Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)[CH3:12])=[CH:8][C:6]=2[N:7]=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[O:26]1[CH2:27][CH2:28][N:23]([C:4]2[C:5]3[S:10][C:9]([CH:11]([N:13]4[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]4)[CH3:12])=[CH:8][C:6]=3[N:7]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([NH2:29])=[N:31][CH:32]=3)[N:3]=2)[CH2:24][CH2:25]1
Reactant: CC(c1cc2nc(Cl)nc(N3CCOCC3)c2s1)N1CCN(S(C)(=O)=O)CC1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: CC(c1cc2nc(-c3ccc(N)nc3)nc(N3CCOCC3)c2s1)N1CCN(S(C)(=O)=O)CC1

Procedure:
2-Chloro-6-[1-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in General Procedure A. Purification on silica yielded 299. NMR: (CDCl3): 1.43 (3H, d, J 7.2, Me), 2.56-2.68 (4H, m, CH2), 2.73 (3H, s, Me), 3.18-3.29 (4H, m, CH2), 3.80-3.83 (4H, m, CH2), 3.94-3.99 (5H, m), 4.58 (2H, br s, NH2), 6.48 (1H, d, J 8.1, Ar), 7.19 (1H, s, Ar), 8.38 (1H, dd, J 8.1 and 2.0, Ar) and 9.07 (1H, d, J 2.0, Ar). MS: (ESI+): MH+=504.26
Reaction SMILES: [CH2:1]([CH:3]([CH2:13][CH3:14])[CH2:4][CH:5]=[CH:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17].C1(C=CC(O)=CC=1)O>C(#N)C>[CH2:13]([CH:3]([CH2:1][CH3:2])[CH2:4][CH:5]1[CH2:17][CH:16]([C:15]([O:19][CH2:20][CH3:21])=[O:18])[CH:6]1[N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:14]
Reactant: CCC(CC)CC=CN1CCCCC1
Reactant: C=CC(=O)OCC
Agent: Oc1ccc(O)cc1
Solvent: CC#N
Product: CCOC(=O)C1CC(CC(CC)CC)C1N1CCCCC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1-(4-Ethyl-1-hexenyl)piperidine (98.1 g) and acetonitrile (70 mL) were mixed. To the mixture were added ethyl acrylate (53.0 mL) and hydroquinone (271 mg). The mixture was stirred at 100° C. overnight. The reaction mixture was concentrated in vacuo to give the title compound (132 g) as a crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH:13]([N:17]([CH3:28])[C:18]([O:20]CC1C=CC=CC=1)=[O:19])[C:14]([OH:16])=O.S(Cl)(Cl)=O>CCCCCC>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH:13]1[C:14](=[O:16])[O:20][C:18](=[O:19])[N:17]1[CH3:28]
Reactant: COc1cccc(CCC(C(=O)O)N(C)C(=O)OCc2ccccc2)c1OC
Solvent: CCCCCC
Solvent: O=S(Cl)Cl
Product: COc1cccc(CCC2C(=O)OC(=O)N2C)c1OC

Procedure:
18.5 g of 4-(2,3-dimethoxyphenyl)-2-(N-methyl-N-benzyloxycarbonyl-amino)-butyric acid (0.048 mole) and 28.7 g of thionyl chloride are placed into a 250 ml round-bottomed flask, refluxing for 2 hours then distilling off under vacuum the thionyl chloride until obtaining a thick oil. The oil is taken up into 100 ml of hexane, stirring until solidification, then it is decanted and triturated with 100 ml more of hexane, filtered and dried under vacuum at 30° C. to obtain a fine crystalline powder. Yield: 12.5 g, 93% (moles), 68% (weight).
Reaction SMILES: C[N:2](/[CH:4]=[C:5]1/[C:6](=[O:15])[NH:7][CH2:8][C:9]2[C:14]/1=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:3].[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27]C(N)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>C1(C)C=CC=CC=1>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:3]([NH:2]/[CH:4]=[C:5]3\[C:6](=[O:15])[NH:7][CH2:8][C:9]4[C:14]\3=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CN(C)/C=C1/C(=O)NCc2ccccc21
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc(N/C=C3\C(=O)NCc4ccccc43)cc2)CC1
Temperature: 110 °C
Yield: 25.2 %

