Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)/[CH:3]=[C:4](\[C:15]1[NH:16][CH:17]=[CH:18][N:19]=1)/[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)=O.Cl.[C:22]([NH:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])(=[NH:24])[NH2:23].C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1>[C:32]([O:31][C:29]([NH:28][CH2:27][CH2:26][NH:25][C:22]1[N:23]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=2)[C:4]([C:15]2[NH:19][CH:18]=[CH:17][N:16]=2)=[CH:3][N:24]=1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)NCCNC(=N)N
Reactant: CN(C)/C=C(/C(=O)c1ccc(C#N)cc1)c1ncc[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NCCNc1ncc(-c2ncc[nH]2)c(-c2ccc(C#N)cc2)n1
Temperature: 100 °C
Yield: 82.9 %

Procedure:
4-[(2E)-3-(dimethylamino)-2-imidazolylprop-2-enoyl]benzenecarbonitrile (8.0 g, 30.0 mmol) in NMP (5 ml) was added to a stirred mixture of N-[2-(amidinoamino)ethyl](tert-butoxy)carboxamide, hydrochloride (13.8 g, 45 mmol)) and Cs2CO3 (11.72, 36.0 mmol) in NMP (15 ml). The reaction was heated to 100° C. for 48 hours. The reaction was followed by HPLC. Upon completion, the reaction was partitioned with water (50 ml) and dichloromethane (250 ml). The organic layer was separated and washed with water (2×50 ml), brine (50 ml), dried Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by flash chromatography eluting with 10% methanol in dichloromethane. After stripping off the solvents and drying in vacuo, 10.08 g of (tert-butoxy)-N-(2-{[4-(4-cyanophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)carboxamide was obtained as a dark red glass in 83% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Br[CH2:11][CH:12]=[O:13].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][CH2:11][CH:12]=[O:13]
Reactant: O=CCBr
Reactant: Cc1cccc(C)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cccc(C)c1NCC=O
Temperature: 150 °C

Procedure:
2,6-Dimethylaniline (100 grams), the diethyl acetal of 2-bromoacetaldehyde (59.1 grams) and sodium carbonate (31.8 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The mixture was heated at a temperature of about 150°C for a period of about 30 hours. After this time the reaction mixture was cooled to room temperature and was filtered. The filtrate was then distilled under vacuum to yield the desired product the diethyl acetal of 2-(2,6-dimethylanilino)acetaldehyde as the residue.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:36])([F:35])[F:34])=[C:23]([CH3:37])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl.C([O:45]CC)C.CCCCCC>CC(C)=O>[CH3:37][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([OH:45])=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:34])([F:36])[F:35]
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reactant: CCOCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 2,2,2-trichloro-1-(10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)ethanone of Step E (2.3 g, 3.9 mmol) in acetone (20 mL) was added 2.5 N sodium hydroxide (3.1 mL, 7.8 mmol). After stirring overnight, the reaction mixture was acidified with 2 N hydrochloric acid (4.3 mL, 8.6 mmol) and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown solid. Trituration with diethyl ether/hexane provided the title compound (1.32 g) as a white solid, m.p. 233-235° C.
Reaction SMILES: O.O.[Sn](Cl)Cl.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([N+:20]([O-])=O)[CH:11]=1)([CH3:9])([CH3:8])[CH3:7].[OH-].[Na+]>C(OCC)(=O)C>[C:6]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[C:12]([NH2:20])[CH:11]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)c1ccc(S(C)(=O)=O)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1ccc(S(C)(=O)=O)c(N)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
Tin(II) chloride dihydrate (2.73 g, 12.1 mmol) was added to a solution of the above sulfone (777 mg, 3.02 mmol) in ethyl acetate (15 mL). The mixture was heated to reflux for 0.5 h then cooled to room temperature and poured onto aqueous 2.0 M NaOH. The aqueous phase was extracted with diethyl ether and the combined organic layers were washed with saturated aqueous NaHCO3, dried over sodium sulfate, filtered and concentrated in vacuo to provide pure 5-tert-butyl-2-methanesulfonyl-phenylamine (618 mg, 90%) as a white solid.
Reaction SMILES: [CH2:1]([P:3](Cl)[CH2:4][CH3:5])[CH3:2].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([Li])=[CH:10][CH:9]=1.ClC1C=CC(Br)=CC=1>CCOCC>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([P:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:10][CH:9]=1
Reactant: [Li]c1ccc(Cl)cc1
Reactant: CCP(Cl)CC
Agent: Clc1ccc(Br)cc1
Solvent: CCOCC
Product: CCP(CC)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
A solution of 10 g. (0.08 mole) of diethylphosphinous chloride in 100 ml. of ether was added to a solution of p-chlorophenyllithium [prepared from 15.4 g. (0.08 mole) of p-chlorobromobenzene in 100 ml. of ether and 54 ml. of 1.5M n-butyllithium in hexane] under a nitrogen atmosphere. After 30 minutes, the reaction mixture was quenched with a few drops of ethyl acetate and the solvent was removed at reduced pressure. Distillation of the residual oil gave (p-chlorophenyl) (diethyl)phosphine, b.p. 86°-89° C. at 1.5 mm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[N:1]1([C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccccc1Br
Reactant: c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1-n1ccc2ccccc21
Reaction time: 3.5 h
Yield: 47 %

