Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][C:15]([C@H:44]([N:46]2[CH2:51][CH2:50][N:49]([S:52]([CH3:55])(=[O:54])=[O:53])[CH2:48][CH2:47]2)[CH3:45])=[CH:14][N:13]=1.[N:56]1[C:65]2[C:60](=[CH:61][CH:62]=[C:63]([NH2:66])[CH:64]=2)[CH:59]=[CH:58][CH:57]=1>C1COCC1>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][N:25]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:20]2[N:21]=[C:22]([CH3:24])[N:23]=[C:18]([C:17]3[C:12]([NH:66][C:63]4[CH:64]=[C:65]5[C:60]([CH:59]=[CH:58][CH:57]=[N:56]5)=[CH:61][CH:62]=4)=[N:13][CH:14]=[C:15]([C@H:44]([N:46]4[CH2:51][CH2:50][N:49]([S:52]([CH3:55])(=[O:53])=[O:54])[CH2:48][CH2:47]4)[CH3:45])[CH:16]=3)[N:19]=2)=[CH:32][CH:31]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc4cccnc4c3)n2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
Sodium bis(trimethylsilyl)amide (1.0 M in THF) (Aldrich, St. Louis, Mo.; 0.863 mL, 0.863 mmol) was added to a mixture of (R)-4-(2-fluoro-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 146, Step 6; 156.7 mg, 0.246 mmol) and quinolin-7-amine (Ark Pharm, Libertyville, Ill.; 71.1 mg, 0.493 mmol) in THF (2.5 mL) at 0° C., and the resulting dark brown solution was stirred at 0° C. for 2 h. Excess sodium bis(trimethylsilyl)amide was then quenched with saturated aqueous NH4Cl (2 mL), and the reaction mixture was partitioned between EtOAc (50 mL) and saturated aqueous NH4Cl (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic extracts were sequentially washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 6% MeOH/CH2Cl2) furnished (R)-N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-2-yl)quinolin-7-amine (189 mg, 0.249 mmol, 101% yield) as a yellow-orange foam, which was used directly in Step 2. m/z (ESI, +ve) 760.3 (M+H)+.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[CH2:11]([Li])[CH2:12][CH2:13][CH3:14].[CH3:16][CH2:17][CH2:18]CCC>CC1C=C(C=CC=1)C=O.O1CCCC1>[OH:4][C:3]1[CH2:5][CH:8]([C:11]2[CH:18]=[CH:17][CH:16]=[C:13]([CH3:14])[CH:12]=2)[O:7][C:1](=[O:6])[CH:2]=1
Reactant: COC(=O)CC(C)=O
Reactant: CCCCCC
Reactant: [Li]CCCC
Agent: Cc1cccc(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(C2CC(O)=CC(=O)O2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared as described in General Method 1 using 2.0 mL of methyl acetoacetate, 0.8 g of NaH 60% dispersion in oil, 10 mL of 2.0M n-butyl lithium in hexane, 2.6 mL of 3-methylbenzaldehyde and 100 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 10 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 137°-138° C.). 1H NMR (CDCl3) δ2.38 (s, 3H), 2.88 (dd, 1H), 2.95 (dd, 1H), 3.57 (dd, 2H), 5.68 (dd, 1H), 7.16-7.33 (m, 4H).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:23][C:24]1[CH:32]=[C:31]([Cl:33])[C:30]([Cl:34])=[CH:29][C:25]=1[CH2:26][NH:27][NH2:28]>C(O)C>[NH2:10][C:6]1[NH:28][N:27]([CH2:26][C:25]2[CH:29]=[C:30]([Cl:34])[C:31]([Cl:33])=[CH:32][C:24]=2[Cl:23])[C:4](=[O:3])[CH:5]=1
Reactant: NNCc1cc(Cl)c(Cl)cc1Cl
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2cc(Cl)c(Cl)cc2Cl)[nH]1
Reaction time: 2 h

Procedure:
