Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].Cl[C:14]1[N:15]=[C:16]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:17]2[S:22][C:21]([CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([N:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]3)=[CH:20][C:18]=2[N:19]=1>CN(C=O)C.O.[Cl-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:14]1[N:15]=[C:16]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[C:17]3[S:22][C:21]([CH2:23][N:24]4[CH2:25][CH2:26][CH:27]([N:30]([CH3:32])[CH3:31])[CH2:28][CH2:29]4)=[CH:20][C:18]=3[N:19]=1)[CH:6]=[CH:5]2
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C1CCN(Cc2cc3nc(-n4ccc5cc(F)ccc54)nc(N4CCOCC4)c3s2)CC1
Temperature: 150 °C
Yield: 51.1 %

Procedure:
A solution of 5-fluoroindole (0.148 g) in DMF (6 mL) was cooled to 0° C. then sodium hydride (0.06 g) added. After 30 min [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.395 g) was added. The reaction vessel was sealed and heated at 150° C. After 3 h the reaction mixture was cooled to room temperature and diluted with water and saturated aqueous sodium chloride solution. The solid separated was filtered, and then purified by chromatography (silica, 0 to 20% of a 49:1 MeOH:NH4OH mixture in dichloromethane) to furnish 120 (0.252 g, 51%) as a off white solid. MS m/e 495 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.33-1.57 (m, 2H) 1.74 (d, 2H) 2.08 (t, 3H) 2.18 (s, 6H) 2.95 (d, 2H) 3.74-3.87 (m, 6H) 3.89-4.04 (m, 4H) 6.75 (d, 1H) 7.0-7.10 (m, 1H) 7.37 (s, 1H) 7.6-7.7 (m, 1H) 8.33 (d, 1H) 8.5-8.6 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[CH2:14]([Si:21]1(C2C=CC=CC=2)[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:14]([Si@H:21]1[CH2:22][CH2:23][C@H:24]([C:27]([O:13][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:11])([F:12])[F:10])=[C:2]([F:1])[CH:3]=2)=[O:28])[CH2:25][CH2:26]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Oc1ccc(OC(F)(F)F)c(F)c1
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(C(=O)O)CC1
Product: CCCCCCC[Si@H]1CC[C@H](C(=O)Oc2ccc(OC(F)(F)F)c(F)c2)CC1

Procedure:
The general procedure of Example 3 was repeated using 3-fluoro-4-trifluoromethoxyphenol and 4-n-heptyl-4-phenyl-4-silacyclohexanecarboxylic acid, thereby obtaining the intended product.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]3[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][OH:32])[CH2:20]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:33]([C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][CH:36]=1)[CH3:34]>CN(C1C=CN=CC=1)C.C1COCC1>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]3[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[C@H:21]([CH2:31][O:32][C:42](=[O:43])[NH:41][C:38]4[CH:39]=[CH:40][C:35]([CH2:33][CH3:34])=[CH:36][CH:37]=4)[CH2:20]3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CCc1ccc(N=C=O)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1CO
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCc1ccc(NC(=O)OC[C@@H]2C[C@@H](NC(=O)OCC3c4ccccc4-c4ccccc43)CN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,4R)-tert-butyl 4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (403 mg, 0.92 mmol) and DMAP (134 mg, 1.1 mmol) in THF (10 mL) was added 4-ethylphenyl isocyanate (162 mg, 11 mmol). The reaction mixture was stirred at rt overnight and concentrated to give (2S,4R)-tert-butyl 4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-((4-ethylphenylcarbamoyloxy)methyl)pyrrolidine-1-carboxylate, which was used without further purification. LRMS (M+H+) m/z 585.1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([OH:19])=O.[CH:20]([NH:23][NH:24][C:25]([C:27]1[CH:31]=[CH:30][O:29][CH:28]=1)=[O:26])([CH3:22])[CH3:21].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([N:23]([CH:20]([CH3:22])[CH3:21])[NH:24][C:25]([C:27]1[CH:31]=[CH:30][O:29][CH:28]=1)=[O:26])=[O:19]
Reactant: Cc1cccc(-c2ccccc2CCC(=O)O)c1C
Reactant: CC(C)NNC(=O)c1ccoc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2ccccc2CCC(=O)N(NC(=O)c2ccoc2)C(C)C)c1C
Yield: 41.4 %