Procedure:
A toluene (3 mL) solution containing (4E)-4-[(dimethylamino)methylene]-1,4-dihydro-3(2H)-isoquinolinone (300 mg, 1.48 mmol) and 4-(4-methyl-piperazin-1-yl) -phenylamine (318 mg, 1.66 mmol) is heated at 110° C. for 4 h. Using the same workup as example 1, 0.13 g (25%) orange solid is obtained: mp 186-187° C. (dec.); HRMS (ESI) m/z calcd for C21H24N4O 349.20229. found 349.20180 (M+H)+1.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]=[C:9]([C:18]#[N:19])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:1]1([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)[CH:15]=3)[N:10]=[C:9]([C:18]#[N:19])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCN(CCCl)CC1
Reactant: N#Cc1nc(NC2CCCC2)c2cc(O)ccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1CCN(CCOc2ccc3nc(C#N)nc(NC4CCCC4)c3c2)CC1

Procedure:
4-Cyclopentylamino-6-hydroxy-quinazoline-2-carbonitrile (0.4 mmol), 1-(2-Chloro-ethyl)-4-methyl-piperazine dihydrochloride (0.55 mmol) and cesium carbonate (4 mmol) are stirred in DMF (5 ml) at RT for 20 hours. The suspension is filtered, washed with little DMF and water is added to the filtrate until the solution gets turbide. The precipitate formed is filtered off, washed with water and dried (vacuum). A powder with mp. 110-112° C., Rf=0.48 (CH2Cl2/MeOH=9:2) is obtained.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].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.C(O)C>[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(CN2CCNCC2)cc1
Reactant: OB(O)c1ccccc1C(F)(F)F
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: FC(F)(F)c1ccccc1-c1ccc(CN2CCNCC2)cc1
Temperature: 120 °C

Procedure:
This compound could be made in the following manner: 1-(4-Bromo-benzyl)-piperazine would be combined with 1 equ of 2-(Trifluoromethyl)phenyl boronic acid, 10 mol % of tetrakis(triphenylphosphine)palladium(0), 2M sodium carbonate solution, toluene and ethanol. The reaction mixture would be heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture would then be filtered through Celite and concentrated in vacuo. The residue would then be purified by flash chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.ClC1C=C(C=CC=1Cl)CC1C=C(C(N)C(C)C)C=C[N:18]=1>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:11])[NH2:18])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: CC(C)C(N)c1ccnc(Cc2ccc(Cl)c(Cl)c2)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cccc(NC(N)=O)c1
Reaction time: 1 h

Procedure:
3-methoxyphenyl isocyanate (37 μl, 0.28 mmol) was added to a solution of provide 1(RS)-[(3,4-dichlorobenzyl)pyridin-4-yl]-2-methylpropylamine (88 mg, 0.28 mmol) in methylene chloride solution (2 ml) at room temperature. After 1 h, the reaction mixture was diluted with ethyl acetate and washed with sodium bicarbonate solution (5 ml). The organic layer was separated and dried over magnesium sulfate, filtered and concentrated to provide 1-{1(RS)-[1-(3,4-dichlorobenzyl)piperidin-4-yl]-2-methylpropyl)}-3-(3-methoxyphenyl)urea. (104 mg) as a white solid. mp 161.4-161.8° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1>O1CCOCC1>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][N:14]2[CH2:15][CH2:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)=[CH:5]1
Reactant: c1ccc2cnccc2c1
Reactant: BrCCc1c[nH]c2ccccc12
Solvent: C1COCCO1
Product: c1ccc2c(c1)CCN(CCc1c[nH]c3ccccc13)C2