54.7 g of β-amino-β-ethoxyacrylic acid ethyl ester and 2 g of p-toluenesulphonic acid were dissolved in 400 ml of ethanol. A solution of 77.6 g of 2,4,5-trichlorobenzylhydrazine in 200 ml of ethanol was added dropwise thereto, under nitrogen. After stirring for a further two hours, the mixture was left to stand overnight and the precipitate which had separated out was filtered off and dissolved in 2 N sodium hydroxide soltuion. The alkaline solution was repeatedly extracted with ether and subsequently slightly acidified with dilute acetic acid, whereupon the compound identified above precipitated. After recrystallisation from ethanol, this product melted at 195°-196°. 38 g (38%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[NH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19])=[O:7]
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of 17.9 gm (86 mmol) of 3-trifluoromethylbenzoyl chloride in 70 mL of dichloromethane was added 10.0 gm (66 mmol) of methyl 3-aminobenzoate. Triethylamine (9.38 gm, 13 mL, 93 mmol) was then added slowly to the mixture. After the addition was complete, the solution was warmed to 45° C. and stirred overnight. Ice was added to the solution to quench excess benzoyl chloride. After one hour, the layers were separated. The organic fraction was washed with 5% aqueous hydrochloride acid, saturated sodium bicarbonate, and finally with saturated sodium chloride solution. The dichloromethane solution was dried over magnesium sulfate. The drying agent was filtered off, and the solvent was removed by rotoevaporation to give the desired methyl 3-(3-trifluoromethylbenzamido)benzoate. 1H NMR (CDCl3): δ3.92 (s. 3H), 7.52 (t, 1H), 7.74 (t, 1H), 7.80 (m, 1H), 7.92 (m, 1H), 7.96 (m, 1H), 8.21 (d, 1H), 8.26 (s, 1H), 8.43 (s, 1H), and 9.07 (br s, 1H). MS m/z: 324.0 (M+H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:17][CH2:16][NH:15][CH2:14]1)=[O:12])[CH3:9].[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]=[C:41]=[O:42]>ClCCl>[CH2:8]([O:10][C:11]([C:13]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[CH:22][CH:21]=2)[CH2:17][CH2:16][N:15]([C:41](=[O:42])[NH:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[Cl:33])[CH2:14]1)=[O:12])[CH3:9]
Reactant: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCNC1
Reactant: O=C=Nc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)Nc2ccccc2Cl)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
Triethylamine (0.23 mL, 1.67 mmol) was added to a stirred solution of 3-(4′-fluoro-biphenyl-4-yloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (see Preparation 65) (185 mg, 0.54 mmol) in dichloromethane (10 mL) and the resulting mixture cooled to 0° C. 2-Chloro phenyl isocyanate (0.065 mL, 0.54 mmol) was added and the reaction mixture stirred at room temperature for 16 hours. The mixture was partitioned between water (25 mL) and dichloromethane (25 mL). The organic layer was separated, washed brine (25 mL), dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 25% ethyl acetate in hexane to afford the title compound as a colourless liquid (245 mg, 91%).
