Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[S:3])=[S:2].[CH3:4][C:5]([C:8]1[CH:9]=[C:10]([C:25]([NH:27][NH2:28])=N)[CH:11]=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:13]=1[O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])([CH3:7])[CH3:6]>C(O)C.C(OC(C)C)(C)C>[CH3:7][C:5]([C:8]1[CH:9]=[C:10]([C:25]2[S:2][C:1](=[S:3])[NH:28][N:27]=2)[CH:11]=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:13]=1[O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])([CH3:4])[CH3:6]
Reactant: COCCOCOc1c(C(C)(C)C)cc(C(=N)NN)cc1C(C)(C)C
Reactant: S=C=S
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: COCCOCOc1c(C(C)(C)C)cc(-c2n[nH]c(=S)s2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.5 %

Procedure:
Carbon disulfide (1.6 g, 0.021 mole) is added dropwise to a stirred 0° C. solution of 3,5-bis(1,1- dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzene carboximidic acid hydrazide (3.0 g, 0.085 mole) in absolute ethanol (36 ml). The mixture is allowed to warm to room temperature and stir three hours. The mixture is stripped of volatiles under reduced pressure and the residue is dissolved in isopropyl ether and the solvent removed under reduced pressure. The resulting solid is recrystallized from isopropyl ether/hexane to give 2.8 g of 5-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]phenyl]-1,3,4-thiadiazole-2(3H)-thione (3.5 g theor., 80%); mp 134°-135° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[O:11][CH:10]([CH:12]3[CH2:14][CH2:13]3)[CH2:9][O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[CH:12]1([CH:10]2[CH2:9][O:8][C:6]3[N:7]=[C:2]([C:29]4[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=4)[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]=3[O:11]2)[CH2:14][CH2:13]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Clc1nc2c(c(N3CCOCC3)n1)OC(C1CC1)CO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1ncc(-c2nc3c(c(N4CCOCC4)n2)OC(C2CC2)CO3)cn1
Temperature: 120 °C
Yield: 9.2 %

Procedure:
A microwave vial was charged with 2-chloro-6-cyclopropyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine (191 mg, 0.64 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (283 mg, 1.28 mmol), Pd(PPh3)2Cl2 (45 mg, 0.06 mmol), sodium carbonate (2.11 mL, 2.11 mmol, 1M aqueous solution) and acetonitrile (2.5 mL). The vessel was sealed then evacuated and refilled with argon (×3) before being heated at 120° C. for 30 minutes using microwave irradiation. The reaction mixture was filtered before being purified by column chromatography (SiO2, gradient 0-4% methanol in DCM). The resultant residue was triturated with diethyl ether to give 107 as a white solid (21 mg, 9%). LCMS: RT=3.54 min, [M+H]+=357. 1H NMR (400 MHz, DMSO-d6): δ 8.89 (2H, s), 7.00 (2H, s), 4.53 (1H, dd, J=11.48, 2.34 Hz), 4.22 (1H, dd, J=11.50, 7.87 Hz), 3.75-3.67 (8H, m), 3.65-3.58 (1H, m), 1.01-0.99 (1H, m), 0.63-0.55 (2H, m), 0.51-0.42 (2H, m).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][NH:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31](Cl)[N:30]=4)=[CH:25][CH:24]=3)[CH:17]=2)[NH:12][CH:11]=1)#[N:9]>>[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][NH:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)[N:30]=4)=[CH:25][CH:24]=3)[CH:17]=2)[NH:12][CH:11]=1)#[N:9]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: CN1CCNCC1
Product: CN1CCN(c2nccc(-c3ccc(C(=O)NCCc4ccc5[nH]cc(C#N)c5c4)cc3)n2)CC1

Procedure:
Using N-methyl-piperazine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 466 (M+H)+.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[CH2:12]1[CH:16]2[CH2:17][C@H:18](O)[CH:14]([CH2:15]2)[CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH:14]12[CH2:15][CH:16]([CH2:17][CH2:18]1)[CH2:12][CH:13]2[O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1]
Reactant: O[C@H]1CC2CCC1C2
Reactant: COc1ccc(C=O)cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C=O)cc1OC1CC2CCC1C2
Temperature: 25 °C
Yield: 40.7 %

