoxycarbonylphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-6,7-dihydro-5H-benzocyclohepten-8-carboxamide (0.4 g) as colorless prisms.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](OCC2C=CC=CC=2)=[C:6]([N+]([O-])=O)[CH:5]=1)=[O:3].C(C1C=CC=CC=1)(=O)C.[Br:30]Br.CC#N>C(Cl)(Cl)Cl.CO>[Br:30][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Solvent: CC(=O)c1ccccc1
Solvent: CC#N
Solvent: CO
Product: O=C(CBr)c1ccccc1

Procedure:
The optically pure epoxide 1 is prepared from commercially available 4-benzyloxy-3-nitroacetophenone. Thus, the acetophenone may be brominated with bromine in an inert organic solvent such as CH3CN, MeOH or chloroform to give the α-bromoacetophenone. The bromoacetophenone is then reduced with a borane reducing agent such as BH3THF or BH3Me2S in the presence of a chiral oxazaborolidine catalyst to give the optically active bromohydrin by extraction from aqueous acid in excellent yield (>98%) and good enantiomeric excess (ee=95%). An example of such a catalyst is cis-(1R,2S)-aminoindanol-B-Me, or AIBMe, which is the product of the reaction between cis-(1R,2S)-aminoindanol and trimethylboroxine, according to the procedure described in U.S. Pat. No. 5,495,821. The bromohydrin can be further enriched to >99.8% ee by crystallization. The absolute configuration of the bromohydrin is determined by the chirality of the oxazaborolidine catalyst. The resulting compound is converted to optically pure 4-benzyloxy-3-nitrostyrene oxide with a base such as aq. NaOH or K2CO3 in an alcohol solvent or solvent mixture such as MeOH/THF. The epoxide can be isolated by extraction of the reaction mixture with ethyl acetate/water, drying the organic phase and evaporating the solvent.
Reaction SMILES: [Br:1][CH:2]([CH2:19][CH2:20][CH2:21]Br)[C:3]([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:4].[H-].[Na+]>CN(C=O)C>[Br:1][CH:2]1[CH2:19][CH2:20][CH2:21][N:5]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:3]1=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)C(Br)CCCBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCCC(Br)C2=O)CC1
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To a solution of tert-butyl 4-(2,5-dibromopentanamido)piperidine-1-carboxylate (2.21 g, 5.00 mmol) dissolved in DMF (10 mL) was added 60% sodium hydride (0.220 g, 5.5 mmol). The reaction was allowed to stir for 2 hours and then concentrated under vacuum. The resulting material was diluted with water and EtOAc. The organic layer was separated and the aqueous layer washed with EtOAc. The combined organic layers were dried with MgSO4 and concentrated. The residue was purified over silica gel (2:1 hexanes:EtOAc) to give tert-butyl 3-bromo-2-oxo-1,4′-bipiperidine-1′carboxylate (1.35 g, 75%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:24])=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1.C(N(CC)CC)C>O1CCCC1>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[C:3]([CH3:24])=[C:2]([NH:1][C:31]([C:30]5[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=5)=[O:32])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Cc1c(N)cccc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2C)n(C)n1
Yield: 81.5 %

Procedure:
Using N-[6-(3-amino-2-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (130 mg, 0.402 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (83 mg, 0.523 mmol), triethylamine (122 mg, 1.21 mmol) and tetrahydrofuran (5.0 mL) as starting materials and in the same manner as in Example 96, the title compound (146 mg, 82%) was obtained as a white powder.
Reaction SMILES: COC(=O)[CH:4]([C:13]#[N:14])[C:5]1[CH:10]=[C:9]([S:11][CH3:12])[N:8]=[CH:7][N:6]=1.[Na+].[Cl-].O>CS(C)=O>[CH3:12][S:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]([CH2:4][C:13]#[N:14])[CH:10]=1
Reactant: COC(=O)C(C#N)c1cc(SC)ncn1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1cc(CC#N)ncn1

