Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[I:20][C:21]1[CH:29]=[C:28]2[C:24]([C:25]([CH3:31])([CH3:30])[CH2:26][NH:27]2)=[CH:23][CH:22]=1.Cl.O1CCOCC1>CN1C(=O)CCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:27]3[C:28]4[C:24](=[CH:23][CH:22]=[C:21]([I:20])[CH:29]=4)[C:25]([CH3:31])([CH3:30])[CH2:26]3)=[C:3]([CH3:19])[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: CC1(C)CNc2cc(I)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(I)cc21
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (250 mg, 0.92 mmol), 6-iodo-3,3-dimethylindoline (250 mg, 0.92 mmol) and 4.0M solution of HCl in 1,4-dioxane (0.22 mL, 0.92 mmol) in NMP (1.0 mL) and heating at 150° C. for 3 h in the microwave. After purification 7-fluoro-4-(6-iodo-3,3-dimethylindolin-1-yl)-3-methyl-2-(pyridin-2-yl)quinoline was obtained as a foam. Mass Spectrum (ESI) m/e=510 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:27])=[CH:24][C:23]=1[O:38][CH3:39].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH3:12][N:11]1[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]2[N:20]=[C:2]([NH:21][C:22]3[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]4)=[O:27])=[CH:24][C:23]=3[O:38][CH3:39])[N:3]=[CH:4][C:5]1=2
Reactant: CC(C)CCN1CC(C)C(=O)N(C)c2cnc(Cl)nc21
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(CCC(C)C)CC(C)C(=O)N2C
Yield: 55 %

Procedure:
A solution of 0.05 g, (0.00017 mole) of (rac)-2-chloro-5,7-dimethyl-9-(3-methyl-butyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-27), 0.044 g, (0.00017 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.049 g, (0.00026 mole) of p-toluenesulfonic acid monohydrate and 4 mL of 2-propanol was heated at 180 degree for 2 hours in a microwave reactor. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (100:0-75:25) to give 0.049 g of (rac)-4-[5,7-dimethyl-9-(3-methyl-butyl)-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-27). HRMS (ES+) m/z Calcd for C28H41N7O2+H [(M+H)+]: 524.3344. Found: 524.3342.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10](Cl)=[CH:9][CH:8]=1)[CH3:2].[CH3:16]NC(=N)S.OS(O)(=O)=O.NC1OC(C2C=CC(SC)=CC=2)=CC(=O)N=1>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([CH3:16])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CNC(=N)S
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Agent: CSc1ccc(-c2cc(=O)nc(N)o2)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared from ethyl(4-chloro)benzoylacetate (5.0 g, 22 mmol) (obtained in preparation 2) and methylthiopseudourea.H2SO4 (3.31 g, 12 mmol) by following the procedure described in preparation 4, (0.573 g, 11.6%). MS m/z: 223 (M+). Preparation 6 Synthesis of 2-amino-6-(4-methylsulfanyl-phenyl)-1,3-oxazin-4-one
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[CH:20]2[CH2:21][CH2:22][CH:15]1[CH2:16][NH:17][C:18](=O)[CH2:19]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([N:14]1[CH:20]2[CH2:21][CH2:22][CH:15]1[CH2:16][NH:17][CH2:18][CH2:19]2)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CC2CCC(CN1)N2Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CN2C3CCNCC2CC3)cc1
Reaction time: 8 h

Procedure:
Neat LAH (0.4 g, 10.54 mmol) was added in small portions to a stirred solution of 9-benzyl-3,9-diazabicyclo[4.2.1]nonan-4-one (1.2 g, 5.21 mmol) in THF (40 ml) and the mixture was stirred under nitrogen overnight. Reaction mixture was cooled in ace bath and quenched by consecutive addition of water (0.4 ml), 15% NaOH (1.2 ml) and water (0.4 ml) and then stirred for 30 min. Precipitated sodium aluminate was filtered off and the filtrate was dried over MgSO4, filtered and evaporated to dryness to afford 9-benzyl-3,9-diazabicyclo[4.2.1]nonane as a light yellow oil. LC/MS: m/e 217 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[CH:18]=[C:17]([C:19](O)=[O:20])[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[CH3:29][NH:30][CH3:31]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[CH:18]=[C:17]([C:19]([N:30]([CH3:31])[CH3:29])=[O:20])[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1
Reactant: CNC
Agent: Cl
Product: CN(C)C(=O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1