Procedure:
To a magnetically-stirred solution of isovanillin (10 mmol, 1.52 g) in dry tetrahydrofuran (15 mL) at -10° C. is added endo-norborneol (10 mmol, 1.12 g) followed by triphenylphosphine (14 mmol, 3.67 g). After a few minutes, a solution of diethylazodicarboxylate (14 mmol, 2.44 g; 2.22 mL) in dry tetrahydrofuran (5 mL) is added dropwise at -10° C. and the resulting solution is allowed to warm to room temperature over 20 hours. The solvent is removed in vacuo and the residue partitioned between ethyl acetate and water. The organic phase is dried (Na2SO4) and concentrated in vacuo to afford the crude product. This material is purified by flash chromatography (SiO2 : 20% ethyl acetate/hexane) to give the title compound as a colorless oil (4.07 mmol, 1.00 g; 41%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:40]1([CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:43]3[CH2:42][CH2:41][N:40]([CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50])[CH2:45][CH2:44]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)NCCN1CCNCC1
Reactant: CC(C)(C)c1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)Cl)c(OCC(F)(F)F)c1
Agent: Cl
Product: CC(=O)NCCN1CCN(C(=O)N2C(c3ccc(C(C)(C)C)cc3OCC(F)(F)F)=N[C@@H](c3ccc(Cl)cc3)[C@H]2c2ccc(Cl)cc2)CC1

Procedure:
N-(2-{4-[(4S,5R)-2-[4-tert-Butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethyl)-acetamide hydrochloride was prepared from (4S,5R)-2-[4-tert-butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12l) and N-(2-piperazin-1-yl-ethyl)-acetamide hydrochloride (example 23) in an analogous manner as described in example 25. LR-MS: 718.5 [(M+H)+]
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:41])[C@@H:15]([NH2:40])[CH2:16][CH2:17][CH2:18][NH:19]/[C:20](/[NH2:39])=[N:21]/[S:22]([C:25]2[C:26]([CH3:38])=[C:27]([CH3:37])[C:28]3[O:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]=3[C:35]=2[CH3:36])(=[O:24])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH:44]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46][C:45]=1[S:54](Cl)(=[O:56])=[O:55]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:41])[C@@H:15]([NH:40][S:54]([C:45]2[CH:46]=[CH:47][C:48]3[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:44]=2)(=[O:56])=[O:55])[CH2:16][CH2:17][CH2:18][NH:19]/[C:20](/[NH2:39])=[N:21]/[S:22]([C:25]2[C:26]([CH3:38])=[C:27]([CH3:37])[C:28]3[O:32][C:31]([CH3:33])([CH3:34])[CH2:30][C:29]=3[C:35]=2[CH3:36])(=[O:23])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](N)C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of compound B (28.0 g, 46.2 mmol) in THF (250 mL) was added aqueous 1N NaOH (171 mL). The reaction mixture was cooled to ˜5° C., a solution of 2-naphthalene sulfonylchloride (26.19 g, 115.6 mmol) in THF (125 mL) was added dropwise. The reaction mixture was stirred at ˜5° C. for 10 min, with stirring continued at room temperature for 2 h. The reaction mixture was diluted with EtOAc (1 L), washed with aqueous 1N NaOH (1 L), water (1 L) and brine (1 L). The organic layer was separated, dried over Na2SO4 and removal of the solvent in vacuo to afford compound C (36.6 g, 46.2 mmol). LC-MS [M+H] 785.5 (C38H52N6O8S2+H, calc: 785.9).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]=[C:9]([C:11]3[N:15]([CH3:16])[C:14]([C:17]4[CH2:18][CH2:19][N:20](C(OC(C)(C)C)=O)[CH2:21][CH:22]=4)=[N:13][C:12]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:15]1[C:11]([C:9]2[S:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[N:10]=2)=[C:12]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:13]=[C:14]1[C:17]1[CH2:18][CH2:19][NH:20][CH2:21][CH:22]=1
Reactant: Cn1c(C2=CCN(C(=O)OC(C)(C)C)CC2)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(C2=CCNCC2)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
tert-Butyl 4-[5-(7-amino[1,3]thiazolo[5,4-d]pyrimidin-2-yl)-1-methyl-4-phenyl-1H-imidazol-2-yl]-3,6-dihydropyridine-1(2H)-carboxylate (Example 102) (20 mg) was dissolved in DCM (0.5 mL), TFA (2 mL) added, stirred at ambient temperature for 2 hours then concentrated in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate, extracted with DCM (2×5 mL), organics dried, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with 10% MeOH/DCM gave the title compound as a colourless solid (11 mg, 69%);
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]C)=O)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:30])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[NH3:32]>CO>[O:31]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][C:26]([NH2:32])=[O:28])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:30])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)CCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12
Reactant: N
Solvent: CO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCC(N)=O)c2c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A mixture of methyl N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alaninate and a solution of ammonia in methanol (7 N, 10 mL) was heated with stirring at 85° C. in a sealed tube overnight. The resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford 59.2 mg of the desired product as a solid. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.95 (d, J=6.82 Hz, 1 H), 7.88 (dd, J=7.83, 1.26 Hz, 1 H), 7.66-7.60 (m, 2 H), 7.50-7.42 (m, 2 H), 7.31 (d, J=8.59 Hz, 1 H), 7.22 (dd, J=8.46, 1.64 Hz, 1 H), 6.97 (brs, 1 H), 6.73 (t, J=5.68 Hz, 1 H), 6.06 (s, 1 H), 5.06 (brs, 2 H), 4.40 (brs, 2 H), 3.68-3.56 (m, 2 H), 3.51 (q, J=6.65 Hz, 2 H), 2.42 (t, J=7.07 Hz, 2 H), 2.34 (s, 3 H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[N:26]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:34][CH2:33][CH2:32][N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCCN1CCNCC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCN3CCNCC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-(piperazin-1-yl)ethanamine. MS obsd. (ESI+) [(M+H)+] 466, 1H NMR (400 MHz, DMSO-d6) ppm 7.925 (d, J=8.0 Hz, 1 H), 7.806 (d, J=7.2 Hz, 1 H), 7.516-7.575 (m, 2 H), 7.359-7.395 (m, 2 H), 7.238 (m, 1 H), 5.98 (s, 1 H), 5.10 (s, 2 H), 4.49 (brs, 2 H), 3.538 (m, 2 H), 3.542 (m, 2 H), 3.44 (t, J=6.57 Hz, 2 H), 3.32 (s, 2 H), 2.89 (t, J=4.80 Hz, 4 H), 2.71 (t, J=6.57 Hz, 2 H), 2.56 (brs, 4 H), 2.37 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[N:19][CH:20]=2)[C:4]2[C:9]([C:10]=1[C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.C1C=C2N=NN(O)C2=CC=1.N.C(N(CC)CC)C.[NH2:39][CH2:40][C:41]1[C:42]([OH:49])=[N:43][C:44]([CH3:48])=[CH:45][C:46]=1[CH3:47]>ClCCl>[CH3:47][C:46]1[CH:45]=[C:44]([CH3:48])[NH:43][C:42](=[O:49])[C:41]=1[CH2:40][NH:39][C:11]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:14][C:15]2[CH:20]=[N:19][CH:18]=[N:17][CH:16]=2)[C:2]=1[CH3:1])=[O:13]
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1c(C(=O)O)c2ccccc2n1Cc1cncnc1
Agent: N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(Cc3cncnc3)c3ccccc23)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.2 %

