Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[O:12])[N:7]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27](C(OC(C)(C)C)=O)[N:26]=[CH:25]3)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.CCO.Cl>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[O:12])[N:7]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][N:26]=[CH:25]3)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(-n3nc(C(C)(C)C)cc3NC(=O)Nc3cccc(Cl)c3Cl)ccc21
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)n(-c2ccc3[nH]ncc3c2)n1
Temperature: 80 °C
Yield: 58.8 %

Procedure:
t-Butyl 5-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate (0.1155 g, 0.213 mmol, 1.00 eq) was dissolved in satd. HCl/EtOH. The solution was heated at 80° C. for 1 h. After cooling to RT, the reaction was concentrated to dryness and treated with 80:20 MeCN/H2O. The resulting suspension was thoroughly chilled. The solids were collected by filtration, rinsed with 80:20 MeCN/H2O, MeCN and dried on the filter to yield 1-(3-t-butyl-1-(1H-indazol-5-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (55.5 mg, 54.4% yield) as the HCl salt. 1H NMR (DMSO-d6): 9.18 (s, 1H), 8.76 (s, 1H), 8.19 (s, 1H), 8.08-8.06 (m, 1H), 7.89-7.88 (m, 1H), 7.70-7.67 (m, 1H), 7.47-7.44 (m, 1H), 7.33-7.28 (m, 2H), 6.40 (s, 1H), 1.29 (s, 9H); MS (ESI) m/z: 502.0 (M+H+), 504.0 (M+2+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][NH:8][S:7]1(=[O:13])=[O:12].[CH3:20][O:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([CH2:32]O)=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.C(P(CCCC)CCCC)CCC.CN(C(/N=N/C(N(C)C)=O)=O)C>C1COCC1.[Ni]>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][N:8]([CH2:32][C:28]2[CH:27]=[C:26]3[C:31]([C:22]([O:21][CH3:20])=[CH:23][CH:24]=[N:25]3)=[CH:30][CH:29]=2)[S:7]1(=[O:13])=[O:12]
Reactant: COc1ccnc2cc(CO)ccc12
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)c(OC)c1
Agent: [Ni]
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CN(Cc3ccc4c(OC)ccnc4c3)S2(=O)=O)c(OC)c1
Reaction time: 18 h

Procedure:
745 mg (2.60 mmol) of the title B compound in Example 9, 2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one, 328 mg (1.73 mmol) of the title E compound, (4-methoxyquinoline-7-yl)-methanol and 448 mg (526 mg., 2.60 mmol) of tributylphosphine are stirred in 5 mL of THF. 448 mg (2.60 mmols) of TMAD is added and the mixture is stirred for 18 h. A spatula tip of Raney nickel is added, the mixture is stirred for 10 min, and then filtered through Celite. The filtrate is evaporated to dryness and chromatographed on a Biotage 40M column with 98:2 EtOAc/EtOH to afford 2-(2,4-dimethoxy-benzyl)-5-(4-methoxy-quinolin-7-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one: mp=128-132° C.; 1H-NMR (CDCl3) δ 3.79 (2H, s), 3.81 (3H, s), 3.85 (3H, s), 4.06 (3H, s), 4.51 (2H, s), 4.82 (2H, s), 6.46 (2H, m), 6.78 (1H, d, J=5.2) 7.30 (1H, m), 7.53 (1H, dd, J=8.5, 1.5), 7.96 (1H, s), 8.22 (1H, d J=8.5), 8.77 (1H, d, J=5.2); [M+1]+=458.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:3]=1[O:4][C:5]1[C:6]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][N:24]=2)(=[O:22])=[O:21])=[N:7][C:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:9][C:10]=1[CH:11]=[O:12].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:3]=1[O:4][C:5]1[C:6]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][N:24]=2)(=[O:22])=[O:21])=[N:7][C:8]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[N:9][C:10]=1[CH2:11][OH:12]
Reactant: COc1ccc(Cl)c(Oc2c(C=O)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)C)cn2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Cl)c(Oc2c(CO)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)C)cn2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
0.1 g of the compound obtained in Example 37 in 3 ml of ethanol was treated with 0.014 g of sodium borohydride. The reaction mixture was stirred at 80° C. for 1 hour. Thereafter, the ethanol was distilled off and the residue was partitioned between chloroform and 1 N HCl. The organic phase was washed with water and dried, the solvent was evaporated and the residue was chromatographed over silica gel with chloroform-methanol. After recrystallization from dichloromethane-ethanol there was obtained 0.072 g of 5-isopropyl-pyridine-2-sulphonic acid 5-(2-chloro-5-methoxy-phenoxy)-6-hydroxymethyl-2-morpholin-4-yl-pyrimidin-4-ylamide. M.p. 105° C.
