Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C@H:5]([CH2:7][S:8][CH2:9][C@@H:10]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:6])[CH3:2].[C:30]([O:34][C:35](=[O:39])[CH:36](Br)[CH3:37])([CH3:33])([CH3:32])[CH3:31].C(N(CC)CC)C>CN(P(N(C)C)(N(C)C)=O)C>[C:30]([O:34][C:35](=[O:39])[C@H:36]([CH3:37])[NH:6][C@H:5]([C:4]([O:3][CH2:1][CH3:2])=[O:29])[CH2:7][S:8][CH2:9][C@@H:10]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: CCOC(=O)[C@@H](N)CSC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CSC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)N[C@@H](C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 46 g quantity of S-[(S)-2-benzyloxycarbonylamino-3-phenylpropyl]-L-cysteine ethyl ester and 27 g of 2-bromopropionic acid t-butyl ester were dissolved in 150 ml of HMPA. To the solution was added 18 ml of triethylamine and the mixture was stirred at room temperature for 48 hours. The reaction mixture was poured into ice water and the mixture was extracted with ethyl acetate. The extract was washed with water and with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure and the residue was separated and purified by silica gel column chromatography (a 5:4 mixture of ether and n-hexane as an eluent), giving the α-isomer of the title compound as a colorless oil from the first eluate. Yield 10.6 g.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[C:9]1[N:18]=[C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:16]2[CH2:15][C:14](Cl)([Cl:30])[CH:13]=[CH:12][C:11]=2[N:10]=1.O>CN(C)C=O>[N:1]1([C:9]2[N:18]=[C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:30])[CH:15]=3)[N:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Clc1nc2c(c(NCc3ccc4c(c3)OCO4)n1)CC(Cl)(Cl)C=C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2nc(-n3ccnc3)nc(NCc3ccc4c(c3)OCO4)c2c1
Reaction time: 0.17 h
Yield: 65.8 %

Procedure:
103 mg of imidazole was added to a suspension of 66 mg of sodium hydride in 6 ml of dimethylformamide at 0° C. The obtained mixture was stirred for 10 minutes. 500 mg of 2,6-dichloro-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline was added to the resulting mixture at room temperature. The mixture thus prepared was stirred at 100° C. for 20 minutes, followed by the addition of water. The crystals precipitated were recovered by filtration and washed with water and ethanol/acetone successively to give 325 mg of the title compound.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:14]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:3][C:4](=[O:13])[O:5]CC1C=CC=CC=1.[CH2:32]([S:39](Cl)(=[O:41])=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OCC)(=O)C.C(Cl)Cl>[C:33]1([CH2:32][S:39]([NH:1][C@H:2]([C:14]([NH:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:15])[CH2:3][C:4](=[O:13])[OH:5])(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)NCCc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(O)C[C@H](NS(=O)(=O)Cc1ccccc1)C(=O)NCCc1ccccc1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
The keto amide (8) (109 mg, 0.24 mmol) was dissolved in ethyl acetate (5 mL) and cooled in an ice bath. Dry HCl gas was bubbled through until the solution was saturated and then the solution was stirred at r.t. until the starting material had been consumed as indicated by tlc (˜30 min). The solvent was removed under reduced pressure. The residue (22) was dissolved in dry CH2Cl2 (5 mL) and triethylamine (61 mg, 84 μL) added. The solution was then added dropwise to a solution of benzyl sulfonyl chloride (46 mg, 0.24 mmol) in dry CH2Cl2 (5 mL) cooled in an ice bath. The resulting solution was allowed to stir at r.t. for 16 h. It was washed with 1M HCl, 5% sodium bicarbonate solution and saturated brine, then dried (MgSO4) and the solvent removed under reduced pressure to yield the product as a white solid (51 mg, 42%): mp 128-130° C. 1H NMR (CDCl3) δ2.61 & 2.99 (ABX, 2H, β-CH2), 2.86 (t, 2H, CH2Ph), 3.57 (m, 2H, NH—CH2), 4.74 (m, 1H, α-CH), 5.14 (2×s, 4H, benzyl CH2's), 6.53 & 6.74 (m, 2H, NH's), 7.29 (m, 15H, aromatic CH's); FABMS m/e 509 (M++1).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4](C=[CH:6]1)[CH:3]1[C:9]([O:11][C:12](=[O:13])[CH:2]21)=[O:10].[OH-:14].[Na+:15]>CO>[CH:4]12[CH2:6][CH:1]([CH:8]=[CH:7]1)[CH:2]([C:12]([O-:11])=[O:13])[CH:3]2[C:9]([O-:10])=[O:14].[Na+:15].[Na+:15]
Reactant: O=C1OC(=O)C2C3C=CC(CC3)C12
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: O=C([O-])C1C2C=CC(C2)C1C(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of bicyclo[2.2.2]-oct-5-en-2,3-dicarboxylic anhydride (2.01 g, 11.3 mmole) in MeOH (50 mL) was added 1 N aq. NaOH (22.4 mL, 22.4 mmol). The reaction mixture was stirred for 1 hour at room temperature. The solvent was removed in vacuo and the resulting colorless solid was dried: mp>400 C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[CH2:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[CH3:11]>>[CH2:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[CH3:11]
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(O)c1ccccn1
Product: CCOc1ccc(NC(=O)c2ccccn2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from picolinic acid and 4-ethoxy-2-nitroaniline as a yellow solid as described in Example 15. 1H NMR (CDCl3): 12.54 (s, 1H), 8.92 (d, J=9.3, 1H), 8.73 (d, J=3.9, 1H), 8.28 (d, J=6.9, 1H), 7.95-7.90 (m, 1H), 7.74 (d, J=3.0, 1H), 7.54-7.50 (m, 1H), 7.31-7.27 (m, 1H), 4.11 (q, J=6.9, 2H), 1.46 (t, J=6.9, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[F:11][C:12]([F:18])([F:17])[O:13][CH2:14][CH2:15][NH2:16]>>[NH2:1][C:2]1[CH:9]=[C:8]([NH:16][CH2:15][CH2:14][O:13][C:12]([F:18])([F:17])[F:11])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: NCCOC(F)(F)F
Reactant: N#Cc1cnc(N)cc1F
Product: N#Cc1cnc(N)cc1NCCOC(F)(F)F