Procedure:
A mixture of indole (4.16 g; 35.53 mmol), methyl 2-bromobenzoate (2.64 g; 35.53 mmol), potassium carbonate (5.50 g) and CuO (2.0 g) in 40 mL of DMF was refiuxed uncler an argon atmosphere for 3.5 hrs. The crude material obtained upon extraction into ethyl acetate and removal of the solvent was purified on a silica gel column (10% ethyl acetate/hexane) to obtain 4.20 g (47%) of methyl 2-(1-indolyl)benzoate, 1H NMR (CDCl3): δ 3.45 (s, 3H); 6.43 (d, 1H); 6.99-7.20 (m, 4H); 7.35-7.42 (m, 2H); 7.60 (m, 2H); 7.88 (d, 1H).
Reaction SMILES: Cl.[CH3:2][C:3]1([NH2:13])[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5]([CH3:12])([CH3:11])[CH2:4]1.Br[CH2:15][CH2:16][CH2:17][C:18]#[N:19].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCCC1>[C:18]([CH2:17][CH2:16][CH2:15][NH:13][C:3]1([CH3:2])[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5]([CH3:12])([CH3:11])[CH2:4]1)#[N:19]
Reactant: N#CCCCBr
Reactant: CC1(C)CC(C)(C)CC(C)(N)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC(C)(C)CC(C)(NCCCC#N)C1
Yield: 78.7 %

Procedure:
A mixture of 1,3,3,5,5-pentamethylcyclohexylamine hydrochloride (1) (2-06 g, 10 mmol) 4-bromobutyronitrile (1.55 g. 10.5 mmol) and sodium carbonate (3.18 g, 30 mmol) in tetrahydrofuran (50 ml) was refluxed for 85 h, the poured into water (100 ml) and extracted with ether (3*30 ml). The combined organic phases were washed with brine (20 ml) and dried over K2CO3. The solution was filtered and evaporated and the crude product was purified by chromatography on silica gel, eluting with hexane-ether (10:1), (6:1), (4:1) to give product 2 (1.86 g, 86%) as an colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[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.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][C:26]=1[C:34]([F:37])([F:36])[F:35].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][C:2]2[CH:23]=[CH:22][CH:21]=[C:4]([O:5][C:6]3[CH:7]=[CH:8][C:9]4[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]5[CH2:20][CH2:19]5)=[O:17])[N:14]=4)[N:11]=3)[CH:3]=2)=[O:30])=[CH:27][C:26]=1[C:34]([F:35])([F:36])[F:37]
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.32 mmol) in N,N-dimethylformamide (6.0 mL) were added 4-chloro-3-(trifluoromethyl)benzoic acid (73 mg, 0.32 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (65 mg, 0.34 mmol) and 1-hydroxybenzotriazole (46 mg, 0.34 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→80/20) and precipitated from ethyl acetate/diisopropyl ether to give the title compound (130 mg, 77%) as a white powder.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[N:31][CH:30]=1>>[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:8](=[O:9])[CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH:13]=[N:12]2)[CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:31][CH:30]=1
Reactant: Cc1ccccc1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Reactant: COC(=O)c1ccc(N)nc1
Product: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3C)cc2=O)nc1
Yield: 32 %