Reaction SMILES: [C:1]([C:5]1[N:9]=[CH:8][NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Br:12]Br>O>[Br:12][C:8]1[NH:7][N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:9]=1
Reactant: CC(C)(C)c1nc[nH]n1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1n[nH]c(Br)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
The mixture of 2.51 g of 3-t-butyl-1H-1,2,4-triazole, 35 ml of water and 2.5 ml of 50% aqueous solution of sodium hydroxide was cooled to 0° C., then 3.5 g of bromine was added to it. It was stirred at room temperature for 3 hours. The reaction mixture was extracted by ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane to obtain 3.80 g of 5-bromo-3-t-butyl-1H-1,2,4-triazole.
Reaction SMILES: [I-].C[S+](C)C.[CH3:6]C(C)([O-])C.[K+].[C:12]([O:16][C:17]([N:19]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:20]([CH:28]=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(#N)C.O>[C:12]([O:16][C:17]([N:19]([C@@H:20]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C@@H:28]1[O:29][CH2:6]1)[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@H](C=O)Cc1ccccc1
Agent: C[S+](C)C
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@@H](Cc1ccccc1)[C@H]1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a suspension of 0.90 g (4.42 mmoles) of trimethylsulfonium iodide in 18 mL of acetonitrile was added 0.495 g (4.42 mmoles) of potassium t-butoxide. A solution of 1.0 g (2.95 mmoles) of N-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninal in 7 mL of acetonitrile was added and the mixture was stirred at room temperature for one hour. The mixture was diluted with 80 mL of water and extracted twice with 80 mL of ethyl acetate. The organic layers were combined and washed with 100 mL water, 30 mL brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1.04 g of a yellow crude oil. The crude product was a mixture of the two diastereomers N,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2S-oxiranemethanamine and N,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2R-oxiranemethanamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16](I)=[CH:15][N:14]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[C:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]=1.[CH2:41]([N:49]1[CH:53]=[C:52](B2OC(C)(C)C(C)(C)O2)[CH:51]=[N:50]1)[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:52]4[CH:51]=[N:50][N:49]([CH2:41][CH2:42][C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)[CH:53]=4)=[CH:15][N:14]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[C:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(CCc3ccccc3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Yield: 94 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(2-fluoro-4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (intermediate 66Q) (170 mg, 0.253 mmol) was coupled with 1-phenethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 59) (151 mg, 0.506 mmol) using Pd(dppf)Cl2 (10 mg, 0.012 mol) and sodium carbonate (161 mg, 0.759 mmol) in toluene/ethanol/water (20/10/5 ml) to afford 171 mg (94% yield) of the titled. MS: m/z=718.3 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH3:18])[C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1.O.[OH-].[Na+]>O1CCCC1>[CH3:18][N:8]([CH2:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[NH2:16])[CH3:7]