Procedure:
From intermediate 21 and 2-(trifluoromethoxy)ethanamine, reacted in an analogous manner to the preparation of intermediate 102. (UPLC-MS 3) Rt=0.54 min; MS m/z [M+H]+ 247.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C(O[CH:13]=[C:14]([C:20]#[N:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>C(O)C.C(OCC)C>[CH2:18]([O:17][C:15]([C:14]1[CH:13]=[N:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:20]=1[NH2:21])=[O:16])[CH3:19]
Reactant: NNc1ccc(Br)cc1
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1N
Yield: 70.2 %

Procedure:
A solution of 4-bromophenylhydrazine (2.76 g, 14.7 mmol) and ethyl (ethoxymethylene)cyanoacetate (2.50 g, 14.8 mmol) in ethanol (15 mL) was heated at reflux for 2 hours. Upon cooling, a tan precipitate formed. The suspension was diluted with diethyl ether and suction filtered to remove solid. The filtercake was rinsed with diethyl ether and vacuum oven dried to afford 3.20 g (70%) of product as a tan solid: 1H NMR (CDCl3) d 7.79 (s, 1H), 7.64 (d, J=8.7 Hz, 2H), 7.45 (d, J=8.7 Hz, 2H), 5.30 (s, 2H), 4.31 (q, J=7.2 Hz, 2H), 1.37 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[CH3:49][CH:50]([C:52]1[CH:62]=[C:61]([CH:63]([CH3:65])[CH3:64])[CH:60]=[C:59]([CH:66]([CH3:68])[CH3:67])[C:53]=1[O:54]CC(O)=O)[CH3:51]>>[CH3:68][CH:66]([C:59]1[CH:60]=[C:61]([CH:63]([CH3:65])[CH3:64])[CH:62]=[C:52]([CH:50]([CH3:51])[CH3:49])[C:53]=1[O:54][CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:31])[CH3:32])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:23])[CH3:24])=[CH:20][CH:21]=1)=[O:15])[CH3:67]
Reactant: CC(C)c1cc(C(C)C)c(OCC(=O)O)c(C(C)C)c1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1cc(C(C)C)c(OCC(=O)c2ccc(C(C)C)c(OS(N)(=O)=O)c2C(C)C)c(C(C)C)c1

