Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35]([C:27]1[CH:28]=[C:29]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([OH:14])([C:15]3[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=2)[CH:30]=[CH:31][C:26]=1[Cl:25])=[O:36])[CH3:39]
Reactant: COc1ccc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)cn1
Reactant: CCOC(=O)c1cc(B(O)O)ccc1Cl
Product: CCOC(=O)c1cc(-c2ccc(C(C)C(O)(c3ccc(OC)nc3)C(F)(F)F)c(Cl)c2)ccc1Cl

Procedure:
In analogy to Example 150, step 2, 3-(4-bromo-2-chloro-phenyl)-1,1,1-trifluoro-2-(6-methoxy-pyridin-3-yl)-butan-2-ol (Example 175, step 3) was reacted with 4-chloro-3-ethoxycarbonylphenylboronic acid to give the title compound as a colorless foam. MS (m/e)=528.2 [M+H+].
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[CH:40]([N:43]1[CH:47]=[C:46](B(O)O)[CH:45]=[N:44]1)([CH3:42])[CH3:41]>>[NH2:32][C:4]1[S:3][C:2]([C:46]2[CH:45]=[N:44][N:43]([CH:40]([CH3:42])[CH3:41])[CH:47]=2)=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: CC(C)n1cc(B(O)O)cn1
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: CC(C)n1cc(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@@H](F)CO3)c(N)s2)cn1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (1-isopropyl-1H-pyrazol-4-yl)boronic acid gave 256. 1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.15 (s, 1H), 7.83 (s, 1H), 7.77 (s, 1H), 7.25 (s, 2H), 5.12-4.80 (m, 2H), 4.60-4.45 (m, 1H), 4.18-3.95 (m, 2H), 3.72 (s, 3H), 3.38-3.26 (m, 1H), 2.33-2.22 (m, 1H), 1.83-1.56 (m, 5H), 1.44 (d, J=6.7 Hz, 6H). LCMS (ES+) m/z 463 (M+1).
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH2:12][CH2:13][N:14]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[CH2:15][CH:16]=1
Reactant: COc1ccc(CCl)cc1
Reactant: C1=C(c2cc3ccccc3s2)CCNC1
Agent: Cl
Product: COc1ccc(CN2CC=C(c3cc4ccccc4s3)CC2)cc1
Yield: 4.18 %

Procedure:
4-(Benzothiophen-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (250 mg, 0.99 mmol) was reacted with 4-methoxybenzyl chloride (0.13 ml, 0.99 mmol) as exemplified in Example 1. The crude product was triturated with hot methanol to give the title compound as a pale yellow solid mp 158°-160° C. (Found: C, 75.09; H, 5.05; N, 4.31; C21 H21NOS requires C, 75.19; H, 6.31; N, 4.18%). δH (CDCl3) 2.65 (2H, m, NCH2CH2), 2.74 (2H, m, NCH2 CH2), 3.20 (2H, m, NCH2CH2), 3.61 (2H, s, NCH2Ar), 3.81 (3H, s, OMe), 6.18 (1H, m, NCH2CH), 6.87 (2H, d, J 8.6Hz, ArH), 7.12 (1H, s, ArH), 7.28 (4H, m, ArH), 7.65 (1H, d, J 6.8Hz, ArH), 7.73 (1H, d, J 6.9Hz, ArH). m/z (ES+) 336 (M+1)+.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nc(-c2ccc(O)cc2)c(Cc2ccccc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a 50 ml eggplant-shaped flask were added 0.50 g (1.69 mmol) 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1 and 15 ml dichloromethane, and then added dropwise 2.9 ml (5.06 mmol) of 1.76 M BBR3 solution in dichloromethane. The resulting mixture was stirred at room temperature for 2 hours, the resultant was poured into 20 ml of a saturated aqueous sodium bicarbonate solution, a solid was precipitated, filtered, washed with water, and dried to obtain a crude product, which was subjected to a silica gel column chromatography eluted with petroleum ether/ethyl acetate (3:2) to obtain a 0.46 g product as a white solid in a yield of 95.8%, mp: 170-172□. 1H-NMR (DMSO-d6, 400 MHz) δ: 4.02 (2H, s, CH2), 6.74˜6.76 (4H, m, 2ArH+NH2), 7.15˜7.40 (7H, m, ArH), 9.49 (1H, s, OH); EI-MS m/e (%): 282.0 (M+, 100), 205.0 (37); HREI-MS Calcd. for C16H14N2OS: 282.0827. found: 282.0824.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)=[CH:3][CH:2]=1.[H-].[Na+].CN(C)C=O.[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([N:8]1[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:9]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1cc(-c2n[nH]c(-c3ccncc3)n2)ccn1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: c1ccc(Cn2nc(-c3ccncc3)nc2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3,5-Bis(4-pyridyl)-1,2,4-triazole (4.4 g., 0.02 mol) in dry tetrahydrofuran (200 ml.) is added 57% sodium hydride in mineral oil (1 g., 0.024 mol.) and the mixture is heated 45 minutes at reflux. The suspension is concentrated to a solid, N,N-dimethylformamide (70 ml.) and benzyl chloride (2.8 g., 0.022 mol.) are added. The mixture is stirred 0.5 hour at ambient temperature followed by 4 hours at steam bath temperature. The solution is concentrated to a gum, water is added and the material solidifies. After recrystallization from methylcyclohexane 1.4 g. of 1-benzyl-3,5-bis(4-pyridyl)-1,2,4-triazole, melting at 136-138° C. is obtained.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:17])[CH2:13][N:14]([CH3:16])[CH3:15])=[C:7]([N+:18]([O-])=O)[CH:6]=1)[CH2:2][CH2:3][CH3:4].[H][H]>[Pt]=O.C(O)C>[NH2:18][C:7]1[CH:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:10]=[CH:9][C:8]=1[NH:11][C:12](=[O:17])[CH2:13][N:14]([CH3:16])[CH3:15]
Reactant: CCCCc1ccc(NC(=O)CN(C)C)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CCCCc1ccc(NC(=O)CN(C)C)c(N)c1
Yield: 74.7 %

Procedure:
N-(4-n-butyl-2-nitrophenyl)-2-dimethylaminoacetamide (36 g), prepared as described above, platinum oxide (0.2 g) and ethanol (100 ml) were shaken together in an atmosphere of hydrogen at laboratory temperature and atmospheric pressure until the uptake of hydrogen was complete; 8.2 litres were absorbed. The mixture was filtered and the ethanol evaporated off. The resultant solid was recrystallised from petroleum spirit (b.p. 60°-80° C.) to give N-(2-amino-4-n-butylphenyl)-2-dimethylaminoacetamide (24.0 g), m.p. 63°-66° C.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(OC)ccn1
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccnc(N(CCCCCCC(=O)NO)c2ccccn2)c1
Reaction time: 17 h
Yield: 84 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (10 mg, 0.028 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 17 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:3 to 100:10) to furnish IV as a colourless oil (8 mg, 84%).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH2:13][F:14])/[C:8](O)=[O:9])[N:3]=1.C(Cl)(=O)C([Cl:18])=O.CN(C)C=O>O1CCCC1>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH2:13][F:14])/[C:8]([Cl:18])=[O:9])[N:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1nc(/C(=N/OCF)C(=O)O)ns1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1nc(/C(=N/OCF)C(=O)Cl)ns1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 30.0 ml of tetrahydrofuran (THF), 11.0 g of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-fluoromethoxyiminoacetic acid were stirred at -20° C., followed by the dropwise addition of a chlorinating reagent, which had been prepared beforehand by gradually adding 6.97 g of oxalyl chloride at 5° C. to a mixture of 80 ml of THF and 4.0 g of N,N-dimethylformamide (DMF) and then reacting them for 30 minutes. After they were reacted for 5 minutes, the reaction mixture was poured into 400 ml of ice water to precipitate crystals. The crystals were collected by filtration, washed with 100 ml of ice water, and then stirred for 30 minutes in 100 ml of n-hexane. After filtration, the resulting crystals were dried under reduced pressure, whereby the title compound was obtained. Yield: 6.70 g (56.3%). Purity: 91.5%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[C:10]=1[CH2:11][CH2:12][CH2:13][NH:14]C(=O)C.[ClH:18]>>[ClH:18].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[C:10]=1[CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: CC(=O)NCCCc1c(F)ccc2c1CCO2
Agent: Cl
Product: NCCCc1c(F)ccc2c1CCO2

Procedure:
N-[3-[2,3-Dihydro-5-fluorobenzofuran-4-yl]propyl]acetamide (0.55 g) was heated under reflux in 2M hydrochloric acid (10 ml) for 24 h. The mixture was cooled and washed with dichloromethane, basified with 2M sodium hydroxide and extracted with dichloromethane. Evaporation of the extracts gave an oil which was dissolved in 0.7M methanolic hydrogen chloride (8 ml). Evaporation gave the title compound as a beige solid (0.28 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[Cl:20][C:21]1[CH:26]=[C:25](F)[C:24]([CH3:28])=[CH:23][C:22]=1[N+:29]([O-:31])=[O:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:25]4[CH:26]=[C:21]([Cl:20])[C:22]([N+:29]([O-:31])=[O:30])=[CH:23][C:24]=4[CH3:28])=[C:11]3[CH:10]=[N:9]2)=[CH:18][CH:19]=1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1F
Reactant: COc1ccc(Cn2ncc3c(O)ccnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ncc3c(Oc4cc(Cl)c([N+](=O)[O-])cc4C)ccnc32)cc1
Temperature: 95 °C
Yield: 9 %

Procedure:
A stirred mixture of 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (255 g, 999 mmol, prepared using the procedure described in Example 1, Step B), 1-chloro-5-fluoro-4-methyl-2-nitrobenzene (94.7 g, 499 mmol), cesium carbonate (325 g, 1.0 mol) and DMF (2 L) was heated to 95° C. for 6 hours. The reaction was cooled to ambient temperature and partitioned between EtOAc and water. The phases were filtered and then separated. The aqueous phase was re-extracted with EtOAc. The combined organic phases were washed with water, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude was purified by Biotage Flash 75 L chromatographic system, eluting with 5% EtOAc/hexanes (12 L), 10% EtOAc/hexanes (6 L), 20% EtOAc/hexanes (6 L), then 30% EtOAc/hexanes (6 L). The product was obtained as a viscous oil (42 g, 9%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][C:8]2[O:13][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=2)=[CH:2]1.[OH-:19].[Na+]>CO>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][C:8]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:19])=[O:14])=[O:13])=[CH:2]1
Reactant: O=c1oc(C=Cc2ccsc2)nc2ccccc12
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: O=C(C=Cc1ccsc1)Nc1ccccc1C(=O)O
Temperature: 70 °C
Yield: 96 %

Procedure:
To 2-[2-(3-thienyl)vinyl]-4H-3,1-benzoxazine-4-one (800 mg, 3.13 mmol) was added 1N-NaOH (21.9 ml) and the mixture was heated to 70° C. After adding methanol (30 ml), and the mixture was reacted for 1 hour. The methanol was removed from the reaction mixture under reduced pressure, and the residue was acidified with 10% HCl under cooling (pH about 4) to give a white solid, which was collected on a filter, washed with water, and dried to give the title compound (826 mg, yield, 96%). m.p., 218°-219° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([I:12])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.S(OC)(O[CH3:18])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([I:12])[C:5]([O:11][CH3:18])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)c(C)c(I)c1O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1c(C(C)=O)cc(Cl)c(C)c1I
Yield: 86.6 %

Procedure:
A mixture of 1-(5-chloro-2-hydroxy-3-iodo-4-methylphenyl)ethanone (10 g, 32 mmol), dimethyl sulfate (3.7 mL, 39 mmol) and potassium carbonate (8.9 g, 64 mmol) in acetone (200 mL) was heated at reflux overnight. After evaporation to dryness, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 20% ethyl acetate in hexane, to yield the desired product (8.99 g, 86%). LCMS calculated for C10H11ClIO2 (M+H)+: m/z=324.9. found: 324.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:34])[C:14]([C:16]1[S:33][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29]([O:31]C)=[O:30])=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15].O[Li].O>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:10])[CH3:11])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:34])[C:14]([C:16]1[S:33][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29]([OH:31])=[O:30])=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15]
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccc(C(=O)N(C)C)cc3Cl)sc1-2
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
Methyl 2-((2-chloro-4-(dimethylcarbamoyl)phenyl)(methyl)-carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate (25.00 g, 50.1 mmol) was dissolved in THF (50 mL) and water (50 mL). The solution was treated with LiOH.H2O (5.26 g, 125.3 mmol). The reaction mixture was stirred at room temperature for 2 h. Concentrated to remove the solvent THF and the mixture was acidified by 2N HCl. The resulting precipitate was filtrated, washed by water, dried to give 2-((2-chloro-4-(dimethylcarbamoyl)phenyl)(methyl) carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid (20.00 g, 82%). ESI-MS: 485.1. 1H NMR (CDCl3, 400 MHz): δ7.66-7.60 (m, 3H, ArH), 7.46-7.42 (m, 3H, ArH), 6.99 (s, 1H, ═CH), 4.23 (t, J=5.0 Hz, 2H, CH2), 3.39 (s, 3H, CH3), 3.14 (s, 3H, CH3), 3.07 (t, J=5.0 Hz, 2H, CH2), 3.02 (s, 3H, CH3).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]([NH2:9])=[O:8])=[O:5])#[N:2].[CH:10](=O)[CH3:11].C(O)(=O)C.C([O-])(=O)C.[NH4+]>CN(C)C=O.[C].[Pd]>[C:1]([CH:3]([CH2:10][CH3:11])[C:4]([NH:6][C:7]([NH2:9])=[O:8])=[O:5])#[N:2]
Reactant: CC=O
Reactant: N#CCC(=O)NC(N)=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCC(C#N)C(=O)NC(N)=O

Procedure:
Cyanoacetylurea (38.7 g) was suspended in N,N-dimethylformamide (77.4 ml), and acetaldehyde (18.8 ml), acetic acid (3.43 ml) and ammonium acetate (2.31 g) were added. This suspension was subjected to catalytic hydrogenation in the presence of 10% palladium carbon (0.78 g, 50% wet product) under normal pressure at 30° C. for 5 hours. The catalyst was filtered off. Water (350 ml) was added to the filtrate to allow precipitation of crystals. The crystals were collected by filtration to give crystals of N-(2-cyanobutanoyl)urea (yield 24.2 g). 1H-NMR(270 MHz, DMSO-d6)δ 0.99(3H,t), 1.75-1.95(2H,m), 3.86(1H,t), 7.42(2H,br), 10.50(1H,br)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[O-]CC.[Na+].Br[CH2:17][CH:18]=[CH2:19]>C(O)C>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([CH2:19][CH:18]=[CH2:17])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: C=CCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: C=CCC(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
Malonic acid diethyl ester (100 g, 0.625 mol) was added dropwise at 0° C. to a mixture of sodium ethoxide (46.8 g, 0.688 mol) in ethanol (1 L). The reaction mixture was stirred for 4 hours. 3-Bromo-propene (83.2 g, 0.688 moles) was added dropwise to the mixture at 0° C. After addition, the mixture was warmed to reflux and stirred overnight. The mixture was cooled to room temperature, filtered and the solvent was removed in vacuo to afford the title compound in 86% yield, 100 g which was used for the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][C@@H:11]1[NH:29][C:28](=[O:30])[C@@H:27]([NH:31]C(OC(C)(C)C)=O)[CH2:26][C:25]2[CH:39]=[C:21]([CH:22]=[CH:23][C:24]=2[OH:40])[C:20]2=[CH:41][C:16](=[C:17]([OH:42])[CH:18]=[CH:19]2)[CH2:15][C@@H:14]([C:43]([NH:45][C@H:46]([C:51]([NH:53][C@H:54]([C:58]([NH:60][CH2:61][CH2:62][NH2:63])=[O:59])[CH2:55][CH2:56][NH2:57])=[O:52])[CH2:47][CH2:48][CH2:49][NH2:50])=[O:44])[NH:13][C:12]1=[O:64])(C)(C)C.[ClH:66]>O1CCOCC1>[ClH:66].[ClH:66].[ClH:66].[ClH:66].[ClH:66].[NH2:31][C@H:27]1[CH2:26][C:25]2[CH:39]=[C:21]([CH:22]=[CH:23][C:24]=2[OH:40])[C:20]2=[CH:41][C:16](=[C:17]([OH:42])[CH:18]=[CH:19]2)[CH2:15][C@@H:14]([C:43]([NH:45][C@H:46]([C:51]([NH:53][C@H:54]([C:58]([NH:60][CH2:61][CH2:62][NH2:63])=[O:59])[CH2:55][CH2:56][NH2:57])=[O:52])[CH2:47][CH2:48][CH2:49][NH2:50])=[O:44])[NH:13][C:12](=[O:64])[C@H:11]([CH2:10][CH2:9][CH2:8][NH2:7])[NH:29][C:28]1=[O:30]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H]1NC(=O)[C@@H](NC(=O)OC(C)(C)C)Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@@H](C(=O)N[C@@H](CCCN)C(=O)N[C@@H](CCN)C(=O)NCCN)NC1=O
Agent: Cl
Solvent: C1COCCO1
Product: NCCC[C@H](NC(=O)[C@@H]1Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@H](N)C(=O)N[C@@H](CCCN)C(=O)N1)C(=O)N[C@@H](CCN)C(=O)NCCN
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
7 mg (0.008 mmol) of tert-butyl{3-[(8S,11S,14S)-8-{[((1S)-4-amino-1-{[((1S)-3-amino-1-{[(2-aminoethyl)amino]carbonyl}propyl)amino]carbonyl}butyl)amino]carbonyl}-14-[(tert-butoxycarbonyl)amino]-5,17-dihydroxy-10,13-dioxo-9,12-diazatricyclo[14.3.1.12,6]henicosa-1(20),2(21),3,5,16,18-hexaen-11-yl]propyl}carbamate tris(hydroacetate) (Example 208A) are added into 0.6 ml of a 4N solution of hydrogen chloride in dioxane and stirred at RT for 30 min. The reaction solution is concentrated, coevaporated with dichloromethane several times and dried under high vacuum.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[C:31]([CH3:33])([CH3:32])[CH2:30][CH2:29][C:28](=[O:34])[NH:27][C:26]=2[CH:35]=1>>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])=[N:7][C:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[C:31]([CH3:32])([CH3:33])[CH2:30][CH2:29][C:28](=[O:34])[NH:27][C:26]=3[CH:35]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCC(=O)Nc2cc(N)ccc21
Reactant: N#CCOc1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CC1(C)CCC(=O)Nc2cc(Nc3ncc(Cl)c(Nc4c(F)cccc4OCC#N)n3)ccc21

Procedure:
The title compound was prepared from [2-(2,5-dichloropyrimidin-4-ylamino)-3-fluorophenoxy]-acetonitrile and 8-amino-5,5-dimethyl-1,3,4,5-tetrahydrobenzo[b]azepin-2-one in an analogous manner to Example 927 to afford a yellow foam (37 mg, 48%). Mp: 142-8° C. LCMS (m/e) 481 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.52 (m, 1H), 7.38 (s, 1H), 7.32 (s, 1H), 7.28 (s, 1H), 7.21 (d. J=8 Hz, 1H), 7.08 (m, 1H), 6.96 (d, J=8 Hz, 1H), 6.82 (d, J=8 Hz, 1H), 6.55 (s, 1H), 4.79 (s, 2H), 2.37 (m, 2H), 2.10 (m, 2H), 1.36 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:21][C:22]([O:24]CC)=[O:23])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:20])[CH:12]=1)=[O:10].[OH-].[Na+]>C1COCC1.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:21][C:22]([OH:24])=[O:23])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:20])[CH:12]=1)=[O:10]
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2cn(C)c3ccccc23)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1cc(C(=O)Nc2ccc(CC(=O)O)cc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.1 %

Procedure:
To a solution of ethyl 3-chloro-4-(1-methyl-3-indolylcarbonylamino)phenylacetate (639 mg, 1.72 mmol) in THF (17.5 mL) was added 0.25N NaOH (10.3 mL, 2.58 mmol). The resulting mixture was stirred at room temperature for 4 hours. Under ice cooling, the reaction mixture was poured in 1N HCl (15 ml). The crystals thus precipitated were collected by filtration, washed with water and dried under reduced pressure, whereby 3-chloro-4-(1-methyl-3-indolylcarbonylamino)phenylacetic acid (549 mg, 93%) was obtained as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=NN=1)=[O:5])[CH3:2].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1>C(Cl)Cl>[C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=[N:8][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:18]2[C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=1[NH:17]2
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCOC(=O)c1nnc(C(=O)OCC)nn1
Solvent: ClCCl
Product: CCOC(=O)c1nnc(C(=O)OCC)c2c1[nH]c1ccccc12
Reaction time: 4 h
Yield: 49.6 %

Procedure:
To a solution of 5.71 (318 mg, 1.61 mmol) in anhydrous methylene chloride (15 mL) was added a solution of indole (100 mg, 0.85 mmol) in anhydrous methylene chloride (50 mL) dropwise over 4 h with stirring at mild reflux. Following the addition, stirring was continued for 4 h and the reaction mixture was then cooled down. After filtration, the filtrate was evaporated under (reduced pressure and the residue oil was submitted to chromatography (flash column, silica gel, methylene chloride:ethyl acetate=1:1, v/v as eluent) to afford the title compound 5.72 as an orange solid (132 mg, 52%), mp. 151-152° C. 1H NMR (200 MHz, CDCl3) δ (ppm): 11.10 (s, 1H), 8-63 (d, J=8.2 Hz, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.50 (t, J=7.0 Hz, 1H), 7.26 (t, J=7.0 Hz, 1H), 4.62 (q, J=7.0 Hz, 2H), 4.47 (q, J=7-0 Hz, 2H), 1.44 (I:, J=7.0 Hz, 3H), 1.34 (t, J=7.0 Hz, 3H). Anal. (C16H15N3O4) C, H, N.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCCCc1ccccc1
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Product: O=C(NC(=O)C(c1ccccc1)c1ccccc1)OCCCCc1ccccc1

Procedure:
The title compound, light yellow solid, m.p.=118° C. and MS: m/e=387.5 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and 4-phenyl-butan-1-ol.