Reactant: CN(C)C(=O)c1cccc(N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1cccc(N)c1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A stirred suspension of lithium aluminium hydride (0.24 g, 6.3 mmol) in tetrahydrofuran (THF) (15 ml) at 0° C. under Argon, was treated dropwise over a period of fifteen minutes, with a solution of N,N-Dimethyl-3-aminobenzamide (D24) (0.68 g, 4.2 mmol) in THF (15 ml). The reaction mixture was allowed to warm to room temperature after which it was heated to reflux for 2 hours. The reaction mixture was allowed to cool to room temperature then treated sequentially with water (0.24 ml), 10% sodium hydroxide solution (0.24 ml) then water (0.72 ml). The reaction mixture was filtered through kieselguhr and the filtrate dried (Na2SO4) and concentrated in vacuo to afford the title compound as a pale brown oil (0.55 g, 87%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([N:21]4[N:25]=[N:24][C:23]([CH2:26][CH3:27])=[N:22]4)[C@@H:18]([OH:28])[C@H:17]3[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:40]3[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=3)[C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)[N:8]=2)[CH2:3]1.[ClH:47].C1(C(C2C=CC=CC=2)CNC2N=C(N3CC[C@@H](N[C:72]([NH:74][C:75]4[CH:80]=[CH:79][N:78]=[CH:77][CH:76]=4)=[O:73])C3)N=C3C=2N=CN3[C@@H]2C[C@H](N3N=NC(CC)=N3)[C@@H](O)[C@H]2O)C=CC=CC=1>>[ClH:47].[OH:46][C:43]1[CH:44]=[CH:45][C:40]([CH:32]([C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[CH2:31][NH:30][C:9]2[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:72]([NH:74][C:75]4[CH:80]=[CH:79][N:78]=[CH:77][CH:76]=4)=[O:73])[CH2:3]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@@H:16]2[CH2:20][C@H:19]([N:21]3[N:25]=[N:24][C:23]([CH2:26][CH3:27])=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])=[CH:41][CH:42]=1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)Nc6ccncc6)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(N5CC[C@@H](NC(=O)Nc6ccncc6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-{2-((R)-3-amino-pyrrolidin-1-yl)-6-[2,2-bis-(4-hydroxy-phenyl)-ethylamino]-purin-9-yl}-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 106) using a procedure analogous to that of (1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-4-yl-urea hydrochloride (Example 108). MS (ES+) m/e 748.42 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]2)=[CH:10][CH:9]=1.[F:19][C@H:20]1[CH2:22][C@H:21]1[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[F:19][C@H:20]1[CH2:22][C@H:21]1[C:23]([NH:18][C:13]1[N:14]=[CH:15][C:16]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH:17]=2)=[O:24]
Reactant: O=C(O)[C@@H]1C[C@@H]1F
Reactant: Cc1ccncc1-c1ccc2cc(N)ncc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccncc1-c1ccc2cc(NC(=O)[C@@H]3C[C@@H]3F)ncc2c1
Temperature: 70 °C
Yield: 3.1 %

Procedure:
A mixture of 7-(4-methylpyridin-3-yl)-isoquinolin-3-amine (350 mg, 1.5 mmol), (1S,2S)-2-fluorocyclopropanecarboxylic acid (232 mg, 2.2 mmol), HATU (1.13 g, 3.0 mmol), and N,N-diisopropylethylamine (0.52 mL, 3.0 mmol) in N,N-dimethylformamide (3 mL) was heated at 70° C. for 3 hours. The cooled reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as an off-white solid (15 mg, 23%). 1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 9.20 (s, 1H), 8.53 (s, 1H), 8.50 (s, 1H), 8.49 (d, J=5.0 Hz, 1H), 8.09 (s, 1H), 7.98 (d, J=8.6 Hz, 1H), 7.76 (dd, J=8.5, 1.4 Hz, 1H), 7.40 (d, J=5.0 Hz, 1H), 4.95 (m, 1H), 2.33 (s, 3H), 2.28 (m, 1H), 1.70 (dtd, J=23.2, 6.8, 3.8 Hz, 1H), 1.25-1.14 (m, 1H). LCMS (Method E): RT=3.063 min, M+H+=322.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=2)(=[O:17])=[O:16])[N:12]([C:25]2[C:26]([F:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[N:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:33][N:34](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:32])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:33]#[N:34])[CH:19]=2)(=[O:17])=[O:16])[N:12]([C:25]2[C:26]([F:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[N:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(S(=O)(=O)c2cccc(Br)c2)n(-c2cccnc2F)n1)C(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CN(Cc1cc(S(=O)(=O)c2cccc(C#N)c2)n(-c2cccnc2F)n1)C(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A solution of tert-butyl({5-[(3-bromophenyl)sulfonyl]-1-(2-fluoropyridin-3-yl)-1H-pyrazol-3-yl}methyl)methylcarbamate (315 mg) and zinc cyanide (107 mg) in dimethylformamide (3 mL) was sufficiently deaerated, tetrakis(triphenylphosphine)palladium(0) (138 mg) was added, and the mixture was further deaerated. After stirring under an argon atmosphere at 110° C. for 2 hr, the reaction mixture was allowed to cool to room temperature, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→2:1) to give the title compound as a yellow oil (yield 247 mg, yield 87%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCOCC2)no1