Procedure:
Using the method described in Example 66, 3-cyclopentyl-2-(6-oxo-4-o-tolyloxy-6H-pyridazin-1-yl)-propionic acid (Intermediate 41) and 6-amino-nicotinic acid methyl ester afforded 6-[3-cyclopentyl-2-(6-oxo-4-o-tolyloxy-6H-pyridazin-1-yl)-propionylamino]-nicotinic acid methyl ester as a yellow solid (230 mg, 32%); ESI-LRMS m/e calcd for C26H28N4O5 [M+] 477, found 477 [M+H+]. 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.95-1.25 (m, 1H) 1.31-1.81 (m, 8H) 1.85-2.07 (m, 1H) 2.16 (s, 3H) 2.21-2.41 (m, 1H) 3.85 (s, 3H) 5.51-5.60 (m, 1H) 5.58 (d, J=2.8 Hz, 1H) 7.22 (dd, J=7.5, 1.5 Hz, 1H) 7.24-7.38 (m, 2H) 7.38-7.45 (m, 1H) 8.11 (d, J=8.8 Hz, 1H) 8.19 (d, J=2.8 Hz, 1H) 8.27 (dd, J=8.8, 2.4 Hz, 1H) 8.87 (d, J=2.4 Hz, 1H) 11.39 (s, 1H).
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:22]=[CH:21][C:9]([CH2:10][O:11][CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][CH:7]=1.[O-]CC.[Na+].C(O)C.Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)=[O:33]>O>[CH:46]1([CH2:45][O:44][C:36]2[CH:35]=[C:34]([C:32](=[O:33])[CH2:31][CH:14]([C:13](=[O:20])[CH2:12][O:11][CH2:10][C:9]3[CH:8]=[CH:7][C:6]([O:5][CH3:4])=[CH:22][CH:21]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:39]=[CH:38][C:37]=2[O:40][CH:41]([F:43])[F:42])[CH2:48][CH2:47]1
Reactant: O=C(CBr)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: CCOC(=O)CC(=O)COCc1ccc(OC)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CC(=O)c1ccc(OC(F)F)c(OCC2CC2)c1)C(=O)COCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
To 460 ml of an ethanol solution containing 13.5 g (50.7 mmol) of ethyl 4-(4-methoxybenzyloxy)-3-oxobutyrate (see WO 2004060890) was added 18.9 ml (50.6 mmol) of 21% sodium ethoxide-ethanol solution under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Then, to the above mixture was added dropwise 300 ml of ethanol solution containing 16.5 g (42.3 mmol) of 2-bromo-1-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)ethanone obtained in Reference example 45-(a) under ice-cooling, and the mixture was further stirred at 10° C. or lower for 2.5 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=4:1→7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 14.0 g of the title compound as a pale yellowish oil. (Yield: 63%)
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=O.N1CCCCC1.[CH2:19]([O:21][C:22](=[O:38])[CH2:23][C:24]([C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:25])[CH3:20]>C1C=CC=CC=1>[C:34]([O:33][C:31]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[C:24](=[O:25])/[C:23](/[C:22]([O:21][CH2:19][CH3:20])=[O:38])=[CH:1]/[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[O:32])([CH3:36])([CH3:37])[CH3:35]
Reactant: O=Cc1ccc(CC(=O)O)cc1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CCOC(=O)/C(=C\c1ccc(CC(=O)O)cc1)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 33.6 %