Procedure:
45 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylic acid 14 was coupled to dimethylamine HCl via General Procedure B. The product was purified via reverse phase HPLC to give 33 mg of 130. MS (Q1) 409.2 (M)+.
Reaction SMILES: C[Si]([NH:5][OH:6])(C)C.[OH:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[NH:11][C:10](=[O:21])[C:9]=1[C:22](OCC)=[O:23]>O1CCOCC1>[OH:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[NH:11][C:10](=[O:21])[C:9]=1[C:22]([NH:5][OH:6])=[O:23]
Reactant: CCOC(=O)c1c(O)c2ccc([N+](=O)[O-])cc2[nH]c1=O
Reactant: C[Si](C)(C)NO
Solvent: C1COCCO1
Product: O=C(NO)c1c(O)c2ccc([N+](=O)[O-])cc2[nH]c1=O
Temperature: 100 °C
Reaction time: 20 h
Yield: 55.8 %

Procedure:
4 ml of trimethylsilylhydroxylamine (30 mmol) were sprayed at room temperature into a suspension of 1.38 g of ethyl 4-hydroxy-7-nitro-2-oxo-1,2-dihydro-quinoline-3 -carboxylate (5 mmol) in 40 ml of dioxan. After heating to 100° C. all passed slowly into solution. The reaction mixture was left to stir at 90° C. for 20 hrs., cooled to room temperature and the separated voluminous precipitate was filtered off. This was washed with water and dried in a high vacuum. 740 mg of 4,N-dihydroxy-7-nitro-2-oxo-1,2-dihydro-quinoline-3-carboxamide (65%) were obtained as pale beige crystals.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:25][S:26][CH2:27][C@H:28]([NH:43][C:44](=[O:56])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:3](=[O:24])[NH:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][P:16](=[O:23])([O:20]CC)[O:17]CC.C[Si](Br)(C)C>C(Cl)Cl>[NH2:1][C@@H:2]([CH2:25][S:26][CH2:27][C@H:28]([NH:43][C:44](=[O:56])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:3](=[O:24])[NH:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][P:16](=[O:17])([OH:20])[OH:23]
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)NC(=O)CCCCCCCCCCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(O)O)NC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of diethyl ((14R,18R)-14-amino-18-dodecanamido-13-oxo-3,6,9,20-tetraoxa-16-thia-12-azadotriacontyl)phosphonate (1 eq) in DCM (0.1 M) was added trimethylsilyl bromide (10 eq). The reaction mixture was stirred at 25° C. overnight and concentrated. The crude mixture was purified by reverse phase high performance liquid chromatography (HPLC) with C4 column eluting with a gradient of 40-100% MeCN/10 mM NH4OAc (95:5) in 10 mM NH4OAc (pH 9) to give ((14R,18R)-14-amino-18-dodecanamido-13-oxo-3,6,9,20-tetraoxa-16-thia-12-azadotriacontyl)phosphonic acid as a white solid after lyophilizing. 1H NMR (CDCl3): δ 8.84 (s, 2H), 6.54 (d, 2H), 4.20 (t, 2H), 4.07-4.11 (m, 2H), 3.49-3.70 (m, 12H), 3.31-3.36 (m, 4H), 3.00-3.02 (m, 4H), 2.72 (d, 4H), 2.15 (t, 2H), 1.43-1.55 (m, 6H), 1.16-1.22 (m, 32H), 0.80 (t, 6H). LRMS [M+H]=784.5.
Reaction SMILES: C(OC(N1CCC(C(N2C3N=CN=CC=3C(C([O-])=O)=C2C)C)CC1)=O)(C)(C)C.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH:42]([N:44]2[C:48]3[N:49]=[C:50](Cl)[N:51]=[CH:52][C:47]=3[C:46]([C:54]([O:56][CH2:57][CH3:58])=[O:55])=[C:45]2[CH3:59])[CH3:43])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].[H][H]>CO.[Pd]>[C:29]([O:33][C:34]([N:36]1[CH2:37][CH2:38][CH:39]([CH:42]([N:44]2[C:48]3[N:49]=[CH:50][N:51]=[CH:52][C:47]=3[C:46]([C:54]([O:56][CH2:57][CH3:58])=[O:55])=[C:45]2[CH3:59])[CH3:43])[CH2:40][CH2:41]1)=[O:35])([CH3:31])([CH3:32])[CH3:30]
Reactant: CCOC(=O)c1c(C)n(C(C)C2CCN(C(=O)OC(C)(C)C)CC2)c2nc(Cl)ncc12
Reactant: [H][H]
Agent: [Pd]
Agent: Cc1c(C(=O)[O-])c2cncnc2n1C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CO
Product: CCOC(=O)c1c(C)n(C(C)C2CCN(C(=O)OC(C)(C)C)CC2)c2ncncc12
Yield: 75 %