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.3 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl)-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (300 mg, 0.76 mmol) in ethanol (4 ml) was cooled to 0° C. then treated with morpholine (0.066 ml, 7.60 mmol). The resulting mixture was warmed to room temperature and stirred under a nitrogen atmosphere for 17 hours. Further morpholine (0.53 ml, 6.08 mmol) was added and the mixture heated to 60° C. for 8 hours. The mixture was cooled and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:ethyl acetate (80:20) to afford title compound as a yellow oil (269 mg)
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:13])[C:10]([NH2:12])=[O:11].[C:14]([O-:17])(=[O:16])[CH3:15].[K+].CN(C)C=O.C(OCC)(=O)C>[I-].[K+].CCOCC>[C:14]([O:17][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:13])[C:10]([NH2:12])=[O:11])(=[O:16])[CH3:15]
Reactant: NC(=O)C(=O)c1ccccc1CCl
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccccc1C(=O)C(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.6 %

Procedure:
A mixture of 2-(2-chloromethylphenyl)-2-oxoacetamide (3.41 g), potassium acetate (2.03 g), potassium iodide (0.14 g) and N,N-dimethylformamide (35 ml) was stirred at room temperature for 24 hours. To the reaction mixture was added a mixed solution (about 300 ml) of ethyl acetate and ether in a mixing ratio of about 1:1. The mixture was washed with water twice and saturated brine once. The resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product (3.55 g). The crude product was recrystallized from ethyl acetate-hexane, the resulting mother liquor was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2) to give the title compound (2.62 g in total, yield: 68.6%, white crystals).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](=[O:12])[N:9](CC3C=CC(OC)=CC=3)[CH:8]=[N:7][C:6]=2[N:5]([CH3:22])[C:4](=[O:23])[C:3]=1[CH3:24]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][CH:8]=[N:7][C:6]=2[N:5]([CH3:22])[C:4](=[O:23])[C:3]=1[CH3:24]
Reactant: COc1ccc(Cn2cnc3c(c(Cl)c(C)c(=O)n3C)c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cl)c2c(=O)[nH]cnc2n(C)c1=O
Yield: 171.3 %

Procedure:
5-Chloro-3-(4-methoxybenzyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (8.75 g, 23.9 mmol, compound 8C) was dissolved in trifluoroacetic acid (15 mL) and subjected to microwave irradiation at 150° C. for 1 hour. TFA was evaporated in vacuo and the residue azeotroped with toluene (2×20 mL) then DCM (2×20 mL) to give 9.24 g of the title compound as a crude material which was used without further purification. [M+H] calc'd for C9H8ClN3O2, 226; found, 226.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][C:43]([OH:45])=O.[F:46][C:47]([F:68])([F:67])[C:48]1[CH:49]=[C:50]([S:54]([CH2:57][CH2:58][S:59][C:60]2[C:65]([NH2:66])=[CH:64][CH:63]=[CH:62][N:61]=2)(=[O:56])=[O:55])[CH:51]=[CH:52][CH:53]=1>C(Cl)Cl.CCCCCC>[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][C:43]([NH:66][C:65]1[C:60]([S:59][CH2:58][CH2:57][S:54]([C:50]2[CH:51]=[CH:52][CH:53]=[C:48]([C:47]([F:67])([F:68])[F:46])[CH:49]=2)(=[O:56])=[O:55])=[N:61][CH:62]=[CH:63][CH:64]=1)=[O:45]
Reactant: COc1ccccc1CC(=O)O
Reactant: Nc1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1ccccc1CC(=O)Nc1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