Procedure:
To a solution of 4-formylphenylacetic acid (4.31 g, 26.3 mmol) in benzene (75 ml) and piperidine (0.95 ml, 9.5 mmol) was added tert-butyl (2S)-2-(3-ethoxy-3-oxopropanoyl)-1-pyrrolidinecarboxylate (8.1 g, 28.4 mmol). The solution was refluxed under a Dean-Stark trap for 8 h. The solvent was removed by rotary evaporation. The product was purified by silica gel column chromatography (silica gel/75% ethyl acetate in petroleum ether) giving A as an off-white solid (3.81 g, 34% yield). LCMS m/z 432 (MH)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[C:4]([C:13]([O:15][CH3:16])=[O:14])[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=1.CO.[CH:20]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[C:3]([O:17][CH3:20])=[C:4]([C:13]([O:15][CH3:16])=[O:14])[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1sc(-c2ccnn2C)c(Br)c1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1sc(-c2ccnn2C)c(Br)c1OC
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a solution of methyl 4-bromo-3-hydroxy-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (175 mg, 0.554 mmol), MeOH (26 μL, 0.609 mmol), PPh3 (189 mg, 0.720 mmol) in THF (6 mL) at 25° C. was added DEAD (113 μL, 0.720 mmol) in one portion. After 30 min, the reaction was concentrated and purified via column chromatography (silica, 20% EtOAc in hexanes) affording the title compound (135 mg, 74%) as a white solid: LC-MS (ES) m/z=332 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:21])[CH2:5][CH:6]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[C:7]=1[C:8](O)=[O:9].[Cl:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([NH2:32])[CH:30]=2)[NH:25][N:24]=1.N=C=N>CN(C=O)C>[Cl:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([NH:32][C:8]([C:7]3[CH:6]([C:11]4[CH:20]=[CH:19][C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[CH:12]=4)[CH2:5][C:4](=[O:21])[NH:3][C:2]=3[CH3:1])=[O:9])[CH:30]=2)[NH:25][N:24]=1
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Reactant: CC1=C(C(=O)O)C(c2ccc3ccccc3c2)CC(=O)N1
Agent: N=C=N
Solvent: CN(C)C=O
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Cl)c3c2)C(c2ccc3ccccc3c2)CC(=O)N1
Yield: 12.9 %

Procedure:
The product from Example 1, Step 2 (100 mg, 0.36 mmol, 1.0 equiv) was combined with 3-chloro-1H-indazol-5-amine (90 mg, 0.53 mmol, 1.5 equiv) and PS-carbodiimide resin (0.994 mmol/g loading, 564 mg, 0.53 mmol, 1.5 equiv) in 5 mL of DMF and reacted overnight at room temperature. The reaction mixture was filtered and washed alternately with MeOH and CH2Cl2 (twice), then with diethyl ether. The filtrate was concentrated en vacuo and redissolved in ethyl acetate. The solution was washed with 0.5 N HCl, 0.5 N NaOH, and satd. NaCl. The organic layer was concentrated en vacuo. The residue was triturated with methylene chloride/methanol/ethyl acetate to provide 20 mg (13%) of the title compound as a light pink powder. MS (ES+) m/e 431 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6](O)=[O:7].C(Cl)(=O)C([Cl:16])=O.CN(C)C=O>C(Cl)Cl>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6]([Cl:16])=[O:7]
Reactant: Cc1ccccc1CCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccccc1CCC(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-methylhydrocinnamic acid (3.0 g, 18.3 mmole), oxalyl chloride (3.19 ml, 36.6 mmole) and methylene chloride (30 ml) was cooled in an ice bath and N,N-dimethylformamide (0.14 ml, 1.81 mmole) was added dropwise. The mixture was stirred at room temperature overnight. Concentration in vacuo gave 3-(2-methylphenyl)propanoyl chloride which was taken up in methylene chloride and used in the next step as a crude.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12].C>C(Cl)Cl>[CH3:1][S:2]([NH:5][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][Br:6])(=[O:4])=[O:3]
Reactant: CS(N)(=O)=O
Reactant: O=C(Cl)CCCCBr
Agent: C
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)CCCCBr
Yield: 86 %