Procedure:
tethyl 7-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate, Intermediate 9. A mixture of compound ethyl 7-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)-2-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (75 mg, 0.16 mmol) and Pd/C(10 mg) in methanol (10 mL) was stirred under 50 psi of hydrogen at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated to give product ethyl 7-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (50 mg, yield: 72%). LRMS (M+H+) m/z: calcd 450.2. found 451.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl.[F:15][C:16]([F:43])([F:42])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>COCCOC>[F:15][C:16]([F:42])([F:43])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:38])=[CH:35][CH:34]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A solution of 26.6 g. of diethyl malonate and 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 4.5 hours, cooled, poured on ice, acidified, and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. Addition of a small amount of ethanol to the residue gives a solid which is filtered and discarded. The ethanol filtrate is concentrated and the residue is recrystallized from ether to yield the product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:12]([NH:14][CH2:15][CH2:16][C@H:17]([OH:21])[C:18](O)=[O:19])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.[Na+]>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:12]([N:14]1[CH2:15][CH2:16][C@H:17]([OH:21])[C:18]1=[O:19])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)NCC[C@H](O)C(=O)O)cc1OCc1ccccc1
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc(C(=O)N2CC[C@H](O)C2=O)cc1OCc1ccccc1

Procedure:
6.5 g of (S)-4-[(3-benzyloxy-4-methoxybenzoyl)amino]-2-hydroxybutyric acid and 1.0 g of sodium trifluoroacetate are boiled at reflux while stirring in 40 ml of trifluoroacetic acid anhydride for 48 hours. After evaporation of the mixture, the residue is shaken three times with toluene, and the toluene is thereafter evaporated in vacuo. The residue, containing (S)-1-(3-benzyloxy-4-methoxybenzoyl)-2-oxo-3-pyrrolidinyltrifluoroacetate, is boiled at reflux in 40 ml of absolute methanol for 30 minutes. Thereafter, the mixture is stirred at room temperature for an additional 1 hour, whereupon the solid material is removed by filtration and washed with methanol. There is obtained (S)-1-(3-benzyloxy-4-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone which melts at 166°-167° after recrystallization from methanol; [α]D20 =-146°; [α]54620 =-180°; [α]36520 =-879° (chloroform, c=1.0).
Reaction SMILES: O1CCOCC1.Cl.[NH2:8][C:9]1[CH:10]=[C:11]([CH:43]=[CH:44][C:45]=1[OH:46])[CH2:12][N:13]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:42])[CH2:20][NH:21][C:22](=[O:41])[C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=2[NH:33]C(OC(C)(C)C)=O)[CH2:14]1>>[NH2:8][C:9]1[CH:10]=[C:11]([CH:43]=[CH:44][C:45]=1[OH:46])[CH2:12][N:13]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:42])[CH2:20][NH:21][C:22](=[O:41])[C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[CH:25][C:24]=2[NH2:33])[CH2:14]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(O)c(N)c2)C1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cc(CN2CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3N)C2)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 4 M HCl dioxane (2.0 mL) solution of (R)-1-(3-amino-4-hydroxybenzyl)-3-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (20 mg) synthesized according to the method of Example 808 was stirred at room temperature overnight. The solution was concentrated, and the residue was then dissolved in methanol, loaded onto a VarianM SCX column, washed with methanol, subsequently eluted with a 2 M methanol solution of NH3, concentrated and then purified by preparative TLC (SiO2, ethyl acetate/methanol=4:1) to thereby provide (R)-1-(3-amino-4-hydroxybenzyl)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (Compd. No. 2187) (9.6 mg, 59%). The purity was determined by RPLC/MS (86%). ESI/MS m/e 452.3 (M++H, C21H24F3N5O3).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][C:7]2[NH:8][C:9](=[O:26])[CH2:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N:19]4[C:23]([CH2:24]O)=[CH:22][N:21]=[N:20]4)[CH:14]=3)=[N:12][C:6]=2[CH:5]=1)[CH3:2].O=S(Cl)Cl.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>>[CH:37]1([NH:40][CH2:24][C:23]2[N:19]([C:15]3[CH:14]=[C:13]([C:11]4[CH2:10][C:9](=[O:26])[NH:8][C:7]5[CH:27]=[C:28]([C:29]([F:30])([F:31])[F:32])[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=5[N:12]=4)[CH:18]=[CH:17][CH:16]=3)[N:20]=[N:21][CH:22]=2)[CH2:39][CH2:38]1
Reactant: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: NC1CC1
Solvent: O=S(Cl)Cl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CNC3CC3)c1)=N2