1.7 g (4.0 mmol) HATU and 1.36 ml (8.0 mmol) DIPEA were added to a solution of 582 mg (3.5 mmol) 2-(2-methoxyphenyl)acetic acid in DCM (10 ml) and the mixture was cooled to 0° C. After stirring for 15 min a solution of 725 mg (2.0 mmol) [2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]amine (VPF-001) in DCM (6 ml) was added at 0° C. The mixture was then stirred for 16 h at room temperature. Then it was diluted with DCM and washed successively with a saturated aqueous NH4Cl solution, a saturated aqueous NaHCO3 solution and brine. The organic phase was dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 7:3) of the residue yielded 827 mg (1.6 mmol, 81%) 2-(2-methoxyphenyl)-N-[2-[2-[[3-(trifluoromethyl)-phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]acetamide. MS: m/z 511.1 [M+H]+.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([CH:16]3[CH2:18][CH2:17]3)[N:14]=2)[CH:10]=[C:9]([Cl:19])[CH:8]=1)[CH3:6].[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2([CH2:43][OH:44])[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1>ClCCl.C1CCCCC1>[Cl:19][C:9]1[CH:8]=[C:7]([CH:5]([O:44][CH2:43][C:30]2([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=3)[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[CH2:34][CH2:35]2)[CH3:6])[C:15]2[C:11](=[CH:12][N:13]([CH:16]3[CH2:18][CH2:17]3)[N:14]=2)[CH:10]=1
Reactant: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Cl)cc2cn(C3CC3)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(C3CC3)nc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-1-(5-Chloro-2-cyclopropyl-2H-indazol-7-yl)ethyl 2,2,2-trichloroacetimidate (365 mg, 0.96 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (366 mg, 1.05 mmol) were combined in a dichloromethane/cyclohexane mixture (1:1, 10 mL) and cooled to 0° C. The reaction was treated with tetrafluoroboric acid-diethyl ether complex (26 μL, 0.19 mmol), stirred at 0° C. for 1 h, quenched by addition of saturated sodium bicarbonate and diluted with diethyl ether. The layers were separated. The ethereal was washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (18% ethyl acetate/hexanes) gave 0.32 g (62%) as an oil. 1H-NMR (CDCl3, 500 MHz) δ 7.86 (s, 1H), 7.40 (m, 1H), 7.28-7.31 (m, 2H), 6.99-7.03 (m, 2H), 6.75 (m, 1H), 4.90 (q, J=6.4 Hz, 1H), 3.86-3.90(m, 2H), 3.32-3.36 (m, 2H), 3.00-3.09 (m, 2H), 2.04-2.17 (m, 2H), 1.84-1.95 (m, 2H), 1.43 (s, 9H), 1.41 (d, J=6.4 Hz, 3H), 1.26-1.30 (m, 2H), 1.12-1.16 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 163.7, 161.4 (d, J=244.7 Hz), 152.2, 145.3, 138.9, 135.1, 128.9, 127.7, 122.3, 117.2, 115.2, 115.1, 79.5, 77.8, 73.9, 60.5, 41.3, 34.7, 28.6, 22.7, 14.3, 7.4. Mass spec.: 528.62 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[NH2:6][CH:7]([C:12]([NH2:14])=[O:13])[CH2:8][CH2:9][S:10][CH3:11].[OH-].[Na+]>O>[CH3:1][O:2][C:3]([NH:6][CH:7]([C:12]([NH2:14])=[O:13])[CH2:8][CH2:9][S:10][CH3:11])=[O:4]
Reactant: CSCCC(N)C(N)=O
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)NC(CCSC)C(N)=O
Yield: 60.4 %

Procedure:
85 ml (1.11 moles) methylchloroformate were dripped into a solution of 150 g (1.02 moles) DL-methionine amide in 200 ml water at 5-10° C., during which the pH was maintained at 8-10 by the addition of sodium hydroxide solution. After 30 min of subsequent reaction, 60 ml water was added, whereupon crystals formed which were filtered off, washed with water and dissolved in 250 ml water. This solution was extracted twice and the crystallization mother liquor extracted once with 500 ml methylene chloride in each instance. After drying in a vacuum, 162 g yellowish, crystalline residue remained. It was dissolved in 200 ml hot ethanol. Then, 400 ml MTBE was added and after the appearance of the first colorless crystals another 200 ml MTBE. After cooling in an ice bath, filtering off, washing with 200 ml MTBE and drying, 127 g (60k) Nα-methoxycarbonyl-DL-methionine amide with a melting point of 93-94° C. was obtained.