Procedure:
A mixture of 2-methyl-1-(pyrimidin-5-ylmethyl)-1H-indole-3-carboxylic acid (60 mg, 0.22 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (65 mg, 0.34 mmol), N-hydroxybenzotrizole (180 mg, 1.33 mmol) and triethylamine (46 mg, 0.34 mmol) in dichloromethane (30 mL) was stirred for 30 minutes at room temperature. Then to the mixture, 3-(aminomethyl)-4,6-dimethyl pyridin-2-ol (33.44 mg, 0.22 mmol) was added. The resultant mixture was stirred at room temperature for 12 hours. Then the mixture was washed with water (20 mL×3). The organic layer was concentrated to give a residue which was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(pyrimidin-5-ylmethyl)-1H-indole-3-carboxamide (17 mg, 19%). LRMS (M+H+) m/z: calcd 401.19. found 401. HPLC purity (214 nm): 92%. 1H. NMR (300 MHz, CD3OD): δ 9.03 (s, 1H), 8.43 (s, 2H), 7.80-7.78 (m, 1H), 7.39-7.36 (m, 1H), 7.19-7.16 (m, 2H), 5.56 (s, 2H), 4.55 (s, 2H), 2.62 (s, 3H), 2.42 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH:11]([CH3:13])[O:10][CH:9]([CH3:14])[CH2:8]1.[H-].[Na+].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][C:23]#[N:24])=[CH:20][CH:19]=1>CN(C=O)C>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([CH:22]([CH2:3][CH2:4][CH2:5][CH2:6][N:7]2[CH2:12][CH:11]([CH3:13])[O:10][CH:9]([CH3:14])[CH2:8]2)[C:23]#[N:24])=[CH:20][CH:19]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CC1CN(CCCCCl)CC(C)O1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(CCCCC(C#N)c2ccc(Cl)cc2)CC(C)O1