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with [2,4,6-tris(1-methylethyl)phenoxy]acetic acid, mp 126°-128° C.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)CC(C)C.[CH2:35]([O:37][CH2:38][C@H]1CC[C@H](N)CC1)[CH3:36].COCC1CCC(N(CCC(C)C)C(=O)NC2SC(SCC(O)=O)=CN=2)CC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH2:35]([O:37][CH2:38][C@H:4]1[CH2:3][CH2:2][C@H:1]([N:7]([CH2:21][CH2:22][CH:23]([CH3:24])[CH3:28])[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5]1)[CH3:36]
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Reactant: CCOC[C@H]1CC[C@H](N)CC1
Agent: CC(C)CC=O
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: COCC1CCC(N(CCC(C)C)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Product: CCOC[C@H]1CC[C@H](N(CCC(C)C)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid using isovaleraldehyde, trans-4-ethoxymethyl-cyclohexylamine (prepared in accordance with the general method given for the preparation of {2-[3-(4-methoxymethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid) and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:21]=[CH:22][C:23]5[O:27][C:26]([C:28](OC)=[O:29])=[CH:25][C:24]=5[CH:32]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.[OH:33][CH2:34][CH2:35][NH2:36]>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:21]=[CH:22][C:23]5[O:27][C:26]([C:28]([NH:36][CH2:35][CH2:34][OH:33])=[O:29])=[CH:25][C:24]=5[CH:32]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: NCCO
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc5c(c4)OCCO5)n3)ccc2o1
Product: O=C(NCCO)c1cc2cc(Nc3ncc(F)c(Nc4ccc5c(c4)OCCO5)n3)ccc2o1

Procedure:
In like manner to preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, the reaction of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine with 2-hydroxyethylamine yielded N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-2-hydroxyethylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine.
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[NH2:37][CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:37][CH:38]1[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43]1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 50 °C

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (1.484 g, 5.37 mmol) in dry dichloromethane (60 ml) was added triethylamine (1.88 ml, 13.49 mmol), 2-chloro-1-methylpridinium iodide (1.60 g, 6.26 mmol), and 4-amino-1-BOC-piperidine (1.30 g, 6.49 mmol) sequentially at room temperature under nitrogen. The reaction was then heated to 50° C. for 1 hour. The reaction mixture was concentrated under vacuum and purified by silica gel chromatography on an Isco Combiflash (40 g silica gel, 40 mL/min, 254 nM, 15% to 100% EtOAc/hexane over 14 column volumes then 100% EtOAc for 4 column volumes; title compound eluted at 65% ethyl acetate/hexane) to afford the title compound as a pale orange solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:30])[C:4]([O:22]CC2C=CC=CC=2)=[C:5]2[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)[CH2:8][CH2:7][N:6]2[CH:21]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>>[Cl:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[F:19])[CH2:12][N:9]1[CH2:8][CH2:7][N:6]2[CH:21]=[C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])[C:3](=[O:30])[C:4]([OH:22])=[C:5]2[C:10]1=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cn2c(c(OCc3ccccc3)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Product: CS(=O)(=O)Nc1cn2c(c(O)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2