Reaction SMILES: [SH:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.[CH2:7]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10].[CH2:16]=O>C1(C)C=CC=CC=1>[CH2:7]([N:11]([CH2:16][N:6]1[CH:5]=[CH:4][S:3][C:2]1=[S:1])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10]
Reactant: SC1=NCCS1
Reactant: CCCCNCCCC
Reactant: C=O
Solvent: Cc1ccccc1
Product: CCCCN(CCCC)Cn1ccsc1=S
Temperature: 50 °C
Reaction time: 5 h
Yield: 91.7 %

Procedure:
A suspension of 47.3 g (0.4 mol) of 2-mercaptothiazoline together with 52.3 g (0.4 mol) of dibutylamine and 34.3 g (0.41 mol) of 36% aqueous formaldehyde in 150 ml of toluene is stirred for 5 hours at 50° C. The water is then separated off from the clear toluene phase and the latter is evaporated under reduced pressure. This gives 94.8 g (yield 91%) of 3-(dibutylaminomethyl)-thiazoline-2-thione in the form of a yellowish, highly fluid oil. nD20 1.5512.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.N(C([C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[N:21][CH:20]=1)=O)=[N+]=[N-].C[N:31](C)[CH:32]=[O:33]>>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:32]([NH:31][C:19]2[N:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:22]=[N:21][CH:20]=2)=[O:33])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: CN(C)C=O
Reactant: [N-]=[N+]=NC(=O)c1cnnn1-c1ccccc1
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cnnn2-c2ccccc2)c1O
Yield: 1.4 %

Procedure:
Under Ar, a solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (104 mg, 0.46 mmol) and 5-(azidocarbonyl)-1-phenyl-1H-1,2,3-triazole (100 mg, 0.46 mmol) in 5 mL of N,N-dimethyl-formamide was stirred at room temperature for 3 days. Purification upon Gilson HPLC twice, eluting with acetonitrile/water (10/90, v/v to 90/10, v/v, over 10 min), gave the desired product (2.7 mg, 1.4%). LC-MS (m/z) 409.9 (M+).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](OC)=[O:5].[CH3:10][C:11]1[C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOC(C)=O>[CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4]([NH:18][CH2:17][C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:10])=[O:5]
Reactant: Cc1ccccc1CN
Reactant: COC(=O)C(OC)OC
Solvent: CCOC(C)=O
Product: COC(OC)C(=O)NCc1ccccc1C
Temperature: 55 °C
Reaction time: 264 h

Procedure:
A mixture of methyl dimethoxyacetate (2.11 g, 15.6 mmol) and o-xylylamine (1.90 g, 15.4 mmol) in a 15 mL sealed tube was stirred at 55° C. for 11 d. The reaction solution was dissolved in EtOAc (≈60 mL) and washed with dil. HCl, water, sat. NaHCO3 solution, and brine, and dried over MgSO4. The EtOAc extract was filtered, concentrated, and dried in vacuo overnight to give the title compound as pale yellow oil. 1H NMR (400 MHz, CDCl3): δ=7.25-7.16 (m, 4H), 6.69 (brs, 1H), 4.75 (s, 1H), 4.48 (d, J=5.6 Hz, 2H), 3.40 (s, 6H), 2.33 (s, 3H). MS(ES+): m/z=246.07 (83) [MNa+], 224.11 (100) [MH+], 192.14 (60) [MH+-MeOH], 160.10 (95) [MH+-2 MeOH]. HPLC: tR=2.82 min (polar—5 min, ZQ3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[CH:4][C:3]=1[N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].[O:25]=[C:26]1[NH:30][C:29](=[O:31])[CH:28]([CH2:32][C:33]2[CH:43]=[CH:42][C:36]([O:37][CH2:38][C:39](O)=[O:40])=[CH:35][CH:34]=2)[S:27]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:25]=[C:26]1[NH:30][C:29](=[O:31])[CH:28]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:37][CH2:38][C:39]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[OH:15])=[CH:4][C:3]=3[N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:40])=[CH:42][CH:43]=2)[S:27]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2O)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2O)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 66.3 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(2-hydroxyphenoxy)phenyl]-N-methylcarbamate (0.99 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.93 g), diethyl cyanophosphonate (0.54 g), triethylamine (0.33 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (1.18 g).
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[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[CH2:31][CH2:30][CH2:29][NH:28][C:27](=[O:32])[C:26]=2[CH:33]=1.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O>C(O)(C)C>[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[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[CH2:31][CH2:30][CH2:29][NH:28][C:27](=[O:32])[C:26]=3[CH:33]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)C(=O)NCCC2
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)C(=O)NCCC3)ncc1Cl
Yield: 15.3 %

Procedure:
Combined 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (104 mg, 0.33 mmol), 8-Amino-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (70 mg, 0.397 mmol), DL-10-Camphorsulfonic acid (82 mg, 0.353 mmol) and isopropanol (4 mL) in a microwave tube. Microwaved reaction at 120° C. for 30 minutes. Evaporated off solvent and purified with normal phase chromatography to yield a white solid, 2-[5-Chloro-2-(1-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide (23 mg, 15%). mp 200° C.; LCMS: m/z=455.37 (M+H+), 1H NMR (400 MHz, CD3OD) δ 8.06 (s, 1H), 7.66 (m, 1H), 7.43 (m, 2H), 7.03 (d, 1H, J=9.1 Hz), 3.03 (m, 2H), 2.84 (s, 3H), 2.75 (m, 2H), 1.98 (m, 2H).