Procedure:
This intermediate (400 mg.) was prepared using the procedure described in Example 2a except using 1.0 g. (4.13 mmoles) of 4-(4-chlorobutyl)-2,6-dimethylmorpholine hydrochloride, 1.81 g. (0.021 mole) of sodium hydride, and 3.18 g. (0.021 mole) of 4-chlorobenzyl cyanide in 40 ml. of DMF.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]([Cl:17])([Cl:16])[C:13](Cl)=[O:14]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]2[C:8]([C:13](=[O:14])[C:12]([Cl:17])([Cl:16])[Cl:11])=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2nccn12
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(c1cnc2cccc(Cl)n12)C(Cl)(Cl)Cl
Yield: 8.3 %

Procedure:
To a solution of 45.77 g (0.30 mol) of 5-chloroimidazo[1,2-a]pyridine and 120.9 g (0.99 mol) of 4-dimethylaminopyridine in 500 ml of chloroform was added dropwise 163.5 g (0.90 mol) of trichloroacetyl chloride. The mixture was heated for 43 hours under reflux. After cooling, the reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate/n-hexan=1:1) to give 7.41 g of the desired compound (8.3%, pale brown solid).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]C)=[O:20])=[CH:14][C:13]=2[Cl:23])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:24])[NH:6]2.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1>[Cl:23][C:13]1[CH:14]=[C:15]([CH2:18][C:19]([OH:21])=[O:20])[CH:16]=[CH:17][C:12]=1[O:11][C:10]1[C:2]([NH:1][S:33]([C:27]2[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=2[Cl:25])(=[O:35])=[O:34])=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5](=[O:24])[CH2:4]2
Reactant: COC(=O)Cc1ccc(Oc2ccc3c(c2N)CC(=O)N3)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Product: O=C(O)Cc1ccc(Oc2ccc3c(c2NS(=O)(=O)c2ccc(Cl)cc2Cl)CC(=O)N3)c(Cl)c1

Procedure:
23.2 (35 mg, 0.1 mmol) and 2,4-dichlorobenzenesulfonyl chloride (52 mg, 0.21 mmol) were stirred in pyridine (0.5 mL) at 25° C. for 4 h. The reaction mixture was loaded directly to a prepacked Redisep Column and flash chromatographed (gradient, 0-100% EtOAc in Hexanes) to give the sulfonamide, which was then hydrolyzed in MeOH/THF/water (0.3 mL each) with LiOH (7 mg, 0.3 mmol) at 25° C. for 2 h. Reverse phase HPLC (C18, 10-90% ACN in water with 0.1% TFA as eluant) of the reaction mixture afforded 23 as a yellow solid. MS ESI (pos.) m/e calcd for (M+H)+ 543.0.1. found 543.0. 1H NMR (500 MHz) (CDCl3) δ 12.45 (br. s, 1H); 10.47 (s, 1H); 10.08 (s, 1H); 7.73 (d, J=8.5 Hz, 1H); 7.58 (s, 1H); 7.34 (d, J=8.5 Hz, 1H); 7.33 (s, 1H); 7.04 (d, J=7.8, 1H); 6.71 (d, J=8.3 Hz, 1H); 6.54 (d, J=8.1 Hz, 1H); 6.43 (d, J=8.3 Hz, 1H); 3.57 (s, 2H); 3.56 (s, 2H).
Reaction SMILES: [C:1]([NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([Cl:25])=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]([C:17]#[N:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:26].[Na+].OO>CO.CS(C)=O>[C:1]([NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([Cl:25])=[C:15]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:16]([C:17]([NH2:18])=[O:26])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [OH-]
Reactant: CC(C)(C)NC(=O)N1CCn2c(Cl)c(-c3ccccc3)c(C#N)c2C1
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)(C)NC(=O)N1CCn2c(Cl)c(-c3ccccc3)c(C(N)=O)c2C1