Procedure:
A solution of 3-(2′,3′-dimethyl-biphenyl-2-yl)-propionic acid (227 mg, 0.89 mmoles) and furan-3-carboxylic acid N′-isopropyl-hydrazide (150 mg, 0.89 mmoles) in DMF (8 mL) was treated with triethylamine (0.37 mL, 2.67 mmoles), HOBT (144 mg, 1.07 mmoles) and EDCI (205 mg, 1.07 mmoles) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and dichloromethane. The organic layer was washed successively with 1N NaOH and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product (149 mg, 41%). LC-MS m/e 405.52 (M+H+)
Reaction SMILES: [C:1]([O:5][CH2:6][C@H:7]([CH3:19])[CH2:8]/[CH:9]=[CH:10]/[C@H:11]([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Ni].C(OCC)(=O)C>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][C@@H:11]([CH3:18])[CH2:10][CH2:9][CH2:8][C@@H:7]([CH3:19])[CH2:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:17]
Reactant: [H][H]
Reactant: CCOC(=O)C[C@@H](C)/C=C/C[C@@H](C)COC(C)(C)C
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H](C)CCC[C@@H](C)COC(C)(C)C

Procedure:
A mixture of 1.104 g. (4.084 mmoles) of (3R,7R)-E-Ethyl 8-tert. butoxy-3,7-dimethyl-4-octenoate, a small amount of Raney nickel, and 30 ml. of ethyl acetate was stirred in an atmosphere of hydrogen, at room temperature, for 2 hours during which time approximately one equivalent of hydrogen was taken up. The catalyst was filtered off and washed with ethyl acetate. Concentration of the combined filtrate and washes in vacuo followed by evaporative distillation afforded 1.045 g. (95%) of saturated ester (3S,7R)-Ethyl 8-tert. butoxy-3,7-dimethyloctanoate as a colorless oil, b.p. 80°-83° C. (bath temperature) (0.15 mm Hg.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([N+:17]([O-])=O)[CH:11]=2)[CH2:4][CH2:3]1.CO.Cl.[OH-].[Na+]>C(OCC)(=O)C.[Fe]>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([NH2:17])[CH:11]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(NCc2cc(F)cc([N+](=O)[O-])c2)CC1
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1CCC(NCc2cc(N)cc(F)c2)CC1
Temperature: 25 °C
Yield: 69 %

Procedure:
Combine 1-methyl-4-(N-(3-nitro-5-fluorophenyl)methylamino)piperidine (Preparation 28) (0.06 g, 0.22 mmole), iron dust (0.06 g, 1.12 mmol), methanol (5 mL) and 1M HCl (0.22 mL, 0.22 mmol), stir, and heat at reflux for 18 hr. Cool the reaction mixture to ambient temperature, dilute with ethyl acetate (50 mL), and add 1N sodium hydroxide solution until basic (pH=9). Separate organic layer, wash with saturated aqueous NaCl solution, dry over sodium sulfate, filter, and concentrate to obtain 0.036 g (69%) of the title intermediate: 1H N (CDCl3): 5.9 (m, 1H), 5.7 (m, 2H), 3.6 (bs, 2H), 3.4 (m, 1H), 2.9 (m, 2H), 2.7 (s, 3H), 2.3 (s, 3H), 2.0 (m, 2H), 1.8 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH3:15][N:16]([CH3:32])[C:17]1[N:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][N:18]=1.O.N#N>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].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>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([C:20]2[CH:19]=[N:18][C:17]([N:16]([CH3:32])[CH3:15])=[N:22][CH:21]=2)[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=1
Reactant: CN(C)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C(C)=O)cc(Cl)c(C)c1-c1cnc(N(C)C)nc1
Temperature: 100 °C
Yield: 52.1 %

Procedure:
A biphasic solution of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (0.10 g, 0.36 mmol) and N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.11 g, 0.43 mmol) in 1,4-dioxane (1.2 mL) and 10% sodium carbonate in water (0.57 mL, 0.54 mmol) was bubbled with N2 to degas. After tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.014 mmol) was added, the mixture was bubbled with N2 for 5 min. and heated at 100° C. overnight. The mixture was cooled to r.t. and diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with more ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel column, eluting with 0-30% of ethyl acetate in hexane, to give the desired product (60 mg, 50%). LCMS calculated for C16H19ClN3O2 (M+H)+: m/z=320.1. found: 320.1.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:17])=O>CN(C=O)C.O1CCOCC1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([Cl:17])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc2ncccc2c1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2ncccc2c1

Procedure:
Under nitrogen, a 1 L round bottom flask, equipped with septum and drying tube attached to a gas scrubber setup, was charged with 25.4 g (146.5 mmol) quinoline-6-carboylic acid. 1,4-Dioxane (250 mL) was added along with 10 drops of DMF. Inside a glovebox, oxalyl chloride (25.1 g, 197.8 mmol, 1.35 eq) was weighed into a septum vial. The vial was closed, removed from the glovebox, and the weighed oxalyl chloride was added, under nitrogen, to the reaction, in portions, via syringe. The reaction was stirred until most of the gas development ceased. The reaction remained stirring at room temperature overnight. The volatiles were removed using a rotary evaporator. Trace HCl was removed by addition of several aliquots of dry toluene, which were consecutively evaporated using the rotary evaporator. The final product was obtained in form of a colorless to slightly yellow powder (28.0 g, 146.4 mmol, 100%). 1H-NMR: (500 MHz, CDCl3) δ 9.35 (dd, J=5.2, 1.5 Hz, 1H), 9.09 (d, J=8.5 Hz, 1H), 9.09 (d, J=9.0 Hz, 1H), 9.01 (d, J=2.0 Hz, 1H), 8.64 (dd, J=9.1, 2.0 Hz, 1H), 8.14 (dd, J=8.4, 5.2 Hz, 1H); 13C-NMR (126 MHz, CDCl3) δ 122.92, 123.90, 128.21, 133.44, 133.79, 134.55, 140.95, 146.44, 147.11, 166.69.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:18]=[C:19]([NH:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34]CC)=[O:33])=[CH:27][CH:26]=4)[CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[C:37]([F:40])([F:39])[F:38])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)CC1C=CC=C(C2C3C(=C(C(F)(F)F)C=CC=3)N=CC=2C2C=CC=CC=2)C=1)C>>[C:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:18]=[C:19]([NH:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[CH:27][CH:26]=4)[CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[C:37]([F:40])([F:38])[F:39])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cc1ccc(CNc2cccc(-c3c(-c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Agent: CCOC(=O)Cc1cccc(-c2c(-c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(O)Cc1ccc(CNc2cccc(-c3c(-c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound is prepared essentially as described in Example 398, except using ethyl {4-[({3-[3-phenyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amino)methyl]phenyl}acetate instead 3-[3-phenyl-8-(trifluoromethyl)quinolin-4-yl]phenyl acetic acid ethyl ester to afford the title compound as a tan tacky solid (0.021 g, 31%). Calcd mass for C31H23N2F3O2 is 512.53, found MS (ES) m/z 513.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH3:11])[CH:5]=[N:6][CH:7]=1.C([O-])=O.[NH4+:16].Cl>CO.C[C]1[C](C)[C](C)[C](C)[C]1C.C[C]1[C](C)[C](C)[C](C)[C]1C.Cl[Rh]Cl.Cl[Rh]Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:16])[CH2:9][CH2:10][CH3:11])[CH:5]=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: CCCC(=O)c1cncc(C)c1
Agent: Cl[Rh]Cl
Agent: C[C]1[C](C)[C](C)[C](C)[C]1C
Agent: Cl
Solvent: CO
Product: CCCC(N)c1cncc(C)c1
Temperature: 25 °C
Yield: 77 %

Procedure:
To a solution of 1-(5-methylpyridin-3-yl)butan-1-one (800 mg, 4.9 mmol) and ammonium formate (1.55 g, 24.5 mmol) in methanol (5 mL) under nitrogen was added dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer (45 mg, 0.074 mmol). The solution was heated at reflux for 8 h. after which time the solution was cooled to room temperature and acidified to pH ˜2 with 2M HCl. The mixture was washed with dichloromethane (3×15 mL) and the aqueous phase then basified to pH ˜12 by addition of solid KOH. The aqueous phase was extracted with dichloromethane (3×15 mL) and the combined organic layers washed with brine, dried (Na2SO4) and concentrated to give a pure product (620 mg, 77%).
Reaction SMILES: FC1C(O[C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=C(F)C(F)=C(F)C=1F.[CH2:29]([C:32]1[CH:36]=[C:35]([CH2:37][O:38][NH2:39])[O:34][N:33]=1)[CH2:30][CH3:31]>>[CH2:29]([C:32]1[CH:36]=[C:35]([CH2:37][O:38][NH:39][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[O:34][N:33]=1)[CH2:30][CH3:31]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccccc1NCc1ccncc1
Reactant: CCCc1cc(CON)on1
Product: CCCc1cc(CONC(=O)c2ccccc2NCc2ccncc2)on1

Procedure:
Prepared by the same method as described for example 415. Starting materials: 2-[(Pyridin-4-ylmethyl)-amino]-benzoic acid pentafluorophenyl ester (preparation 7C) and O-(3-Propyl-isoxazol-5-ylmethyl)-hydroxylamine (see preparation 63).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:29]([N:36]=[C:37]=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:37]([NH:36][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:38])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C=NCc1ccccc1
Reactant: CCNCc1ccc(C(F)(F)F)cc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc(C(F)(F)F)ccc2CN(CC)C(=O)NCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-5′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and benzyl isocyanate.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][NH+:6]=[C:5]([CH2:10]Cl)[C:4]=1[CH3:12].[CH3:13][O:14][C:15]1[N:20]=[C:19]2[N:21]=[C:22]([SH:24])[NH:23][C:18]2=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[N:20]=[C:19]2[N:21]=[C:22]([S:24][CH2:10][C:5]3[C:4]([CH3:12])=[C:3]([Cl:2])[C:8]([CH3:9])=[CH:7][N:6]=3)[NH:23][C:18]2=[CH:17][CH:16]=1
Reactant: Cc1c[nH+]c(CCl)c(C)c1Cl
Reactant: COc1ccc2[nH]c(S)nc2n1
Agent: [Cl-]
Product: COc1ccc2[nH]c(SCc3ncc(C)c(Cl)c3C)nc2n1

Procedure:
As a further example, 4-chloro-2-chloromethyl-3,5-dimethylpyridinium chloride could be reacted with 5-methoxy-1H-imidazo[4,5-b]pyridine-2-thiol according to the procedure described under Example 39 to give 5-methoxy-2-[(4-chloro-3,5-dimethyl-2-pyridinyl)methylthio]-1H-imidazo[4,5-b]pyridine. Conversion of this product with methanol-d4 following the protocol described under Example 44 would then give rise to formation of 5-methoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylthio]-1H-imidazo[4,5-b]pyridine, which, in turn, could be oxidized according to the procedure used in Example 46 to rac-5-methoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-imidazo[4,5-b]pyridine.
Reaction SMILES: C[C@@:2]1([C:18]([O-:20])=[O:19])[CH2:6][C@:5](C)([C:7]([O-:9])=[O:8])[CH2:4][N:3]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[OH-].[Na+].Cl.[CH2:24]1COCC1>>[C:14]([O:13][C:11]([N:3]1[C@H:2]([C:18]([O:20][CH3:24])=[O:19])[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4]1)=[O:12])([CH3:15])([CH3:16])[CH3:17]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1C[C@@](C)(C(=O)[O-])C[C@@]1(C)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)[C@@H]1C[C@H](C(=O)O)CN1C(=O)OC(C)(C)C
Yield: 70 %