Procedure:
A solution of 3-(2-bromo-ethyl)-1H-indole (4.48 g, 20 mmol) and isoquinoline (5.33 g, 40 mmol) in abs. dioxan (50 mL) was stirred for 6 h at 80° C. The solvent was then removed in a vacuum, the residue mixed with CHCl3 (100 mL) and washed twice with water. The organic phase was dried over Na2SO4, concentrated to low volume in a vacuum, and the remaining residue purified by flash chromatography with CHCl3/MeOH (50:1).
Reaction SMILES: N#N.C[O:4][C:5]([C:7]1[N:8]=[CH:9][O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:13]=1)=[O:6].[Li+].[OH-]>C1COCC1.O>[C:24]([Si:21]([CH3:23])([CH3:22])[O:20][CH2:19][CH2:18][C:14]1[CH:13]=[C:12]([C:11]2[O:10][CH:9]=[N:8][C:7]=2[C:5]([OH:6])=[O:4])[CH:17]=[CH:16][CH:15]=1)([CH3:26])([CH3:25])[CH3:27]
Reactant: COC(=O)c1ncoc1-c1cccc(CCO[Si](C)(C)C(C)(C)C)c1
Agent: N#N
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(-c2ocnc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-{3-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-phenyl}-oxazole-4-carboxylic acid methyl ester (110 mg, 0.30 mmol) in THF (0.5 mL) and H2O (0.5 mL) was treated with LiOH (18 mg, 0.43 mmol). The reaction mixture was stirred at rt for 2.5 h, extracted with EA (2×5 mL), the organic layer was washed with 1N HCl (2 mL) dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a white solid. LC-MS-conditions 02: tR=1.08 min, [M+H]+=348.40.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[N:11]=[CH:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:20]([C:38](=[O:46])[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:19][N:18]=2)=[N:14][CH:15]=1)#[N:9]>ClCCl>[C:8]([C:10]1[N:11]=[CH:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:20]([C:38]([NH:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[O:46])=[CH:19][N:18]=2)=[N:14][CH:15]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2C(=O)Nc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cnc(Nc2cc(NCC3CCNCC3)c(C(=O)Nc3ccccc3)cn2)cn1
Reaction time: 0.33 h
Yield: 65.3 %

Procedure:
TFA (0.05 mL) was added to a solution of tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(phenylcarbamoyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (11.0 mg, 0.02 mmol) in dichloromethane (0.5 mL) at room temperature. After 20 minutes, solvent was evaporated and the crude product was purified by ion exchange on SCX-II acidic resin (500 mg) eluting with methanol, then 2M ammonia-methanol. The basic fractions were combined and solvent was evaporated to give 6-(5-cyanopyrazin-2-ylamino)-N-phenyl-4-(piperidin-4-ylmethylamino)nicotinamide as a yellow solid (5.6 mg, 63%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:42][O:43][C:44](=[O:62])[C@H:45]([NH2:61])[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][C:56]([C:59]#[N:60])=[CH:55][CH:54]=2)=[CH:49][CH:48]=1>>[C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](=[O:20])[NH:61][C@@H:45]([C:44]([O:43][CH3:42])=[O:62])[CH2:46][C:47]2[CH:48]=[CH:49][C:50]([C:53]3[CH:58]=[CH:57][C:56]([C:59]#[N:60])=[CH:55][CH:54]=3)=[CH:51][CH:52]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: COC(=O)[C@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Agent: Cl
Product: COC(=O)[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Yield: 81.1 %