Procedure:
To a solution at 65° C. of 40.0 g (112 mmol) of N-tert-butyl-6-chloro-8-cyano-7-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide in 400 ml of methanol and dimethyl sulfoxide (3:2) are added 10.1 ml (118 mmol) of aqueous 35% sodium hydroxide solution and then 19.8 ml (21.8 mmol) of 35-volumes aqueous hydrogen peroxide solution in 4 fractions every 15 minutes. After reaction for 30 minutes at 65° C., the mixture is cooled, partially concentrated under reduced pressure and taken up in dichloromethane. The organic phase is washed with water and is then dried over sodium sulfate, and the solvent is evaporated off under reduced pressure to give a yellow solid, which is crystallized from acetonitrile and then recrystallized from acetonitrile, to give 25.2 g of N2-(tert-butyl)-6-chloro-7-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the form of a white powder after filtering off and drying.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([N+:20]([O-])=O)=[C:12]2[S:19][CH2:18][CH2:17][N:13]2[C:14](=[O:16])[CH:15]=1.Cl[Sn]Cl.O.Cl>C(O)C>[NH2:20][C:11]1[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[CH:15][C:14](=[O:16])[N:13]2[CH2:17][CH2:18][S:19][C:12]=12
Reactant: O=c1cc(Nc2ccc(I)cc2F)c([N+](=O)[O-])c2n1CCS2
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1c(Nc2ccc(I)cc2F)cc(=O)n2c1SCC2
Yield: 109.6 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Intermediate (I-19f), 7-(2-fluoro-4-iodo-phenylamino)-8-nitro-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (0.08 g, 0.181 mmol) in ethanol (2 mL) was reacted with SnCl2.H2O (0.12 g, 0.541 mmol) and concentrated HCl (0.5 mL) to afford 0.08 g of crude product which was used in the next step without further purification. LCMS: 59%, m/z=403.9 (M+1).
Reaction SMILES: [CH2:1]([O:4][NH:5][C@@H:6]1[C:11]([C:12]([CH3:14])=[CH2:13])=[CH:10][C@@H:9]([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[NH:8][CH2:7]1)[CH:2]=[CH2:3].[CH2:24]([O:27]N1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O)C=C>>[CH2:1]([O:4][N:5]1[C:24](=[O:27])[N:8]2[CH2:7][C@H:6]1[C:11]([C:12]([CH3:14])=[CH2:13])=[CH:10][C@H:9]2[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O
Reactant: C=CCON[C@H]1CN[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C(=C)C
Product: C=CCON1C(=O)N2C[C@H]1C(C(=C)C)=C[C@H]2CO[Si](C)(C)C(C)(C)C

Procedure:
The title compound was prepared from O-allyl-N-((3R,6S)-6-((tert-butyldimethylsilyloxy)-methyl)-4-(prop-1-en-2-yl)-1,2,3,6-tetrahydropyridin-3-yl)hydroxylamine (Intermediate 56, 1.22 g, 3.60 mmol) following the procedure described for Intermediate 16. The desired product was obtained as a light yellow oil (1.16 g, 88%).
Reaction SMILES: C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C(O)=CC4C[CH2:22][O:23]C=4C=3)C2=O)C=CC=CC=1.[Br:34][C:35]1[CH:36]=[CH:37][C:38]([OH:64])=[C:39]([CH:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:43]([CH:50]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:42]2=[O:63])[CH:40]=1>>[Br:34][C:35]1[CH:36]=[CH:37][C:38]([OH:64])=[C:39]([C:41]2([CH2:22][OH:23])[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:43]([CH:50]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[C:42]2=[O:63])[CH:40]=1
Reactant: O=C1C(c2cc(Br)ccc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: O=C1C(c2cc3c(cc2O)CCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(CO)c1cc(Br)ccc1O

Procedure:
Following the procedure as described in PREPARATION 26C, and making non-critical variations to replace 1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1-benzofuran-6-yl)-1,3-dihydro-2H-indol-2-one with 3-(5-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained: MS (ES+) m/z 500.4 (M+1), 502.4 (M+1).
Reaction SMILES: C([C@H](N[C:12](=[O:27])[C@H:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:17]([F:26])[CH:16]=1)[CH3:14])CO)C1C=CC=CC=1.[OH:28]S(O)(=O)=O>O1CCOCC1.O>[F:26][C:17]1[CH:16]=[C:15]([C@H:13]([CH3:14])[C:12]([OH:27])=[O:28])[CH:20]=[CH:19][C:18]=1[NH:21][S:22]([CH3:25])(=[O:23])=[O:24]
Reactant: O=S(=O)(O)O
Reactant: C[C@H](C(=O)N[C@H](CO)Cc1ccccc1)c1ccc(NS(C)(=O)=O)c(F)c1
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](C(=O)O)c1ccc(NS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Yield: 73 %

Procedure:
A solution of N-[(1S)-1-Benzyl-2-hydroxyethyl]-(2S)-2-[3-fluoro-4-(methylsulfonylamino)phenyl]propionamide (100 mg, 0.234 mmol) in 3 N H2SO4 (1 mL) and 1,4-dioxane (1 mL) was heated to 100° C. for 5 h and cooled to room temperature. The solution was diluted with water and extracted with CH2Cl2 several times. The combined organic layers were washed with water, dried over MgSO4, and concentrated in vacuo to afford (2S)-[3-Fluoro-4-(methylsulfonylamino)phenyl]propionic acid.