Procedure:
A Smith vial (10-20 mL) is charged with cyano-(6-methylsulfanyl-pyrimidin-4-yl)-acetic acid methyl ester (0.83 g, 3.72 mmol), NaCl (1.0 g), water (1 mL) and DMSO. The vial is sealed and irradiated at 160° C. for 50 minutes in Smith Synthesizer. The reaction mixture is partitioned between ethyl acetate and brine, and then filtered through a pad of celite and washed with ethyl acetate. The organic layer is separated and washed with brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by silica gel flash chromatography eluting with ethyl acetate in hexanes from 10% to 100% to afford (6-methylsulfanyl-pyrimidin-4-yl)-acetonitrile: 1H NMR 400 MHz (CDCl3) δ 8.93 (s, 1H), 7.47 (s, 1H), 4.20 (s, 2H), 2.56 (s, 3H); MS m/z 166.00 (M+1).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9](=[O:10])[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:7][CH2:6]1)(=[O:3])[CH3:2].[N+](=[CH2:22])=[N-]>C(OCC)C>[C:1]([O:4][CH:5]1[C:9](=[O:10])[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:22])=[O:18])=[CH:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CC=C(CCCCCCC(=O)O)C1=O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)CCCCCCC1=CCC(OC(C)=O)C1=O
Reaction time: 2.5 h
Yield: 100.7 %

Procedure:
A solution of (±)-7-[4-acetoxy-5-oxo-cyclopent-1-enyl]heptanoic acid (1.0 g; prepared as described in Example 1) in dry diethyl ether (10 ml) was treated with a solution of diazomethane (0.32 g) in dry diethyl ether (5 ml). The reaction mixture was allowed to stand at ambient temperature for 2.5 hours. The diethyl ether and excess diazomethane were removed in vacuo to yield methyl (±)-7-[4-acetoxy-5-oxocyclopent-1-enyl]heptanoate (1.06 g). [νmax 1740 cm-1, 1720 cm-1, 1625 cm-1, 1380 cm-1, 1240 cm-1 ; λmax (ethanol) 232 mμ; N.M.R. (approximately 10% solution in deuterochloroform); multiplets at 7.28δ, 3.35-2.7δ, 2.7-2.2δ, 2.5-2.0δ, 2.0-1.05δ, doublet of doublets at 5.15δ (J=3 cycles/second and 7 cycles/second), singlets at 3.7δ and 2.1δ.] .
Reaction SMILES: BrBr.[Cl:3][C:4]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=1[NH2:6].[S-:12][C:13]#[N:14].[Na+]>C(O)(=O)C>[NH2:14][C:13]1[S:12][C:7]2[CH:8]=[C:9]([Cl:11])[CH:10]=[C:4]([Cl:3])[C:5]=2[N:6]=1
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: N#C[S-]
Agent: BrBr
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1nc2c(Cl)cc(Cl)cc2s1
Reaction time: 16 h

Procedure:
197 g (1.23 mol) of bromine were slowly added dropwise, while cooling with ice, to a solution of 200 g (1.23 mol) of 2,4-dichloroaniline and 200 g (2.46 mol) of sodium thiocyanate in 1.5 1 of glacial acetic acid. Stirring was carried out for 16 hours at about 20° C., after which the solid was separated off and washed with 10% strength sodium hydroxide solution and water.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:20]=3)=[C:17]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[N:16]=[CH:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:20]=3)=[C:17]([C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)[N:16]=[CH:15]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccnc(Nc3ccccc3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(-c2ncn(C3CCNCC3)c2-c2ccnc(Nc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1-(1-t-butoxycarbonyl-4-piperidinyl)-4-(4-fluorophenyl)-5-(2-anilino-4-pyridinyl)imidazole (175 mg, 0.34 mmol) was added a cooled solution of TFA (12 mL) at -10° C. The reaction mixture was allowed to warm to ambient temperature and stirred at this temperature for 0.5 h. The solvent was evaporated under reduced pressure and the residue was dissoved in H2 O (10 mL) to which 3N HCl (0.5 mL) was added. The acidic solution was extracted twice with EtOAc and made basic with 50% NaOH and extracted three times with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound as a white solid; 0.70 g (50%): ESMS m/z=414 (M+ +H)
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH2:7][CH2:6]2.B(Br)(Br)Br.CO.C([O-])(O)=O.[Na+]>ClCCl>[CH3:12][N:8]1[C:9]2[C:5](=[CH:4][C:3]([OH:2])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc2c(c1)CCN2C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCc2cc(O)ccc21
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
To a solution of 5-methoxy-1-methylindoline (131 mg, 0.802 mmol) in 4.0 mL of dry dichloromethane was added boron tribromide (0.38 mL, 4.0 mmol) under nitrogen at 0° C. After the reaction mixture was stirred at the same temperature for 30 min, methanol (1 mL) was added with additional stirring at room temperature for 5 min. After the reaction mixture was neutralized by saturated NaHCO3 aqueous solution, the solution was extracted with diethyl ether (20 mL) twice. The combined extracts were washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 50/50) to obtain the title compound (63 mg, 53%).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]2)=[CH:13][C:12]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[NH2:23][C@H:20]1[CH2:19][CH2:18][C@H:17]([NH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=4)[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:5])[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4ccc(O)cc4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4ccc(O)cc4)cc23)CC1