Procedure:
(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (75 mg) was coupled with (R)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (43 mg) according to General Procedure L to give (S)-8-[(R)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (88 mg). This intermediate was deprotected according to General Procedure C to give (R)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester hydrochloride. This compound (100 mg) was further reacted with 2-acetylamino-4-methyl-thiazole-5-sulfonyl chloride to give (R)-2-({(S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester according to General Procedure E. This product (69 mg) was deacylated followed by hydrolysis according to General Procedures N and B to give the title compound. LCMS (m/z): 910.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[OH:10])#[N:2].[N+:11]([O-])([OH:13])=[O:12].O>C(O)(=O)C>[C:1]([C:3]1[CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=[C:5]([CH3:9])[C:4]=1[OH:10])#[N:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(C#N)c1O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C#N)c1O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a heated (45° C.), stirred solution of 2-cyano-6-methylphenol (5 g) in glacial acetic acid (32 mL) was added a solution of fuming nitric acid (3.2 mL) in acetic acid (12 mL). After 1 h at elevated temperature (45° C.), the reaction mixture was cooled (to 0° C.), water added and partitioned between DEE/water. The organic phase was washed with water, brine, dried over sodium sulfate and concentrated in vacuo to afford a solid. Recrystallization from DEE afforded the title compound as yellow crystals (3.6 g).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH:3]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH3:4].[CH2:17]1[C@@H:21]([CH2:22][CH2:23][CH2:24][CH2:25][C:26](O)=[O:27])[S:20][S:19][CH2:18]1>>[CH3:16][N:2]([CH3:1])[CH:3]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[CH2:17][CH2:18][S:19][S:20]1)[CH3:4]
Reactant: CC(c1cccc(OCCCN)c1)N(C)C
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Product: CC(c1cccc(OCCCNC(=O)CCCCC2CCSS2)c1)N(C)C

Procedure:
5-[1,2]dithiolan-3-yl-pentanoic acid {3-[3-(1-dimethylamino-ethyl)-phenoxy]-propyl}-amide (19) was synthesized from 19c (150 mg, 0.67 mmol) and lipoic acid (210 mg, 1.02 mmol) following the procedure described for 17, and purified by gravity column. Elution with petroleum ether/toluene/CH2Cl2/MeOH/aqueous 30% ammonia solution (6:1:1.5:1.5:0.01) afforded 19 as a waxy solid; 30% yield, 1H NMR (200 MHz, CDCl3) δ 7.27 (t, J=8.2 Hz, 1H); 6.78-6.98 (m, 3H), 5.99 (br t, 1H); 4.09 (t, J=6.0 Hz, 2H); 3.21-3.62 (m, 5H), 3.05-3.19 (m, 3H), 2.40-2.53 (m, 1H), 2.32 (s, 6H), 2.22 (t, J=7.2 Hz, 2H); 1.81-2.0 (m, 3H), 1.65-1.73 (m, 4H), 1.47 (d, J=6.6 Hz, 3H); MS (ESI+) m/z 411 (M+H)+. Anal. Calculated for C21H34N2O2S2: C, 61.42; H, 8.35; N, 6.82. Found: C, 61.62; H, 8.36, N, 6.80.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH2:32]([C@H:34]1[CH2:39][NH:38][CH2:37][CH2:36][N:35]1C(OC(C)(C)C)=O)[CH3:33]>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][N:38]3[CH2:37][CH2:36][NH:35][C@@H:34]([CH2:32][CH3:33])[CH2:39]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CC[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Product: CC[C@H]1CN(Cc2cn(CC3CC3)c(=O)c3ccc(-c4cc(C(=O)NC5CC5)cc(F)c4C)cc23)CCN1

Procedure:
The title compound was prepared as a solid according to the method of Example 81 using the product of Example 75 step i) and (S)-2-ethyl-piperazine-1-carboxylic acid, tert-butyl ester.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20]3=[C:21]([CH2:23][O:24][CH2:25][CH2:26][N:19]3[C@H:18]3[CH2:27][CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][C@@H:17]23)[CH:22]=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:13][C:14]1[CH:15]=[C:16]2[C:20]3=[C:21]([CH2:23][O:24][CH2:25][CH2:26][N:19]3[C@H:18]3[CH2:27][CH2:28][NH:29][CH2:30][C@@H:17]23)[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Reactant: O=Cc1ccccc1C(F)(F)F
Product: FC(F)(F)c1ccccc1CNc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCOC2