Procedure:
By subjecting 7-amino-9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (29 mg) obtained in Example 349, Step 2 to a reaction operation similar to that in Example 349, Steps 3 and 4 except that methanesulfonyl chloride was used instead of isobutyryl chloride, N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methanesulfonamide (4.7 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:21]1([C:27]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@H:35]3[C@H:31]([CH2:32][NH:33][CH2:34]3)[C:30](=[O:36])[CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([N:33]1[CH2:32][C@H:31]2[C@H:35]([C:27]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29][C:30]2=[O:36])[CH2:34]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC[C@@H](C(=O)O)c1ccccc1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC[C@@H](C(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1)c1ccccc1
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
N,N'-Carbonyldiimidazole (0.5 g) is added to a solution of (S)-3-tert-butoxycarbonylamino-2-phenylpropionic acid (0.79 g) in dry dichloromethane (20 cc), cooled to +5° C. The mixture is stirred for 1 hour 15 minutes at +5° C. and a solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1 g) and triethylamine (0.4 cc) in dichloromethane (25 cc) is then added. The reaction mixture is stirred for 15 minutes at +5° C. and then for 16 hours at 20° C. The reaction mixture is washed with distilled water (3×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.06 mm, diameter 3 cm, height 30 cm), eluting with a mixture of cyclohexane and ethyl acetate (50/50 by volume) and collecting 50 cc fractions. Fractions 2 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa). (3aR,7aR)-2-[(S)-2-tert-butoxycarbonylaminomethyl-2-phenylacetyl]-7,7-diphenyl-4-perhydroisoindolone (1.2 g) is obtained in the form of a white meringue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:15](Cl)[CH:16]([C:18]([F:21])([F:20])[F:19])[CH3:17].[CH2:23]([NH:26][C:27]#[N:28])[CH2:24][CH3:25].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:27]([NH:26][CH2:23][CH2:24][CH3:25])=[N:28][C:15]([CH:16]([C:18]([F:21])([F:20])[F:19])[CH3:17])=[N:14]1
Reactant: CCCNC#N
Reactant: CC(C(Cl)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCNc1nc(C(C)C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 2 h
Yield: 700.8 %

Procedure:
7.8 g (0.02 mol) of 2-trifluoromethylpropionyl chloride 2,6-dichloro-4-trifluoromethylphenylhydrazone and 1.9 g (0.002 mol) of propyl cyanamide were dissolved in 50 ml of tetrahydrofuran, and 2.6 g (0.026 mol) of triethylamine was dropwise added thereto under stirring and cooling with ice. After completion of the dropwise addition, the stirring was continued at room temperature for 2 hours. The solvent was distilled off under reduced pressure. The residue was dissolved in hexane, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. Then, hexane was distilled off under reduced pressure. Further, the residue was subjected to distillation under reduced pressure. The fraction having a boiling point of 110°-120° C./0.1-0.2 mmHg was subjected to recrystallization from hexane to obtain 6.1 g (yield: 70%) of the desired compound having a melting point of from 73° to 74.5° C. as white prismatic crystals.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:7]([OH:8])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.CCN(CC)CC.[CH2:23]([O:30][C:31](ON1C(=O)CCC1=O)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[OH:8][C@H:7]1[C@@H:3]([CH2:2][NH:1][C:31]([O:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:32])[CH2:4][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)[C@@H](O)C1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](CNC(=O)OCc2ccccc2)[C@H](O)C1
Reaction time: 18 h
Yield: 94.9 %

Procedure:
To a solution of (±)-1,1-dimethylethyl cis-3-(aminomethyl)-4-hydroxy-1-pyrrolidinecarboxylate (10.0 g, 46.0 mmole) in DMF (50 mL) at RT was added Et3N (8.4 mL, 60.0 mmole) and N-(benzyloxycarbonyloxy)succinimide (14.95 g, 60.0 mmole). After 18 h, the DMF was removed under vacuum and the residue purified on silica (25-50% DCM/EtOAc) to give the title compound (15.3 g, 95%) as a white foam: LC-MS (ES) m/e 351 (M+H)+; and a small amount of an N-methylated byproduct [1,1-dimethylethyl (3S,4S)-3-hydroxy-4-[(methyl{[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate] (0.33 g, 2%): LC-MS (ES) m/e 365 (M+H)+.
Reaction SMILES: Cl.Cl.Cl.Cl.[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:19][CH2:18]3)=[O:14])=[CH:8][C:7]=1[NH:30][C:31]1[N:36]=[C:35]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:34]=[CH:33][N:32]=1.C(N(CC)CC)C.[C:50](Cl)(=[O:52])[CH3:51]>CN(C=O)C>[C:50]([N:27]1[CH2:26][CH2:25][N:24]([CH:20]2[C:21]3[C:17](=[CH:16][C:15]([C:13]([NH:12][C:9]4[CH:10]=[CH:11][C:6]([CH3:5])=[C:7]([NH:30][C:31]5[N:36]=[C:35]([C:37]6[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=6)[CH:34]=[CH:33][N:32]=5)[CH:8]=4)=[O:14])=[CH:23][CH:22]=3)[CH2:18][CH2:19]2)[CH2:29][CH2:28]1)(=[O:52])[CH3:51]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCNCC2)cc1Nc1nccc(-c2cccnc2)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(C2CCc3cc(C(=O)Nc4ccc(C)c(Nc5nccc(-c6cccnc6)n5)c4)ccc32)CC1
Reaction time: 0.33 h
Yield: 54.8 %

