Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][Si:8]([CH3:13])([CH3:12])[CH2:9][CH2:10][OH:11].Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1>CN(C=O)C>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([O:11][CH2:10][CH2:9][Si:8]([CH3:13])([CH3:12])[CH3:7])=[N:16][CH:17]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C[Si](C)(C)CCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOc1ccc([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 18 h
Yield: 82.8 %

Procedure:
Potassium t-butoxide (25.8 g) was added portionwise over 20 minutes to a solution of 2-(trimethylsilyl)ethanol (20.8 g) and 2-chloro-5-nitropyridine (27.8 g) in DMF (170 ml). The mixture was stirred for 18 hours and then poured into ice-water (900 ml). The mixture was extracted with ethyl acetate (3×300 ml) and the extracts were washed with water (200 ml), followed by saturated sodium chloride solution (200 ml) and dried (MgSO4). Volatile material was removed by evaporation to give 5-nitro-2-[2-(trimethylsilyl)ethoxy]pyridine (34.9 g) as an oil; NMR: 0.05(s,9H), 1.1-1.2(m,2H), 4.45-4.55(m,2H), 6.75(d,1H), 8.3(dd,1H), 9.05(d,1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](SC)[C:5]([C:10]#[N:11])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:10]#[N:11])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: CSc1nc(N)nc(-c2ccccc2)c1C#N
Reactant: NCc1ccccc1
Solvent: CCO
Product: N#Cc1c(NCc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-Amino-4-(methylthio)-6-phenyl-pyrimidine-5-carbonitrile and benzylamine in ethanol. ES-MS m/e (%): 302 (M+H+, 100).
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH:16]2[CH2:20][S:21](=[O:24])(=[O:23])[CH2:22][CH:15]12.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C(C)=CC=CC=1>[N+:11]([C:4]1[CH:3]=[C:2]([N:14]2[CH2:19][CH2:18][NH:17][CH:16]3[CH2:20][S:21](=[O:24])(=[O:23])[CH2:22][CH:15]23)[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cc(I)c2occc2c1
Reactant: O=S1(=O)CC2NCCNC2C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1cc(N2CCNC3CS(=O)(=O)CC32)c2occc2c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
Xylene (150 mL) was added to 7-iodo-5-nitro-1-benzofuran (1.00 g, 3.46 mmol), octahydrothieno[3,4-b]pyrazine 6,6-dioxide (0.73 g, 4.15 mmol; Intermediate 34), Pd2(dba)3 (0.08 g, 0.87 mmol), Xantphos (0.20 g, 0.35 mmol) and Cs2CO3 (1.59 g, 4.84 mmol). The resulting mixture was stirred at 120° C. overnight, filtered through Celite and the solvent was removed in vacuo. The crude product was purified by flash chromatography [eluent: DCM and DCM:MeOH (1:1)] and then recrystallized from MeOH to afford 0.354 g (8%) of the title product. HPLC 90%, RT: 1.390 (System A; 10-97% MeCN over 3 min). 1H NMR (270 MHz, CDCl3) δ ppm 2.85 (dd, J=12.62, 7.42 Hz, 1H) 3.16-3.49 (m, 6H) 3.71 (t, J=11.63 Hz, 1H) 4.02-4.05 (m, 1H) 5.17-5.25 (m, 1H) 6.93 (d, J=2.23 Hz, 1H) 7.62 (t, J=2.72 Hz, 1H) 7.77 (d, J=1.98 Hz, 1H) 8.19 (d, J=1.98 Hz, 1H). LC-MS 338 (M+H)+.
Reaction SMILES: [BrH:1].[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:16])[C:11](=[O:15])[NH:12]2)=[C:7]([CH2:17][NH:18][CH:19]2CCS(=O)(=O)C2)[CH:6]=1)([O-:4])=[O:3]>CO.C(O)(=O)C>[BrH:1].[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:16])[C:11](=[O:15])[NH:12]2)=[C:7]([CH2:17][NH:18][CH3:19])[CH:6]=1)([O-:4])=[O:3]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])cc(CNC3CCS(=O)(=O)C3)c2[nH]c1=O
Agent: Br
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12

Procedure:
N-(7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl)-N-(1,1-dioxo-2,3,4,5-tetrahydro-thien-3-yl)-amine hydrobromide, FAB-MS: M+ =354; TLC: methanol/acetic acid (9:1) Rf =0.69;
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[Si:5]([O:12][CH2:13][C@@H:14]1[CH:19]=[C:18]([CH3:20])[C:17](=[O:21])[CH2:16][N:15]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[BH4-].[Na+]>CO.[Cl-].[NH4+].O>[Si:5]([O:12][CH2:13][C@@H:14]1[CH:19]=[C:18]([CH3:20])[C@H:17]([OH:21])[CH2:16][N:15]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([C:8]([CH3:11])([CH3:9])[CH3:10])([CH3:7])[CH3:6]
Reactant: CC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC1=O
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Reaction time: 0.25 h
Yield: 91.3 %

Procedure:
To a solution of cerium(III) chloride (14.68 g, 59.57 mmol) and (S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-4-methyl-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 7, 21.18 g, 59.57 mmol) in methanol (300 mL) at 0° C. was added sodium borohydride (2.254 g, 59.57 mmol) portionwise. After 15 minutes, the reaction mixture was diluted with saturated ammonium chloride (100 mL) and water (100 mL), then extracted twice with diethyl ether. The organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded the desired product (19.45 g, 91%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]1[CH:25]=[C:24]([C@@H:26]([CH3:42])[C:27](N2[C@H](C)[C@H](C3C=CC=CC=3)OC2=O)=[O:28])[CH:23]=[CH:22][C:21]=1[O:43][CH3:44])[C:4]([CH:6]1[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH:45]O.[OH-].[Li+].Cl>C1COCC1.O>[CH:6]1([C:4]([N:3]([CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[CH:12][C:11]=2[C:20]2[C:21]([O:43][CH3:44])=[CH:22][CH:23]=[C:24]([C@@H:26]([CH3:42])[C:27]([OH:45])=[O:28])[CH:25]=2)[CH2:1][CH3:2])=[O:5])[CH2:8][CH2:7]1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc([C@@H](C)C(=O)N2C(=O)O[C@@H](c3ccccc3)[C@H]2C)ccc1OC)C(=O)C1CC1
Reactant: OO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc([C@@H](C)C(=O)O)ccc1OC)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclopropanecarboxylic acid ethyl-{2′-methoxy-5′-[(R)-1-methyl-2-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl)-2-oxo-ethyl]-4-trifluoromethyl-biphenyl-2-ylmethyl}-amide (0.011 g, 0.02 mmol) in THF (1 mL) and H2O (1 mL) was treated with hydrogen peroxide (30%; 0.004 mL, 0.04 mmol) and lithium hydroxide (0.002 g, 0.04 mmol), and the reaction was stirred overnight at room temperature. The mixture was acidified to pH 3-4 with 1N aqueous HCl and extracted three times with EtOAc. The combined organic layers were dried and concentrated to give the title compound. M+H is 450.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[N:14][NH:15][C:3]=12>C(N)CCC>[CH2:4]([NH:5][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[N:14][NH:15][C:3]=12)[CH2:3][CH2:2][CH3:7]
Reactant: CCOC(=O)c1cnc2cn[nH]c2c1Cl
Solvent: CCCCN
Product: CCCCNc1c(C(=O)OCC)cnc2cn[nH]c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 135.3 %

Procedure:
Ethyl 7-chloro-1H-pyrazolo[4,3-b]pyridine-6-carboxylate (3.5 g, 15.5 mmol) was dissolved in n-butylamine (25 ml) and stirred at room temperature for 3 h. Excess butylamine was removed in vacuo and the residual solid was washed well with water, and recrystallised from ethyl acetate to give ethyl 7-n-butylamino-1H-pyrazolo [4,3-b]pyridine-6-carboxylate (2.75 g, 67%), m.p. 164°-170° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21](OC)=[O:22])=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[CH3:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([CH2:41][NH:42][CH3:43])=[CH:37][CH:36]=2)[CH2:29]1.C[Al](C)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21]([N:42]([CH2:41][C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:30]4[CH2:31][CH2:32][CH2:33][CH:28]([O:27][CH3:26])[CH2:29]4)=[CH:40][CH:39]=3)[CH3:43])=[O:22])=[N:18][N:17]=2)[CH3:14])(=[O:11])=[O:12])=[C:5]([CH3:25])[CH:4]=1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Reactant: CNCc1ccc(CN2CCCC(OC)C2)cc1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N(C)Cc3ccc(CN4CCCC(OC)C4)cc3)o2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AT using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-oxadiazole-2-carboxylate (30 mg, 0.08 mmol), 1-{4-[(3-methoxypiperidin-1-yl)methyl]phenyl}-N-methylmethanamine (40 mg, 0.16 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (5 mL). The crude product was purified using FCC, eluting with 95:4.5:0.5 DCM:MeOH:NH3. A portion of the fraction collected was further purified using prep method D to afford the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:6]2[C:15]([CH3:16])=[CH:14][NH:13][C:7]=2[N:8]=[C:9]([S:11][CH3:12])[N:10]=1.[Cl:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=2)=[O:23])=[CH:20][CH:19]=1.O>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28][N:13]3[C:7]4[N:8]=[C:9]([S:11][CH3:12])[N:10]=[C:5]([O:4][CH3:3])[C:6]=4[C:15]([CH3:16])=[CH:14]3)=[CH:26][CH:25]=2)=[O:23])=[CH:32][CH:33]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: COc1nc(SC)nc2[nH]cc(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(SC)nc2c1c(C)cn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Yield: 54.2 %

Procedure:
In an argon gas stream, 60% sodium hydride-oil (220 mg) was suspended in anhydrous DMF (5 ml) and a powder of 4-methoxy-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine (1.05 g) was added in small portions with ice-cooling and stirring. After completion of addition, the mixture was stirred for 30 minutes and then a solution of 4-(4-chlorobenzoyl)benzyl bromide (1.63 g) in DMF (5 ml) was added. Then, at room temperature, the mixture was stirred for 2 hours. To this reaction mixture was added water (50 ml) and the resulting precipitate was collected by filtration, rinsed with water, dried, and purified by flash column chromatography (silica gel; hexane: ethyl acetate=9:1) to provide the title compound (1.19 g). 1H-NMR (CDCl3) δ: 2.33(3H,d,J=1.2Hz), 2.60(3H,s), 4.08(3H,s), 5.36(2H,s), 6.57(1H,d,J=1.2Hz), 7.28(2H,d,J=8.6Hz), 7.44(2H,d,J=8.6Hz), 7.70(2H,d,J=8.6Hz), 7.72(2H,d,J=8.6Hz).
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][C:14]2([CH2:18][CH3:19])[CH2:17][O:16][CH2:15]2)=[CH:4][CH:3]=[C:2]1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1.C([Li])CCC.C(O[B:34]1[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]1)(C)C>C1COCC1>[CH2:18]([C:14]1([CH2:13][O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]2[S:1][C:2]([C:20]3[S:21][C:22]([B:34]4[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]4)=[CH:23][CH:24]=3)=[CH:3][CH:4]=2)[CH2:17][O:16][CH2:15]1)[CH3:19]
Reactant: CCC1(COCCCCCCc2ccc(-c3cccs3)s2)COC1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC1(COCCCCCCc2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)s3)s2)COC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
To a stirred solution of 3-(6-[2,2′]bithiophenyl-5-yl-hexyloxymethyl)-3-ethyl-oxetane (6.0 g, 16.46 mmol) in anhydrous THF (100 ml) is added n-butyllithium (2.5 M in hexanes, 7.0 ml, 17.50 mmol) dropwise at −78° C. under nitrogen. After complete addition, the mixture is allowed to warm to room temperature, with stirring, over 2 h, followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.26 g, 17.5 mmol). The resultant mixture is stirred overnight at room temperature. The reaction is quenched with sat. aq. NH4Cl, and the reaction mixture is extracted with ethyl acetate (3×100 ml). The combined organic extracts are washed with water, brine, and dried over sodium sulphate. The solvent is removed under reduced pressure and the residue is further purified by column chromatography on silica, eluting with petroleum ether/ethyl acetate (9:1 to 4:1), to give 2-{5′-[6-(3-ethyl-oxetan-3-ylmethoxy)hexyl]-[2,2′]bithiophenyl-5-yl}-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as a blue oil (4.53 g, 56%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.49 (d, J=3.6 Hz, 1H, Ar—H), 7.14 (d, J=3.6 Hz, 1H, Ar—H), 7.03 (d, J=3.6 Hz, 1H, Ar—H), 6.66 (d, J=3.6 Hz, 1H, Ar—H), 4.43 (d, J=5.8 Hz, 2H, OCH2), 4.34 (d, J=5.8 Hz, 2H, OCH2), 3.48 (s, 2H, OCH2), 3.42 (t, J=6.6 Hz, 2H, OCH2), 2.76 (t, J=7.5 Hz, 2H, ArCH2), 1.32-1.75 (m, 22H, CH2 and CH3), 0.86 (t, J=7.5 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): δ (ppm) 144.8 (quat.), 143.7 (quat.), 137.0 (CH), 133.7 (quat.), 124.0 (CH), 123.1 (CH), 123.0 (CH), 83.1 (quat.), 77.5 (OCH2), 72.4 (OCH2), 70.4 (OCH2), 42.4 (quat.), 30.5 (CH2), 29.1 (CH2), 28.4 (CH2), 27.8 (CH2) 25.8 (CH2), 24.9 (CH3), 8.3 (CH3); MS (m/e): 490 (M+, 16%) □305 (79), 223 (25), 205 (100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:8])[NH:5][CH:6]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:7](=[O:8])[NH:9][CH2:10][CH:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:5]2[CH:6]=1
Reactant: CCOC(=O)/C=C/CNC(=O)c1cc(Br)c[nH]1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)CC1CNC(=O)c2cc(Br)cn21
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
(E)-Ethyl 4-(4-bromo-1H-pyrrole-2-carboxamido)but-2-enoate (2.35 g, 7.80 mmol) was treated with ACN (30 mL) and DBU (0.27 mL, 1.80 mmol) and stirred at RT for 2 h. The mixture was then concentrated in vacuo. Chromatographic purification of the residue (silica gel, 30-50% EtOAc in hexanes) afforded ethyl 2-(7-bromo-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate (1.24 g, 4.12 mmol, 52.8% yield) as a colorless viscous oil which crystallized to a white solid: 1H NMR (400 MHz, CDCl3) δ ppm 6.93 (1H, d, J=1.6 Hz), 6.84 (1H, d, J=1.8 Hz), 5.87 (1H, br. s.), 4.65 (1H, tt, J=6.8, 3.4 Hz), 4.11-4.24 (2H, m), 3.92 (1H, dd, J=12.8, 4.0 Hz), 3.46-3.54 (1H, m), 2.74-2.90 (2H, m), 1.26 (3H, t, J=7.1 Hz). m/z (ESI, +ve ion) 301.0/303.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[O:7][CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[O:7][CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cc(N)cc(C(F)(F)F)c1
Reaction time: 5 h

Procedure:
A mixture of (S)-tert-butyl 2-((3-nitro-5-(trifluoromethyl)phenoxy)methyl)pyrrolidine-1-carboxylate (2.0 g, 5.1 mmol) and Pd/C (10%, 150 mg) in EtOH (30 ml) was stirred under H2 (1 atm) for 5 hr. The mixture was filtered through Celite and washed with MeOH. Evaporation of solvent gave the title product as a light amber oil. MS m/z=361 [M+H]+. Calc'd for C17H23F3N2O3: 360.38.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[N:9]=[CH:8][CH:7]=[C:6]2[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[O:31])=[C:25]([F:40])[CH:24]=1)#[N:2].[OH-].[Na+].O.Cl>CO>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[N:9]=[CH:8][CH:7]=[C:6]2[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)=[O:31])=[C:25]([F:40])[CH:24]=1)#[N:2]
Reactant: CCOC(=O)CCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)c2cc1C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OCCCC(=O)O
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 30.3 %

Procedure:
N-(4-(6-Cyano-7-(3-(ethoxycarbonyl)propoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea (800 mg) was dissolved in methanol (45 ml), 2N NaOH water (15 ml) was added, and the mixture was heated and stirred for 40 minutes at 80° C. After completion of the reaction, the reaction solution was poured into ice water and neutralized with 1N HCl, and the precipitated solid was filtered out. The obtained solid was washed with water and dried to obtain 230 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:15])=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]=2[CH:14]=1.C(N(CC)C1C=CC=CC=1)C.Cl[C:28]([O:30][CH3:31])=[O:29]>ClCCCl>[F:15][C:3]1[C:2]([NH:1][C:28]([O:30][CH3:31])=[O:29])=[CH:14][C:6]2[N:7]([CH:11]([CH3:13])[CH3:12])[C:8](=[O:10])[S:9][C:5]=2[CH:4]=1
Reactant: COC(=O)Cl
Reactant: CC(C)n1c(=O)sc2cc(F)c(N)cc21
Solvent: CCN(CC)c1ccccc1
Solvent: ClCCCl
Product: COC(=O)Nc1cc2c(cc1F)sc(=O)n2C(C)C
Yield: 79.6 %

Procedure:
A mixture of 5-amino-6-fluoro-3-isopropyl-2(3H)-benzothiazolone (2.1 g), N,N-diethyianiline (1.5 g) and methyl chloroformate (1.0 g) was dissolved in 1,2-dichloroethane (10 g), and the resultant mixture was heated under reflux for 3 hours. After cooling, the reaction mixture was washed with water, and the organic layer was concentrated. The residue was washed with methanol to give 6-fluoro-5-methoxycarbonylamino -3-isopropyl-2(3H)-benzothiazolone (2.1 g).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([OH:23])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN(C=O)C.[H-].[Na+].[Cl:31][C:32]1[CH:37]=[C:36]([N+]([O-])=O)[CH:35]=[CH:34][N:33]=1>>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[CH2:12][C@@H:11]([O:23][C:36]2[CH:35]=[CH:34][N:33]=[C:32]([Cl:31])[CH:37]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ccnc(Cl)c2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 0.17 h
Yield: 82.9 %

Procedure:
To a solution of (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol (973.5 mg, 0.002699 mol) in DMF (8.00 mL, 0.103 mol) was added NaH (202 mg, 0.00504 mol) (60% in oil). After stirring the mixture for 10 minutes, 2-chloro-4-nitro-pyridine (400.0 mg, 0.00252 mol) was added and the mixture was stirred overnight. The reaction was quenched with water and extracted with (3×50 ml EtOAc). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (0 to 10% EtOAc/hexanes) to obtain the title compound (0.9859 g, 83%) as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[C:11]3[N:12]=[C:13]([CH3:23])[C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15](Cl)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:25]([O:28][C:29]1([CH3:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH:26]=[CH2:27].Cl.CCN(C(C)C)C(C)C>CN(C=O)C.CCOCC>[CH2:25]([O:28][C:29]1([CH3:35])[CH2:30][CH2:31][N:32]([C:15]2[N:10]3[N:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=4)[CH:24]=[C:11]3[N:12]=[C:13]([CH3:23])[C:14]=2[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:33][CH2:34]1)[CH:26]=[CH2:27]
Reactant: C=CCOC1(C)CCNCC1
Reactant: CCOC(=O)Cc1c(C)nc2cc(-c3cccc(Br)c3)nn2c1Cl
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c(CC(=O)OCC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Yield: 90 %

Procedure:
A mixture of ethyl 2-(2-(3-bromophenyl)-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (28 g, 68.5 mmol) in DMF (150 ml) was treated with 4-(allyloxy)-4-methylpiperidine.HCl (14.3 g, 74.6 mmol) and Hunig's Base (35.9 ml, 206 mmol), and the mixture was heated (60° C. oil bath) for 16 h. At this point LCMS indicates completion of reaction. Mixture was then cooled, diluted with Et2O and washed with water (3×100 mL) and brine (100 mL), then dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was then purified by Biotage (5-50% EtOAc/hexane) to afford ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (32.6 g, 61.8 mmol, 90% yield) as viscous oil. 1H NMR (500 MHz, CDCl3) δ 8.16 (t, J=1.7 Hz, 1H), 7.94 (dt, J=7.8, 1.3 Hz, 1H), 7.54-7.49 (m, 1H), 7.37-7.30 (m, 1H), 6.79 (s, 1H), 6.13-5.99 (m, 1H), 5.51-5.40 (m, 1H), 5.26 (dd, J=10.4, 1.4 Hz, 1H), 4.24 (q, J=7.1 Hz, 2H), 4.03 (dt, J=5.2, 1.6 Hz, 2H), 3.82 (br. s, 4H), 3.32 (br. s., 2H), 2.54 (s, 3H), 1.99 (d, J=13.2 Hz, 2H), 1.86 (br. s., 2H), 1.36 (s, 3H), 1.31 (t, J=7.1 Hz, 3H). LCMS (M+H)=528.8.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:10](=[O:13])[CH2:11][CH2:12][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([CH3:1])[CH:3]=1)[CH3:16]
Reactant: Cc1cccc(CCl)c1
Reactant: C=CC(=O)OCC
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCc1cccc(C)c1
Temperature: 110 °C

Procedure:
A mixture of 14.0 g of 3-methylbenzyl chloride and 50.0 g of ethyl acrylate dissolved in 300 ml of dry toluene was heated to 110° C. Separatively, 3.0 g of 2,2'-azobisisobutyronitrile(AIBN) and 32.0 g of tri-n-butyltin hydride were dissolved in 200 ml of dry toluene, which was added to the above mixture over a period of 2 hours. This reaction mixture was further heated at the boiling temperature for 2 hours and then cooled to the ambient temperature. The residues obtained after removing the solvent from the mixture were purified by silica gel column chromatography to provide ethyl-4-(3-methylphenyl)butanoate.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:18][CH2:17][C:16]([OH:15])([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2ccc(F)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-(4-fluorophenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 77% overall yield. FDMS m/e=384 (M+ of free base). α[D]589 =-11.40 (c=0.66, methanol).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[F:19][C:20]1([F:28])[CH2:24][NH:23][C@H:22]([C:25]([NH2:27])=[O:26])[CH2:21]1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([N:23]3[CH2:24][C:20]([F:28])([F:19])[CH2:21][C@H:22]3[C:25]([NH2:27])=[O:26])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: NC(=O)[C@@H]1CC(F)(F)CN1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: NC(=O)[C@@H]1CC(F)(F)CN1C(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 47 b, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3 c, 50 mg, 214 μmol) and (2S)-4,4-difluoro-2-pyrrolidinecarboxamide hydrochloride (CAN 426844-51-1; 44 mg, 236 μmol) as starting materials and isolated (63 mg, 80%) as off-white solid; LC-MS (UV peak area, ESI) 100%, 366.1629 [MH+].