Procedure:
Using 2-(trifluoromethyl)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 128. 1H NMR(CDCl3) δ: 7.72-7.60 (m, 2H), 7.52 (t, 1H, J=7.7 Hz), 7.38 (t, 1H, J=7.5 Hz), 6.39 (d, 1H, J=1.8 Hz), 6.21 (d, 1H, J=1.8 Hz), 4.57 (ABq, 2H, JAB=14.3 Hz), 4.50 (s, 2H), 4.20 (app d, 1H, J=12.0 Hz), 3.74 (app t, 1H), 3.36-3.30 (m, 1H), 3.28-3.18 (m, 2H), 3.08 (dd, 1H, J=12.5, 6.2 Hz), 3.00-2.90 (m, 2H), 2.65 (app t, 1H), 2.50 (app t, 1H), 2.02-1.90 (m, 2H). LRMS (ES)+: 404.3 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([N-:9][C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[K+].[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Cl)([O-:15])=[O:14]>CN(C)C=O>[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][N:9]1[C:7](=[O:8])[C:5]2=[CH:6][CH:1]=[CH:2][CH:3]=[C:4]2[C:10]1=[O:11])([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccccc1CCl
Reactant: O=C1[N-]C(=O)c2ccccc21
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The mixture of 54.0 of N-potassium phthalimide, 50.0 g of o-nitrobenzyl chloride and 120 ml of dimethylformamide is refluxed for 3 hours and poured into 900 ml of ice-water while stirring. After 30 minutes, it is filtered, and the residue washed with water, to yield the N-o-nitrobenzyl-phthalimide melting at 190°-209°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1F)[O:9][CH2:8][CH2:7][CH:6]2[C:14]([OH:16])=[O:15])#[N:2].C([O-])([O-])=O.[K+].[K+].[Cl:23][C:24]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:25]=1[CH2:26][CH2:27][NH:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>CN1CCCC1=O>[Cl:23][C:24]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:25]=1[CH2:26][CH2:27][NH:28][C:29]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:12]2[CH:11]=[C:10]3[C:5]([CH:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][O:9]3)=[CH:4][C:3]=2[C:1]#[N:2])=[CH:32][CH:31]=1)=[O:37]
Reactant: O=C(NCCc1ccc(Cl)cc1Cl)c1ccc(O)cc1
Reactant: N#Cc1cc2c(cc1F)OCCC2C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)NCCc3ccc(Cl)cc3Cl)cc1)OCCC2C(=O)O
Temperature: 140 °C
Reaction time: 5 h
Yield: 5.2 %

Procedure:
6-cyano-7-fluorochroman-4-carboxylic acid (40 mg, 0.18 mmol) was diluted with N-methylpyrrolidone (2 mL) followed by the addition of K2CO3 (100 mg, 0.72 mmol) and N-(2,4-dichlorophenethyl)-4-hydroxybenzamide (56 mg, 0.18 mmol). The reaction was bubbled with argon for 10 minutes and then heated at 140° C. After stirring for 5 hours, the reaction was loaded directly onto a Biotage 25 cartridge eluting with 0.5% acetic acid/0.5% methanol/CH2Cl2 to 0.5% acetic acid/10% methanol/CH2Cl2 to yield the title compound (4.8 mg, 5.2% yield). 1H NMR (400 MHz, CD3OD) δ 8.57-8.59 (m, NH), 7.84 (d, J=8.7 Hz, 2H), 7.69 (s, 1H), 7.44 (d, J=2.4 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.26 (dd, J=1.7, 8.0 Hz, 1H), 7.13 (d, J=8.7 Hz, 2H), 6.40 (s, 1H), 4.29-4.34 (m, 1H), 4.20-4.26 (m, 1H), 3.85 (t, J=5.1 Hz, 1H), 3.64 (q, J=6.1 Hz, 2H), 3.06 (t, J=7.0 Hz, 2H), 2.32-2.37 (m, 1H), 2.08-2.16 (m, 1H).
Reaction SMILES: [CH2:1]([O:9][CH2:10][C:11]12[CH2:17][CH:14]([CH2:15][CH2:16]1)[CH:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(OO)(=[O:20])C.O>C(Cl)Cl>[CH2:1]([O:9][CH2:10][C:11]12[CH2:17][CH:14]([CH2:15][CH2:16]1)[CH:13]1[CH:12]2[O:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOCC12C=CC(CC1)C2
Reactant: CC(=O)OO
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCOCC12CCC(C1)C1OC12