Procedure:
The title compound was prepared from 7-ethoxy-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 52) (134 mg, 0.3 mmol) by treatment with SOCl2 (3 eq.) and cyclopropylamine (10 eq.) as described in Example 47. Obtained as a yellow solid (55 mg).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[C:5]1[C:10]2=[N:11][C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:17]=3[CH:18]=[C:9]2[C:8](=[O:19])[O:7][C:6]1=[O:20])C.CN>>[CH3:1][N:2]1[CH:4]=[C:5]([C:6]([OH:7])=[O:20])[C:10]2[N:11]=[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:17]3=[CH:18][C:9]=2[C:8]1=[O:19]
Reactant: CN(C)C=C1C(=O)OC(=O)c2cc3cccnc3nc21
Agent: CN
Product: Cn1cc(C(=O)O)c2nc3ncccc3cc2c1=O

Procedure:
From 17e and methylamine, as for 18d except that, after reaction, the volatiles were removed at reduced pressure and water was added. The resultant suspension was stirred and basified with 10% sodium hydroxide, then acidified with concentrated hydrochloric acid (dropwise) and the brown solid was filtered to give 18y, mp >300° C. (from dimethyl sulfoxide/1,4-dioxane). 1H NMR (d6-DMSO): δ 3.64 (s, 3H, NCH3), 7.76 (dd, J=8.2, 4.2 Hz, 1H, H-3), 8.81 (d, J=8.2 Hz, 1H, H-4), 8.85 (s, 1H, H-8), 9.28 (dd, J=3.9, 1.7 Hz, 1H, H-2), 9.58 (s, 1H, H-5), 15.68 (s, 1-H, COOH).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19]CC3C=CC(OC)=CC=3)[C:16]3[C:11](=[C:12]([CH3:31])[CH:13]=[C:14]([O:29][CH3:30])[CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[Cl-].[Cl-].[Cl-].[Cs+].[Cs+].[Cs+].[I-].[Na+].Cl>C(#N)C.O>[OH:19][C:17]1[C:16]2[C:11](=[C:12]([CH3:31])[CH:13]=[C:14]([O:29][CH3:30])[CH:15]=2)[N:10]=[C:9]([C:6]2[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)[CH:18]=1
Reactant: COc1ccc(COc2cc(-c3nc(C(C)C)cs3)nc3c(C)cc(OC)cc23)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C)c2nc(-c3nc(C(C)C)cs3)cc(O)c2c1
Yield: 55 %