Procedure:
N-(4-Methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-1-piperazin-1-yl-2,3-dihydro-1H-indene-5-carboxamide tetrahydrochloride (100 mg, 0.15 mmol) was dissolved in DMF (2 mL), and triethylamine (101 mg, 1 mmol) was added followed by acetyl chloride (16 mg, 0.2 mmol) while being cooled in an ice bath. After being stirred for 20 minutes, the solution obtained was purified by high performance liquid chromatography at pH=10 to obtain 45 mg (55% yield) of the title compound. MS (+1)=548.27. 1HNMR (DMSO-d6, ppm): δ 10.15 (s, 1H); 9.26 (s, 1H); 8.99 (s, 1H); 8.66 (d, J=4.8 Hz, 1H); 8.49 (d, J=5.2 Hz, 1H); 8.45 (d, J=8.4 Hz); 8.05 (s, 1H); 7.79 (s, 1H); 7.76 (d, J=8.0 Hz, 1H); 7.50 (dd, J=8.0 & 4.8 Hz, 1H); 4.37 (t, J=7.0 Hz, 1H); 3.42 (m, 1H); 3.40 (m, 3H); 2.91 (m, 1H); 2.83 (m, 1H); 2.2-2.5 (m, 4H); 2.20 (s, 3H); 2.06 (m, 2H); 1.95 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.ClC(OCC)=O.[NH2:20][CH2:21][CH:22]1[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[CH2:23]1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:20][CH2:21][CH:22]2[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH:29]3[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]3)[CH2:23]2)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCOC(CN)C2)CC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CN(CC2CCN(C(=O)OC(C)(C)C)CC2)CCO1
Yield: 47.6 %

Procedure:
To a suspension of 4-amino-5-chloro-2-methoxybenzoic acid (27.6 g) in chloroform (200 ml) was added dropwise TEA (16.6 g) at room temperature with stirring. The internal temperature of the reaction solution was ice-cooled, and then thereto was slowly added dropwise ethyl chloroformate (16.3 g) so that the internal temperature did not rise over 5° C. After completion of addition, the mixture was stirred at internal temperature of 0 to 5° C. for 1 hour. To the reaction solution was slowly added dropwise a solution of 2-aminomethyl-4-[1-(tert-butoxycarbonyl)-4-piperidinylmethyl]morpholine (Reference Example 12) (42.9 g) in chloroform (50 ml) so that the internal temperature did not rise over 5° C., and after completion of addition, the mixture was stirred overnight without an ice bath. The reaction solution was sequentially washed with water, 5% aqueous potassium hydroxide solution, water, 5% aqueous solution of citric acid, water and brine. The solution was dried over anhydrous magnesium sulfate, and then the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give the titled compound (32.4 g) as an amorphous solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([CH:8]=[O:9])[N:5]=[CH:4]1.[C:10]([O:16][CH2:17]Cl)(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]>O1CCCC1.CN(C=O)C>[C:10]([O:16][CH2:17][N:3]1[CH:7]=[C:6]([CH:8]=[O:9])[N:5]=[CH:4]1)(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=Cc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OCn1cnc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a suspension of sodium hydride (60% in oil, 1.0 g, 26 mmol) in tetrahydrofuran (10 ml) was added dropwise a solution of 1H-imidazole-4-carbaldehyde (1.92 g, 20 mmol) in DMF (5 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. Chloromethyl pivalate (3.92 g, 26 mmol) was further added dropwise at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with 6% aqueous sodium hydrogen carbonate solution and saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (100 g), and eluted with hexane-ethyl acetate (4:1-1:2, v/v) to give the title compound (4.11 g, 98%) as a pale-yellow oil.