Reaction SMILES: [F:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12](=[O:21])[C:11]=2[CH:22]=1>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][C:19]([S:2]([F:1])(=[O:5])=[O:3])=[CH:20][C:13]=3[C:12](=[O:21])[C:11]=2[CH:22]=1
Reactant: O=C1c2ccccc2CCc2ccc(Br)cc21
Reactant: O=S(=O)(O)F
Product: O=C1c2cc(Br)ccc2CCc2ccc(S(=O)(=O)F)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Fluorosulfonic acid, 100 ml., is placed in a 300 ml. 3-necked round bottom flask equipped with polyethylene inlet tube and polyethylene exit tube with drying tube half-filled with anhydrous sodium fluoride. A nitrogen atmosphere is maintained throughout the reaction. With stirring, 17.0 g. (0.059 mole) of 3-bromo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one is added in portions over 20 minutes. After stirring another 10 minutes, the dark green solution is heated on the steam-bath for 61/2 hours. The mixture then is cooled to room temperature, poured cautiously with stirring into 1.5 kg. of crushed ice, and allowed to stand overnight at room temperature. The brown solid is collected, washed with water, dried in a vacuum desiccator over sodium hydroxide, and then extracted in a Sohxlet extractor with 700 ml. of boiling cyclohexane for 16 hours. On cooling, the cyclohexane extract deposits 11.65 g. (53%) of 3-bromo-7-fluorosulfonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one as dark yellow flakes, m.p. 148°-151°C. Recrystallizations from ether and cyclohexane give an analytical sample, m.p. 150°-152°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[NH:37][C:38]([NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[CH:42]=1)=[O:39])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:19][C@@H:20]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:21]([O:23]C)=[O:22])=[O:18])[CH:13]=2)[CH:7]=1.C1COCC1.CO.[OH-].[Na+].Cl>O>[C:30]([O:29][C:27](=[O:28])[CH2:26][CH2:25][C@H:20]([NH:19][C:17]([C:14]1[CH:13]=[C:12]([C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:34]=[CH:35][C:36]([NH:37][C:38]([NH:40][C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[CH:42]=4)=[O:39])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)[NH:16][CH:15]=1)=[O:18])[C:21]([OH:23])=[O:22])([CH3:31])([CH3:33])[CH3:32]
Reactant: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cccc(C)c4)c(F)c3)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)O)c[nH]4)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (S)-5-tert-butyl 1-methyl 2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate (120 mg, 0.19 mmol) in a mixture of solvents THF/MeOH (5 ml/5 ml) was added 1 ml of 1M NaOH (1 mmol) solution. The mixture was stirred at room temperature for 30 minutes, and poured into 100 ml of water. 2M HCl was added dropwise until pH=4. The resulting precipitates were filtered, washed with water, and dried in vacuo to give (2S)-5-tert-butoxy-2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoic acid as white solid. Yield: 100 mg, 85%.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:24]1(=[O:30])[O:29][C:27](=[O:28])[CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>ClCCl>[Cl:23][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][C@@H:3]([NH:2][C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:12][CH:13]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)CCC(=O)O
Reaction time: 2.5 h
Yield: 54 %

Procedure:
A solution of (R)-ethyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (400 mg, 1.13 mmol), succinic anhydride (136 mg, 1.36 mmol) and DIPEA (0.237 mL, 1.36 mmol) in dichloromethane (5 mL) is allowed to stir for 2.5 hours. The reaction is quenched with 1 M aqueous HCl and extracted with dichloromethane. The organic layer is separated and concentrated under reduced pressure. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give (R)-4-(1-(3′-chlorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (255 mg). HPLC retention time=1.15 minutes (condition B); MS (m+1)=418.0; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J=7.08 Hz, 3H) 2.46-2.58 (m, 4H) 2.64-2.67 (m, 2H) 2.87 (A of ABX, Jab=13.6 Hz, Jax=7.8 Hz, 1H) 2.99 (B of ABX, Jab=13.6 Hz, Jbx=6.6 Hz, 1H) 4.12-4.24 (m, 2H) 4.47-4.55 (m, 1H) 6.50 (br d, J=8.8 Hz, 1H) 7.24-7.37 (m, 4H) 7.43-7.46 (m, 1H) 7.48-7.52 (m, 2H) 7.55-7.56 (m, 1H). Chiral HPLC retention time=3.59 min. Column: Daicel CHIRALPAK AD-H (4.6×100 mm); flow rate=1 ml/min.; eluent: EtOH (containing 0.1% TFA)/heptane=4/6.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([C:7]1[CH:8]=[N:9][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[C:28]([CH:29]([F:40])[C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)=[C:27]([CH:41]4[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]4)[C:26]4[CH:25]([O:49]CC5C=CC(OC)=CC=5)[CH2:24][C:23]([CH3:60])([CH3:59])[CH2:22][C:21]=4[N:20]=3)[CH2:15][CH2:14]2)=[N:11][CH:12]=1)([OH:6])=O>>[F:47][C:44]1([F:48])[CH2:43][CH2:42][CH:41]([C:27]2[C:26]3[CH:25]([OH:49])[CH2:24][C:23]([CH3:60])([CH3:59])[CH2:22][C:21]=3[N:20]=[C:19]([CH:16]3[CH2:17][CH2:18][N:13]([C:10]4[N:9]=[CH:8][C:7]([C:4](=[O:6])[N:2]([CH3:3])[CH3:1])=[CH:12][N:11]=4)[CH2:14][CH2:15]3)[C:28]=2[CH:29]([F:40])[C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=2)[CH2:46][CH2:45]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(C(=O)O)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: CNC
Product: CN(C)C(=O)c1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1

Procedure:
Reactions similar to those of the second step of Reference Example 25 and Example 38 were performed except for using dimethylamine aqueous solution instead of methylamine aqueous solution, and from 70 mg of the crude product of 2-[1-(5-Carboxypyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared in the first step of Reference Example 25, 30 mg of the title compound was obtained as a white solid (yield: 56%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.Cl.[N:43]1([C:50]2[CH:55]=[CH:54][N:53]=[CH:52][CH:51]=2)[CH2:48][CH2:47][CH:46]([NH2:49])[CH2:45][CH2:44]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:49][CH:46]5[CH2:45][CH2:44][N:43]([C:50]6[CH:51]=[CH:52][N:53]=[CH:54][CH:55]=6)[CH2:48][CH2:47]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCN(c2ccncc2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(c3ccncc3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a mixture of 0.10 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.2 mL (1.1 mmole) of ethyldiisopropyl amine and 0.062 mL (0.25 mmole) of 3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylamine hydrochloride salt in 2.0 mL of dimethylformamide was added 0.11 g (0.25 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-70:30) gave 0.089 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-benzamide (I-62) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:24]=1.[C:25]([C@:27]1([OH:34])[CH2:31][CH2:30][N:29]([CH3:32])[C:28]1=[O:33])#[CH:26]>>[OH:34][C@@:27]1([C:25]#[C:26][C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[C:12]([C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:24]=2)[CH2:31][CH2:30][N:29]([CH3:32])[C:28]1=[O:33]
Reactant: C#C[C@]1(O)CCN(C)C1=O
Reactant: CC(C)NC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Product: CC(C)NC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(C#C[C@]3(O)CCN(C)C3=O)cc1-2
Yield: 12.2 %

Procedure:
10-bromo-2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-3-carboxyl is acid was reacted with 2-aminopropane similarly to as described in example 2 with non-critical modifications to afford 112 mg (67%) 10-bromo-N3-isopropyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide. 10-bromo-N3-isopropyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 16 mg (12.2%) 10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-N3-isopropyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide.