Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:25])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]=[C:19]=[S:20])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[C:26]([CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][NH2:39])[CH2:32][CH2:31]1)([CH3:29])([CH3:28])[CH3:27]>C1C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:25])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]([NH:39][CH2:38][CH2:37][CH2:36][N:33]3[CH2:32][CH2:31][CH:30]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:35][CH2:34]3)=[S:20])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CC(C)(C)C1CCN(CCCN)CC1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)N1c1cccc(N=C=S)c1
Solvent: c1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)N1c1cccc(NC(=S)NCCCN2CCC(C(C)(C)C)CC2)c1
Yield: 64 %

Procedure:
1,4-Dihydro-2,6-dimethyl-4-(3-isothiocyanatophenyl)-3,5-pyrazinedicarboxylic acid, dimethyl ester (25 mg, 0.069 mmol) was refluxed with 4-tert-butyl-piperidine-1-propanamine (16 mg, 0.081 mmol) in 2 mL of benzene for 30 min. Chromatographic purification (silica gel, eluted with 10% (v/v) methanol in methylene chloride) of the resultant residue after concentration in vacuo gave the title compound as a yellow powder (64%); 1H-NMR (CDCl3) δ 8.20 (br, 1H), 7.98 (br, 1H), 7.05 (t, 1H, J=8.1 Hz), 6.79 (br, 1H), 6.66 (d, 1H, J=8.0 Hz), 6.50-6.60 (m, 2H), 3.70 (s, 6H), 3.55 (m, 2H), 3.28 (m, 2H), 2.72 (m, 2H), 2.30-2.55 (m, 2H), 2.37 (s, 6H), 1.86 (m, 2H), 1.50-1.80 (m, 2H), 0.95-1.25 (m, 1H), and 0.79 (s, 6H); 13C-NMR (CDCl3) δ 180.9, 166.3, 152.8, 150.1, 129.9, 116.3, 112.7, 109.9, 108.5, 53.9, 51.8, 44.9, 42.1, 32.1, 29.8, 27.2, 24.7, 24.5, and 17.8.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.C[O:14][CH:15](OC)[CH2:16][CH2:17][CH2:18][CH:19]=O>CCOC(C)=O.CCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]/[C:9](/[N+:10]([O-:12])=[O:11])=[CH:19]\[CH2:18][CH2:17][CH2:16][CH:15]=[O:14])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])CCc1ccc(Br)cc1
Reactant: COC(CCCC=O)OC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=CCCC/C=C(\Cc1ccc(Br)cc1)[N+](=O)[O-]
Yield: 43 %

Procedure:
Prepared according to the general procedure B from 1-bromo-4-(2-nitroethyl)benzene 112h (24 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (2.15 g, 43% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH3:18])[C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:29])C=CC=CC=1>ClCCl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:29])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH3:18])[C:7]2=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1ncc2cc(C)c(=O)n(C3CCCC3)c2n1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reaction time: 16 h
Yield: 84.8 %

Procedure:
8-Cyclopentyl-6-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (2.56 g, 9.30 mmol) was dissolved in dichloromethane (17 mL) and methanol (17 mL) to which 2-benzenesulfonyl-3-phenyl-oxaziridine was added and the reaction mixture was stirred for 16 hours. The solvent was removed and diethyl ether added. The precipitated solid was collected by filtration to give 8-cyclopentyl-2-methanesulfinyl-6-methyl-8H-pyrido[2,3-d]pyrimidin-7-one as a white solid (2.30 g, 84.8%). 1H NMR δ(400 MHz, CDCl3) 8.85 (s, 1H), 7.54 (s, 1H), 5.99, (m, 1H), 2.95 (s, 3H), 2.27 (d, J=1.2 Hz, 3H), 2.24 (m, 2H), 2.13 (m, 2H), 1.94 (m, 2H), 1.70 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[Cl:37][C:38]1[C:39]([N:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([CH:44]=1)[NH2:43].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.N>CC(O)C.CO>[Cl:37][C:38]1[C:39]([N:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([NH:43][C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]4=[N:10][C:9]=3[C:17]3[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=3)[C:22]([NH:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])=[O:23])[CH:5]=[CH:4][N:3]=2)[CH:44]=1
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(Cl)cc1N
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: N
Agent: c1cc[nH+]cc1
Solvent: CC(C)O
Solvent: CO
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3cc(Cl)c(N4CCN(CCS(C)(=O)=O)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 80 °C
Yield: 38 %

Procedure:
In a 10 mL vial with septum cap, 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (0.200 g, 0.395 mmol), 5-chloro-2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (0.165 g, 0.474 mmol) were taken up in iPrOH (3 mL) and pyridinium p-toluenesulfonate (0.238 g, 0.949 mmol) was added. The vial was sealed and heated to 80° C. overnight. When reaction was complete by MS, it was cooled to rt, neutralized with 7N ammonia in MeOH, absorbed onto silica gel and flash chromatographed. Fractions containing the desired product were concentrated and the resulting solid was triturated with diethyl ether, filtered and air dried to give the title compound (0.12 g, 0.15 mmol, 37%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.71 (s, 1H), 9.38 (dd, J=4.4, 1.1 Hz, 1H), 8.53 (s, 1H), 8.25 (d, J=5.3 Hz, 1H), 8.02 (d, J=0.4 Hz, 1H), 7.87 (s, 1H), 7.63-7.79 (m, 2H), 7.28-7.50 (m, 2H), 7.10-7.28 (m, 3H), 6.97 (t, J=6.9 Hz, 1H), 6.82 (s, 1H), 6.60 (d, J=5.2 Hz, 1H), 4.23 (q, J=6.7 Hz, 2H), 3.83 (s, 3H), 3.27-3.34 (m, 2H), 3.03 (s, 3H), 2.93-3.01 (m, 4H), 2.75 (t, J=6.6 Hz, 2H), 2.51-2.64 (m, 4H), 1.40 (t, J=6.8 Hz, 3H). MS (M+H, ES+) 817.
Reaction SMILES: C([CH:5]1[CH:10]([OH:11])[CH:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=2)[CH2:8][CH2:7][N:6]1[C:25]([OH:27])=[O:26])(C)(C)C.Br[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1>>[CH2:23]([O:22][C:20]([CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([CH:9]2[CH2:8][CH2:7][N:6]([C:25]([O:27][C:9]([CH3:12])([CH3:10])[CH3:8])=[O:26])[CH2:5][CH:10]2[O:11][CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[CH:13][CH:14]=1)=[O:21])[CH3:24]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCOC(=O)CCc1ccc(C2CCN(C(=O)O)C(C(C)(C)C)C2O)cc1
Product: CCOC(=O)CCc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1

Procedure:
Analogously to the procedure described in Example 22(i), by alkylating tert-butyl (3RS,4RS)-4-[4-(2-ethoxycarbonyl-ethyl)-phenyl]-3-hydroxy-piperidine-1-carboxylic acid with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-4-[4-(2-ethoxycarbonyl-ethyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate; MS: 518 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9]C(=O)C)=[C:5]([CH3:13])[C:4]=1[F:14])#[N:2]>Cl.CCO>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:14])[C:5]=1[CH3:13]
Reactant: CC(=O)Nc1ccc(C#N)c(F)c1C
Agent: Cl
Solvent: CCO
Product: Cc1c(N)ccc(C#N)c1F
Temperature: 25 °C
Yield: 96.8 %

Procedure:
N-(4-cyano-3-fluoro-2-methyl-phenyl)-acetamide (72C) (450 mg, 2.34 mmol) was dissolved in 1:1 conc. HCl/EtOH (20 mL,) and the mixture was refluxed for 1 h. The reaction was cooled to rt and concentrated. The residue was dissolved in EtOAc (30 mL), washed with sat. aq. NaHCO3 and brine, dried (MgSO4), filtered and concentrated. The residue was recrystallized from EtOAc/Hexane to provide the title compound (340 mg). LC/MS: m/z 151 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][N:13]([CH:15]=O)[CH3:14]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:12][N:13]([CH3:15])[CH3:14])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Product: CN(C)C=Cc1cc(Cl)ncc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
A solution of 2-chloro-4-methyl-5-nitro-pyridine (2 g, 11.59 mmol) in DMF (11.6 mL) was treated with 3.08 mL (23.2 mmol, 2 eq) of DMF-dimethylacetal and the reaction mixture was stirred at 100° C. for 4 h. All volatiles were removed under reduced pressure. Column chromatography (silica, 20% EtOAc/hexanes) provided 2.37 g (90%) of [2-(2-chloro-5-nitro-pyridin-4-yl)-vinyl]-dimethyl-amine. TLC (silica, 20% EtOAc/hexanes): Rf=0.30. MS (electrospray): exact mass calculated for C9H10ClN3O2, 227.05; m/z found, 228.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.79 (s, 1H), 8.02 (s, 1H), 7.35 (d, J=13 Hz, 1H), 5.94 (d, J=13 Hz, 1H), 2.96 (s, 3H), 2.87 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([CH3:9])=[C:6](Cl)[N:7]=1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[O:27][CH3:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(COC)OC.C(Cl)(Cl)Cl.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>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[N:4][C:5]=2[CH3:9])=[CH:20][C:19]=1[O:27][CH3:28])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1cc(B(O)O)ccc1OCc1ccccc1
Reactant: Cc1nnc(Cl)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2nc(Cl)nnc2C)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A degassed solution of 3,5-dichloro-6-methyl-1,2,4-triazine (151 mg, 0.9 mmol), 4-(benzyloxy)-3-methoxybenzene boronic acid (236 g, 0.9 mmol), tetrakis(triphenylphosphine)palladium(0) (55 mg, 0.05 mmol) and tripotassium phosphate (249 mg, 1.2 mmol) in dimethoxyethane (5 mL) was heated at reflux for 24 h. Upon cooling to room temperature the solution was diluted with CHCl3 and filtered through Celite®. The filtrate was concentrated in vacuo and the product purified by column chromatography using ethyl acetate-hexane (25:75) as eluent to furnish (75 mg, 22%).
Reaction SMILES: [Br:1][C:2]([F:22])([F:21])[C:3]([F:20])([F:19])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[Br:14])[CH:6]=1.[Cl:23][S:24](O)(=[O:26])=[O:25].Cl>C(Cl)(Cl)Cl>[Br:1][C:2]([F:21])([F:22])[C:3]([F:19])([F:20])[O:4][C:5]1[CH:6]=[C:7]([O:11][C:12]([F:17])([F:18])[C:13]([F:15])([F:16])[Br:14])[CH:8]=[CH:9][C:10]=1[S:24]([Cl:23])(=[O:26])=[O:25]
Reactant: O=S(=O)(O)Cl
Reactant: FC(F)(Br)C(F)(F)Oc1cccc(OC(F)(F)C(F)(F)Br)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(OC(F)(F)C(F)(F)Br)cc1OC(F)(F)C(F)(F)Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
In a 250 mL of round-bottom flask resting in an ice-bath were placed 23.35 g (0.05 mol) of this 1,3-di(2-bromotetrafluoroethoxy)benzene and 100 mL of chloroform. Then 116 g of chlorosulfonic acid was added dropwise into the solution. After the initial evolution of hydrogen chloride had subsided, the mixture was brought to room temperature. The reaction mixture was stirred at room temperature for 1 hour, then heated at 35° C. for another day. The contents of the flask were poured into a 1 L beaker filled with crushed ice. The chloroform layer was separated and washed with ice cold water to neutral. The organic layer was dried over sodium sulfate. After the removal of the solid materials by filtration, the chloroform was evaporated off completely. The crude product was purified by distillation under the reduced pressure to collect the fraction boiling at 127-129° C./10−2 torr. A total of 25.1 g (0.0443 mol) of 2,4-bis(2-bromotetrafluoroethoxy)benzenesulfonyl chloride was obtained in 88.7% yield. The quantity of hydrogen by-product was below 3%.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[S:11][C:10]([N:12]=CN(C)C)=[N:9][C:8]=1[CH3:17])=O.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH2:27][C:28]([NH2:30])=[NH:29].COCCO.[OH-].[Na+]>O>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH2:27][C:28]1[N:30]=[C:5]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[CH3:17])[CH:4]=[CH:3][N:29]=1
Reactant: N=C(N)Cc1c(Cl)cccc1Cl
Reactant: Cc1nc(N=CN(C)C)sc1C(=O)/C=C/N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCO
Product: Cc1nc(N)sc1-c1ccnc(Cc2c(Cl)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of N′-[5-((E)-3-dimethylamino-acryloyl)-4-methyl-thiazol-2-yl]-N,N-dimethyl-formamidine (1 g), 2,6-dichlorophenylacetamidine (0.90 g) and 2-methoxyethanol (3.8 ml) is stirred at room temperature for 30 minutes. NaOH (0.3 g) is added and the mixture stirred at 125° C. for 1 hr. After cooling to room temperature water is added and the mixture evaporated to dryness and then purified by normal phase chromatography on silica gel eluting with a gradient from CH2Cl2 to EtOAc to give the title compound as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[Br:23]N1C(=O)CCC1=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Br:23])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1ncc2cc(Cc3ccccc3)ccc2c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2cc(Cc3ccccc3)ccc2c1O

Procedure:
A mixture of 7-Benzyl-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (302 mg, 1.03 mmole, prepared according to procedures in U.S. Pat. No. 7,928,120 B2 for example 22c) and N-bromosuccinimide (202 mg, 1.13 mmole) in anhydrous dichloromethane (5 ml) was stirred at room temperature for twenty hours before it was quenched with water, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a white solid (259 mg). LC-MS ESI+: 372, 374 (79Br/81Br) (M+1)+; ESI−: 370, 372 (79Br/81Br) (M-b) 7-Benzyl-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:4]([C:14]([OH:16])=[O:15])[CH2:3]1.[CH3:17][Si](C=[N+]=[N-])(C)C>CCCCCC>[CH3:17][O:15][C:14](=[O:16])[C@H:4]1[CH2:3][C@@H:2]([OH:1])[CH2:6][N:5]1[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Product: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2 M (triimethylsilyl)diazomethane in hexane (4 mL) was added to a solution of cis-4-hydroxy-N-tert-butoxycarbonyl-D-proline (916 mg) at 0° C. After stirring at room temperature for 1 hr, a solution of 2 M (trimethylsilyl)diazomethane in hexane (6 mL) was added additionally and stirred at room temperature for 30 min. The solvents were evaporated in vacuo to afford the title compound (971 mg) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:30]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4([NH:41]C(=O)OC(C)(C)C)[CH2:40][CH2:39][CH2:38]4)=[CH:33][CH:32]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N:22]5[CH2:27][CH2:26][O:25][C@H:24]([CH2:28][OH:29])[CH2:23]5)[CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:49].O1CCOCC1>C(Cl)Cl>[ClH:49].[ClH:49].[ClH:49].[NH2:41][C:37]1([C:34]2[CH:35]=[CH:36][C:31]([N:30]3[C:11]4=[N:12][C:13]([C:16]5[CH:17]=[C:18]([N:22]6[CH2:27][CH2:26][O:25][C@H:24]([CH2:28][OH:29])[CH2:23]6)[CH:19]=[CH:20][CH:21]=5)=[CH:14][CH:15]=[C:10]4[N:9]=[C:8]3[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:32][CH:33]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(N6CCO[C@H](CO)C6)c5)nc43)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1ncccc1-c1nc2ccc(-c3cccc(N4CCO[C@H](CO)C4)c3)nc2n1-c1ccc(C2(N)CCC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.3 %

Procedure:
tert-Butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-{3-[(2S)-2-(hydroxymethyl)morpholin-4-yl]phenyl}-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (4.60 mg, 0.00710 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 15 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (3.42 mg, 73.3%) as pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][OH:15])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8].[O:17]1[CH:21]=[CH:20][C:19](O)=[N:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][O:15][C:19]3[CH:20]=[CH:21][O:17][N:18]=3)[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: Oc1ccon1
Reactant: O=C1OC(CO)CN1c1ccc(I)c(F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1OC(COc2ccon2)CN1c1ccc(I)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a solution of 3-(3-fluoro-4-iodo-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1.0 g, 2.97 mmol), isoxazol-3-ol (0.30 g, 3.56 mmol) and triphenylphosphine (1.02 g, 3.86 mmol) in THF (15 mL) was added diisopropyl azodicarboxylate (DIAD, 0.74 mL, 3.56 mmol) dropwise at 0° C. The reaction was warmed to room temperature and stirring was continued for 2 h. The solvent was evaporated and the crude was purified on silica gel, eluting with hexanes/EtOAc 2:1 to 3:2, to give 3-(3-fluoro-4-iodo-phenyl)-5-(isoxazol-3-yloxymethyl)-oxazolidin-2-one (1.01 g; 84% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[CH:14]=[N:15][CH:16]=[C:12]2[CH2:11][CH2:10][CH2:9]1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[CH:14]=[N:15][CH:16]=[C:12]2[CH2:11][CH2:10][CH2:9]1
Reactant: OB(O)c1cccs1
Reactant: Brc1ccccc1C1CCCc2cncn21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1csc(-c2ccccc2C2CCCc3cncn32)c1

Procedure:
To a solution of 5-(2-bromophenyl)-5,6,7,8,-tetrahydro-imidazo[1,5-a]pyridine, Example 12D (120 mg, 0.43 mmol) in DME (2 mL) is added thiophene-2-boronic acid (166 mg, 1.3 mmol), aqueous Na2CO3 (2M, 1.0 mL, 2.0 mmol), and Pd(PPh3)4 (20 mg). The reaction mixture is refluxed overnight. The mixture is partitioned between EtOAc and 1M NaOH. The organic layer is washed by sat. NaHCO3, dried and concentrated to give an oil. The crude reaction mixture is subjected to flash chromatography (silica gel) eluting with acetone:hexane to yield the desired compound. MS (ESI) m/z 280 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 1.58-1.74 (m, 1 H), 1.85-2.01 (m, 2 H), 2.14-2.27 (m, 1 H), 2.74-2.94 (m, 2 H), 5.45 (dd, J=8.6, 5.1 Hz, 1 H), 6.81 (s, 1 H), 7.00-7.05 (m, 2 H), 7.06 (s, 1 H), 7.10 (dd, J=5.3, 3.5 Hz, 1 H), 7.31-7.37 (m, 2 H), 7.39 (dd, J=5.2, 1.1 Hz, 1 H), 7.41-7.46 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7]O)=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:4][N:3]=1.CS([Cl:21])(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:6]([CH2:7][Cl:21])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2snc(Cl)c2CO)cc1
Solvent: ClCCl
Product: COc1ccc(-c2snc(Cl)c2CCl)cc1
Temperature: 0 °C

Procedure:
Into a 100-mL round-bottom flask, was placed [3-chloro-5-(4-methoxyphenyl)-1,2-thiazol-4-yl]methanol (223 mg, 0.87 mmol, 1.00 equiv), dichloromethane (20 mL), TEA (261 mg, 2.58 mmol, 2.96 equiv). This was followed by the addition of MsCl (200 mg) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at room temperature. The resulting solution was diluted with 40 mL of DCM. The resulting mixture was washed with 3×10 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 430 mg (crude) of 3-chloro-4-(chloromethyl)-5-(4-methoxyphenyl)-1,2-thiazole as yellow oil.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[OH:11])[CH2:6][CH2:5]1)(=O)C.[OH-].[K+]>C(O)C.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([CH:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)[OH:11])=[CH:19][CH:20]=1
Reactant: CC(=O)N1CCC(C(O)(c2ccccc2)c2ccc(F)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OC(c1ccccc1)(c1ccc(F)cc1)C1CCNCC1
Temperature: 0 °C
Yield: 24.5 %

Procedure:
A mixture of 16.3 g (0.05 mole) of 1-acetyl-α-(4-fluorophenyl)-α-phenyl-4-piperidinemethanol and 5.6 g (0.1 mole) of potassium hydroxide in 150 ml of 95% ethanol and 20 ml of water was heated at reflux for 18 hr. The mixture was poured into 1.5 liter of ice water and a solid precipitated. The solid was collected by filtration and dried. The gummy solid was dissolved in ethyl ethyl ether, the solution was filtered, and the filtrate slowly evaporated to 50 ml volume. The resulting solid was collected by filtration and recrystallized from 2-propanol-isopropyl ether to yield 3.5 g (25%) of white solid, m.p. 144.5°-146° C.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]1[CH2:16][C:17](O)=[O:18].[NH2:20][C:21]1[S:25][CH:24]=[C:23]([C:26]#[N:27])[C:22]=1[C:28]1[S:32][CH:31]=[N:30][CH:29]=1>>[C:26]([C:23]1[C:22]([C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[C:21]([NH:20][C:17](=[O:18])[CH2:16][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:12]([F:13])([F:14])[F:15])=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:25][CH:24]=1)#[N:27]
Reactant: N#Cc1csc(N)c1-c1cncs1
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Product: N#Cc1csc(NC(=O)Cn2c(=O)ccc3cc(C(F)(F)F)ccc32)c1-c1cncs1

Procedure:
The title compound was prepared from 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (0.047 g, 0.17 mmol) and 5-amino-4-(thiazol-5-yl)thiophene-3-carbonitrile (0.055, 0.26 mmol) according to protocol A. The crude product was purified by prep HPLC. Retention time (min)=5.989, method [7], MS(ESI) 461.1 (M+H). 1H NMR (CDCl3) δ 9.95 (s, 1H), 7.91-7.85 (m, 4H) 7.78 (d, J=8.7 Hz, 1H), 7.63 (s, 1H), 6.84 (d, J=8.7 Hz, 1H), 5.06 (s, 2H).