Procedure:
A mixture of 0.950g (0.01 mole) of methanesulfonamide and 1.80 g. (0.01 mole) of 5-bromovaleric acid chloride was heated on a steam bath until gas evolution ceased (ca. 5 minutes). The brown reaction mixture was allowed to cool and was dissolved in methylene chloride. The methylene chloride solution was treated with Darco, was filtered, and was diluted with hexane with cooling to afford the white, crystalline N-methanesulfonyl-5-bromovaleramide weighing 2.22 g. (86.0% yield) which melted at 88°-89°.
Reaction SMILES: [CH3:1][C:2]([CH3:20])=[CH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[N:10]=[CH:11]2)=[CH:6][CH:5]=1.C(OCC)(=O)C.C(O)C>[Pd]>[CH2:3]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[N:10]=[CH:11]2)=[CH:6][CH:5]=1)[CH:2]([CH3:20])[CH3:1]
Reactant: CC(C)=Cc1ccc2cc(NC(=O)C3CC3)ncc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)Cc1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
To a solution of N-(7-(2-methylprop-1-enyl)isoquinolin-3-yl)cyclopropanecarboxamide (100.0 mg, 0.2891 mmol) in ethyl acetate (10.0 mL, 102 mmol) was added palladium (30.6 mg, 0.0288 mmol) (10 wt % on carbon). The reaction vessel was purged first with nitrogen and then with hydrogen, and stirred at room temperature under a hydrogen balloon for 2 hours. Ethanol (5.0 mL, 86 mmol) and palladium (41.9 mg, 0.0394 mmol) were added, and the reaction maintained at room temperature for 19 hours. The reaction mixture was then filtered through celite and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 54.4 mg (70%) of N-(7-isobutylisoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT=5.079, M+H=269.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.06 (s, 1H), 8.41 (s, 1H), 7.86-7.70 (m, 2H), 7.54 (dd, J=8.6, 1.3 Hz, 1H), 2.62 (d, J=7.1 Hz, 2H), 2.13-2.01 (m, 1H), 1.94 (dp, J=13.4, 6.7 Hz, 1H), 0.90 (d, J=6.6 Hz, 6H), 0.86-0.75 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:23]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:23](=[O:24])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)NCCCCBr
Reactant: O=c1ccc2cc(Br)ccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCn1c(=O)ccc2cc(Br)ccc21
Reaction time: 0.25 h

Procedure:
To a solution of 6-bromoquinolin-2(1H)-one (430 mg, 1.91 mmol) in tetrahydrofuran (8 ml) was added sodium bis(trimethylsilyl)amide (2.1 ml, 2.08 mmol). After 15 minutes, 4-(boc-amino)butyl bromide (403 mg, 1.6 mmol) was added. The solution was stirred for 15 hours, concentrated and purified by flash chromatography to provide the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:3]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[CH3:32][S:33]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:5]1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1csc(N2CC(O)C2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N[C@@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (370 mg, 0.827 mmol) (obtained as described in Reference Example 53(7)) in methylene chloride (19 ml) were added methanesulfonyl chloride (192 μl, 2.48 mmol) and triethylamine (348 μl, 2.48 mmol) in an ice bath. The reaction mixture was brought to room temperature in 10 minutes, and then stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (98:2) as the eluant to afford 3-methanesulfonyloxy-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (422 mg, yield 97%) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccccc3F)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2-fluoro-phenylboronic acid to give [1-(2-fluoro-phenyl)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 335(MH+).