Procedure:
Following general procedure A-2, tert-butyl trans-4-[3-(cyclopropanecarbonyl)-6-(4-hydroxyphenyl)quinolin-4-ylamino]cyclohexylcarbamate (48 mg, 0.096 mmol) was reacted with TFA (0.40 mL) to afford the desired product (17.8 mg, 46%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.16 (s, 1H), 8.37 (d, J=1.7 Hz, 1H), 8.07 (dd, J=8.7, 1.8 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.60-7.56 (m, 2H), 6.96-6.92 (m, 2H), 4.29-4.19 (m, 1H), 3.29-3.20 (m, 1H), 2.89-2.80 (m, 1H), 2.37 (d, J=12.8 Hz, 2H), 2.18 (d, J=11.7 Hz, 2H), 1.75-1.64 (m, 2H), 1.64-1.53 (m, 2H), 1.23-1.18 (m, 2H), 1.15-1.09 (m, 2H); ESI MS m/z 402 [C25H27N3O2+H]+; HPLC 98.5% (AUC), tR=11.38 min.
Reaction SMILES: [O:1]=[O+][O-].[CH:4]([C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]=2[N:23]=1)=C.CSC>C(Cl)Cl.O>[CH:4]([C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]=2[N:23]=1)=[O:1]
Reactant: C=Cc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCCC2
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCCc2ccc(C=O)nc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ozone was bubbled through a mixture of tert-butyl 2-vinyl-7,8-dihydro-5H-pyrido[2,3-b]azepine-9(6H)-carboxylate (intermediate 239, 470 mg, 1.66 mmol) in DCM (6.5 ml) at −78° C. After 15 minutes, the intermediate ozonide was treated with dimethyl sulfide (0.86 ml, 11.62 mmol) and then the reaction mixture was slowly warmed to room temperature. After 1.5 h, the mixture was diluted with H2O and extracted with DCM (3×). The combined organic layers were washed with sat. aq. NaHCO3 and brine, dried over Na2SO4 and evaporated to give the crude title compound as a light brown solid. (UPLC-MS 6) tR 1.04; ESI-MS 277.1 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([CH3:24])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[CH:17]=1)=[N:8][CH:9]=[N:10]2.Cl.Cl[CH2:27][C:28]1[N:29]=[CH:30][S:31][CH:32]=1>>[NH2:1][C@H:2]([CH3:24])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:27][C:28]3[N:29]=[CH:30][S:31][CH:32]=3)=[C:18]([Cl:23])[CH:17]=1)=[N:8][CH:9]=[N:10]2
Reactant: C[C@@H](N)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Reactant: ClCc1cscn1
Agent: Cl
Product: C[C@@H](N)COc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(Cl)c3)c12
Yield: 65 %

Procedure:
The procedure described in Example 65 (preparation of starting materials) was repeated using 4-[(5-{[(2R)-2-aminopropyl]oxy}quinazolin-4-yl)amino]-2-chlorophenol and 4-(chloromethyl)-1,3-thiazole hydrochloride give 5-{[(2R)-2-aminopropyl]oxy}-N-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]quinazolin-4-amine in 65% yield; NMR spectrum (DMSO-d6) 1.17 (d, 3H), 3.33-3.45 (m, 1H), 4.00 (dd, 1H)), 4.24 (dd, 1H), 5.32 (s, 2H), 7.11 (d, 1H), 7.30 (d, 1H), 7.33 (d, 1H), 7.67-7.82 (m, 3H), 8.23 (d, 1H), 8.51 (s, 1H), 9.14 (d, 1H); Mass spectrum MH+ 441.9.