Procedure:
A 500 mL round bottom flask equipped with a stirrer bar was charged with 14.3 g (0.056 mol) of 4-n-octyloxymethyl-bicyclo[2.2.1]hept-2-ene, and 80 mL of methylene choride. Peracetic acid (15.6 g, 35 wt. % in acetic acid; 0.072 mol) in methylene chloride (70 mL) was added dropwise to the above mixture over 20 min. in an ice bath. After the above mixture was reacted at room termperature for 3 hrs., 100 mL of water was added to the above reaction mixture, the organic layer was washed with saturated sodium carbonate solution (2×100 mL), then with water (2×100 mL), and dried with sodium sulfate. The solvent was evaporated and the residue was vacuum distilled to give pure product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][NH:6][C:7](=[O:10])[CH2:8][NH2:9])[CH3:2].[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([NH:21][C:22]3[C:23]4[S:30][C:29]([C:31]5[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=5)=[CH:28][C:24]=4[N:25]=[CH:26][N:27]=3)=[CH:18][CH:19]=2)[CH:14]=[CH:13]1>>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][NH:6][C:7](=[O:10])[CH2:8][NH:9][CH2:35][C:34]1[CH:33]=[CH:32][C:31]([C:29]2[S:30][C:23]3[C:22]([NH:21][C:17]4[CH:16]=[C:15]5[C:20](=[CH:19][CH:18]=4)[NH:12][CH:13]=[CH:14]5)=[N:27][CH:26]=[N:25][C:24]=3[CH:28]=2)=[CH:38][CH:37]=1)[CH3:2]
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: CCOC(=O)CNC(=O)CN
Product: CCOC(=O)CNC(=O)CNCc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from (2-amino-acetylamino)-acetic acid ethyl ester and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 98-115° C.; LC-MS: 515 (MH+); HPLC RT: 3.88 minutes.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:11][C:10]3[CH:12]=[C:13]([O:19][CH3:20])[C:14]([N+:16]([O-])=O)=[CH:15][C:9]=3[N:8]([CH3:21])[C:7](=[O:22])[CH2:6]2)[CH2:3][CH2:2]1.C(O)C.C(OCC)(=O)C>[Pd]>[NH2:16][C:14]1[C:13]([O:19][CH3:20])=[CH:12][C:10]2[CH2:11][N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH2:6][C:7](=[O:22])[N:8]([CH3:21])[C:9]=2[CH:15]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C)C(=O)CN(CC1CC1)C2
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N)N(C)C(=O)CN(CC1CC1)C2
Yield: 78.1 %

Procedure:
4-Cyclopropylmethyl-7-methoxy-1-methyl-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.5 g, 0.002 mol) was hydrogenated in Ethanol (40 mL, 0.7 mol) and Ethyl acetate (40 mL, 0.4 mol) with 10% Pd/C (10:90, Palladium:carbon black, 0.082 g) in an analogous manner to example N26-F to give 8-Amino-4-cyclopropylmethyl-7-methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one as an oil (0.43 g, 90%). LCMS (m/e) 276 (M+1); 1H-NMR (DMSO, 400 MHz) δ 6.76 (s, 1H), 6.57 (s, 1H), 4.88 (s, 2H), 3.77 (s, 3H), 3.44 (s, 2H), 3.05 (s, 3H), 2.89 (s, 2H), 2.38-2.37 (d, 2H, J=15.41 Hz), 1.26-1.24 (m, 1H), 0.85-0.75 (m, 2H), 0.49-0.47 (d, 2H, J=7.83 Hz), 0.16-0.15 (d, 2H, J=4.80 Hz).