Procedure:
To a solution of (2S,4S)-1-tert-butyl 2,4-dimethylpyrrolidine-1,2,4-tricarboxylate (9.56 g, 33.3 mmol) in THF (70 mL) at 0° C. (external temperature, ice bath) was added NaOH (1N aqueous, 33 mL, 33.3 mmol) dropwise over 15 min. The solution was stirred at 0° C. for 5 h before acidification with HCl (1N). The solution was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified by silica gel chromatography (2% to 5% to 10% MeOH/CH2Cl2) to provide (3S,5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidine-3-carboxylic acid (6.38 g, 70%).
Reaction SMILES: [CH:1]([Si:4]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:13]([C:16](O)=[O:17])=[CH:14][N:15]=2)[CH:12]=1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[F:31][C:32]1([F:49])[CH2:35][CH:34]([C:36]2[O:40][N:39]=[C:38]([C:41]3[CH:42]=[CH:43][C:44]([CH3:48])=[C:45]([CH:47]=3)[NH2:46])[N:37]=2)[CH2:33]1.O>ClCCl.CN(C=O)C.N1C=CC=CC=1>[F:49][C:32]1([F:31])[CH2:33][CH:34]([C:36]2[O:40][N:39]=[C:38]([C:41]3[CH:42]=[CH:43][C:44]([CH3:48])=[C:45]([NH:46][C:16]([C:13]4[N:11]5[CH:12]=[C:7]([CH2:6][O:5][Si:4]([CH:1]([CH3:2])[CH3:3])([CH:22]([CH3:23])[CH3:24])[CH:19]([CH3:21])[CH3:20])[CH:8]=[CH:9][C:10]5=[N:15][CH:14]=4)=[O:17])[CH:47]=3)[N:37]=2)[CH2:35]1
Reactant: CC(C)[Si](OCc1ccc2ncc(C(=O)O)n2c1)(C(C)C)C(C)C
Reactant: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cn12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirring suspension of 6-(((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid (61) (260 mg, 0.74 mmol) in anhydrous dichloromethane (5 mL) at room temperature oxalyl chloride was added dropwise (0.19 mL, 2.22 mmol). Then, one drop of anhydrous DMF was added and the reaction mixture was stirred at room temperature for 15 minutes. The solvent was concentrated and the crude solid was added to a stirring solution of 5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylaniline (37) (180 mg, 0.74 mmol) in anhydrous pyridine (5 mL) at room temperature. The reaction was stirred for 20 minutes and the solvent was removed to afford residue. To the above residue was added water (20 mL) and sonicated to give precipitate. Then the precipitate was filtered, dried in air and purified by silica chromatography to afford N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridine-3-carboxamide (64). MS m/z 596.3 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH:11]([CH3:13])[CH3:12].C([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)(=O)C=C.[OH-].[Li+]>N1C=CC=CC=1.CO.O1CCCC1.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[S:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][OH:18])=[CH:27][CH:26]=1)(=[O:30])=[O:29]
Reactant: Cc1ccc(NCC(C)C)c(C)c1
Reactant: C=CC(=O)OCCOc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCCO)cc2)c(C)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2,4-dimethylphenyl)(2-methylpropyl)amine (0.2 g, 1.128 mmol) in pyridine (10 mL) stirred in air at room temperature, was added 2-{[4-(chlorosulfonyl)phenyl]oxy}-ethyl 2-propenoate (0.656 g, 1.128 mmol). The reaction mixture was stirred at 20° C. for 30 minutes to ensure dissolution and then left to stand overnight. The pyridine was evaporated in vacuo (biotage V10) to give a residue. This was partially dissolved in methanol and applied to a pre-conditioned aminopropyl (NH2) solid phase extraction (SPE) cartridge eluting with additional methanol. The methanol fraction was then passed down a sulfonic acid (SCX) SPE cartridge again eluting with methanol. Solvent was evaporated in vacuo and the sample loaded in methanol and purified by reverse phase (C18) chromatography. The appropriate fractions were combined and dried under a stream of nitrogen to give the intermediate product. This was then taken up in tetrahydrofuran (THF) (1 mL) and lithium hydroxide (0.027 g, 1.128 mmol) in water (1 mL) was added. The mixture was stirred for 2 hours and then evaporated under a stream of nitrogen to give a residue. This was partitioned between water and dichloromethane and separated with a hydrophobic frit. The organic solvent was evaporated in vacuo (Biotage v10) to give the deprotected product as a colourless oil, 44.8 mg. LCMS [LCMS1] Rt 1.23 min, m/z (ES+) 378 (M+H).
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH:35]1([CH2:38]Br)[CH2:37][CH2:36]1>CN(C)C=O>[CH:35]1([CH2:38][N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:32])[CH2:3][CH2:4]2)=[O:9])[CH2:37][CH2:36]1
Reactant: BrCC1CC1
Reactant: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1)N1CCC(F)(F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2n1CC1CC1)N1CCC(F)(F)CC1
Yield: 80 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (example 44), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a colorless foam (80%).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]([F:21])[C:5]([CH2:6][NH:7][C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[N+:16]([O-])=O)=[C:4]([F:22])[CH:3]=1.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCO>[Br:1][C:2]1[CH:20]=[C:19]([F:21])[C:5]([CH2:6][NH:7][C:8]2[C:9]([NH2:16])=[CH:10][CH:11]=[C:12]([O:14][CH3:15])[CH:13]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1ccc([N+](=O)[O-])c(NCc2c(F)cc(Br)cc2F)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(N)c(NCc2c(F)cc(Br)cc2F)c1
Temperature: 100 °C

Procedure:
To a solution of N-(4-bromo-2,6-difluorobenzyl)-5-methoxy-2-nitroaniline (600 mg, 1.61 mmol) in EtOH (100 mL) was added SnCl2.2H2O (1.8 g, 8.1 mmol). The mixture was heated at 100° Celsius for 16 h. The mixture was cooled to RT and NaHCO3 (200 mL) was added. The mixture was filtered through celite and the filtrate extracted with EtOAc (3×200 mL). The combine organics were concentrated to dryness to provide the title compound which was used in the next step without further purification. MS (ESI): mass calcd. for C14H13BrF2N2O, 342.02; m/z found, 343.1 [M+H]+.