Procedure:
Compound 222f (1.23 g, 2.82 mmol), cesium trichloride (1.58 g, 4.23 mmol), and sodium iodide (423 mg, 2.82 mmol) in ACN (26 mL) were stirred at 85° C. for 1 hr. The mixture was then filtered through celite and the solvent was evaporated. The brown solid obtained was suspended in water, pH was adjusted at 5 with 1N HCl. The mixture was extracted with DCM, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by chromatography on silica gel (petroleum ether/DCM) to yield compound 218f as a brown solid in 55% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.40 (d, J=6.91 Hz, 6H), 2.80 (s, 3H), 3.17-3.24 (m, 1H), 3.89 (s, 3H), 7.00 (s, 1H), 7.21 (m, 1H), 7.55 (s, 1H), 7.79 (s, 1H), 9.56 (brs, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:31]=[CH:30][C:17]2[N:18]([CH2:28][CH3:29])[C:19](=[O:27])[C:20]([CH3:26])([CH3:25])[C:21](=[O:24])[N:22]([CH3:23])[C:16]=2[CH:15]=1.[BH4-].[Na+]>CO>[CH2:28]([N:18]1[C:19](=[O:27])[C:20]([CH3:26])([CH3:25])[C:21](=[O:24])[N:22]([CH3:23])[C:16]2[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][NH:9][CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH:31]=[CH:30][C:17]1=2)[CH3:29]
Reactant: O=Cc1ccncc1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCCN)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCCNCc3ccncc3)ccc21
Temperature: 25 °C

Procedure:
4-Pyridine carbaldehyde (0.15 ml) was added to a methanol solution (10 ml) of 7-(4-aminobutyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.51 g). The mixture was stirred for an hour at room temperature under nitrogen atmosphere. Sodium borohydride (0.2 g) was added to the mixture, and the mixture was stirred at room temperature overnight. The liquid was then condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1→3:2). The purified product was condensed under reduced pressure to give the title compound (0.38 g) as a colorless oily matter.
Reaction SMILES: [CH3:1][SH:2].BrBr.[CH3:5][C:6]([CH3:14])([CH:12]=[CH2:13])[C:7]([O:9]CC)=[O:8]>C(Cl)(Cl)(Cl)Cl>[CH3:5][C:6]([CH3:14])([CH:12]=[CH:13][S:2][CH3:1])[C:7]([OH:9])=[O:8]
Reactant: C=CC(C)(C)C(=O)OCC
Reactant: CS
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CSC=CC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
A solution of methanethiol (8 g) in CCl4 was stirred and treated dropwise at -25° C. with bromine (26.6 g). Ethyl 2,2-dimethyl-3-butenoate (23 g) was then added dropwise at that temperature over two hours. Following the addition, the solution was allowed to warm to room temperature, then concentrated in vacuo. NMR showed near complete conversion to the 4-bromo-3-methylthio ester (38 g). The residual oil was then heated one hour on a steam bath to effect conversion to the thermodynamically favored 3-bromo-4-methylthio ester. This material was then dissolved in 50 mL of DMF and treated with 26 g of DBU. The solution was heated briefly on a steam bath, then was allowed to cool and worked up by pouring into water, extracting with 2×200 mL of ether, drying and concentrating. The residual oil (24.75 g) was hydrolyzed by stirring overnight in a solution of 50 mL of ethanol, 15 mL of water and 7.8 g of sodium hydroxide. Acidification with 1N HCl and extraction into ether followed by drying and concentration furnished a solid which was recrystallized from ether/hexane to give 13.5 g of 2,2-dimethyl-4-methylthio-3-butenoic acid, m.p. 49°-51° C.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([NH:11][CH2:12][CH3:13])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][C@H:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9][NH:11][CH2:12][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCNC(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCNC[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a solution of (S)-tert-butyl 3-cyclohexyl-1-(ethylamino)-1-oxopropan-2-ylcarbamate (444 mg, 1.49 mmol) in anhydrous toluene at 0° C. was added Red-Al (65%, 1.39 g, 1.36 mL, 4.47 mmol) over 20 min. After the addition, the reaction was allowed to stir at rt overnight. The reaction was cooled to 0° C. and quenched with Na2SO4.10H2O. The resulting mixture was stirred for 2-3 h, filtered through Celite, and washed with THF (200 mL). The filtrate was dried and concentrated to give crude product (S)-tert-butyl 1-cyclohexyl-3-(ethylamino)propan-2-ylcarbamate (338 mg, 45% over 2 steps). MS ESI +ve m/z 285 (M+H).