Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:12][S:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)(=[O:15])=[O:14])[N:3]=1.[CH3:24][C:25]1[O:26][C:27]2[C:33]([NH2:34])=[CH:32][CH:31]=[CH:30][C:28]=2[CH:29]=1>O1CCOCC1>[F:23][C:18]1[CH:17]=[C:16]([S:13]([NH:12][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[CH:10]=[CH:11][C:2]([NH:34][C:33]2[C:27]4[O:26][C:25]([CH3:24])=[CH:29][C:28]=4[CH:30]=[CH:31][CH:32]=2)=[N:3]3)(=[O:15])=[O:14])[CH:21]=[C:20]([F:22])[CH:19]=1
Reactant: Cc1cc2cccc(N)c2o1
Reactant: O=S(=O)(Nc1cccc2nc(Cl)ccc12)c1cc(F)cc(F)c1
Solvent: C1COCCO1
Product: Cc1cc2cccc(Nc3ccc4c(NS(=O)(=O)c5cc(F)cc(F)c5)cccc4n3)c2o1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
N-(2-Chloro-quinolin-5-yl)-3,5-difluoro-benzenesulfonamide (150 mg, 0.423 mmol) was dissolved in 3 mL dioxane. Argon was bubbled through the solution for 2 minutes to remove oxygen. (2-Methyl-1-benzofuran-7-yl)amine (245 mg, 1.33 mmol), sodium tert.-butylate (230 mg, 2.40 mmol), 1,1′-bis(diphenylphosphin)ferrocen (36 mg, 0.06 mmol) and 1,1′-bis(diphenylphosphin)ferrocen-palladium(II)chloride (17 mg, 0.02 mmol) were added. The reaction mixture was stirred in a sealed tube at 100° C. for 16 h. The solvent was evaporated and the residue purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->60:40 gradient). The title compound was obtained as a light brown solid (164 mg, 83%), MS: m/e=466.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:7]=1[O:15][CH3:16].[Br:17]Br.CCOC(C)=O>C(O)(=O)C>[Br:17][C:9]1[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[C:7]([O:15][CH3:16])[CH:8]=1
Reactant: BrBr
Reactant: COCCNc1c(OC)cccc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COCCNc1c(OC)cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
To a solution of ca. 20 g (contains 15.65 g, 58.9 mmol) (2-methoxy-ethyl)-(2-methoxy-6-nitro-phenyl)-amine in 150 ml glacial acetic acid, 3.0 ml (58.9 mmol) bromine is slowly added at room temperature. The reaction mixture is stirred at room temperature for 3 h. 600 ml EtOAc are added and this solution is washed with 4n NaOH (2×), water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is recrystallized from diethyl ether/hexane to afford 13 g of the pure title compound as orange crystals and 6.6 g of an orange oil which contained 50% of the starting material.
Reaction SMILES: C([O:3][C:4](=[O:13])[CH:5]([CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)[CH3:6])C.[OH-].[Na+].Cl>O1CCOCC1.O>[O:10]1[CH2:11][CH2:12][CH:7]([CH:5]([CH3:6])[C:4]([OH:13])=[O:3])[CH2:8][CH2:9]1
Reactant: CCOC(=O)C(C)C1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C(=O)O)C1CCOCC1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
To a solution of (Tetrahydro-pyran-4-yl)-acetic acid ethyl ester (2.0 g, 11.6 mmol) in 50 mL of THF at −78° C. LDA (1.0 M, 17.4 mL, 34.8 mmol) is added dropwise. The solution is stirred for 0.5 h and treated with HMPA (3.2 mL, 9.3 mmol) and MeI (4.94 g, 34.8 mmol). The reaction mixture is stirred at the same temperature for 0.5 h and for 1.5 h at 0° C., acidified with aqueous 1 N aqueous HCl solution, and extracted twice with ether (2×40 mL). The organic phase is washed with saturated aqueous NaCl solution, dried (MgSO4), and concentrated in vacuo to give 1.8 g of 2-(Tetrahydro-pyran-4-yl)-propionic acid ethyl ester which is hydrolyzed without further purification. A solution of the crude ester (500 mg, 2.68 mmol) and 5 N aqueous NaOH solution (2.68 mL, 13.4 mmol) in dioxane-water (4 mL/2 mL) is heated at 60° C. for 2 h. The solution is cooled to room temperature, acidified with 1 N aqueous HCl solution, and extracted with ether. The ether layer is washed with saturated aqueous NaCl solution, dried over anhydrous MgSO4, and concentrated in vacuo to give 400 mg of the title compound. MS: 159 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 2 min then 100% CH3CN+0.1% TFA for 1 min, flow 0.5 ml/min): 1.27 min.
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[O:24])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[CH:10]1([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:13]=[CH:14][C:2]([C:17]3[CH:18]=[C:19]([NH:22][C:23]([C:25]4[CH:29]=[CH:28][S:27][CH:26]=4)=[O:24])[CH:20]=[CH:21][C:16]=3[CH3:15])=[N:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1ccc(C(=O)NCC2CC2)cn1

Procedure:
N-Cyclopropylmethyl-6-[2-methyl-5-(thiophen-3-ylcarbonylamino)-phenyl]-nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (Intermediate 14) using General Method B. LCMS: retention time 3.07 min, MH− 392. NMR: δH [2H6]-DMSO 10.11,(1H, s), 9.11,(1H, s), 8.83,(1H, t), 8.35,(1H, s), 8.30,(1H, dd), 7.85,(1H, s), 7.78,(1H, d), 7.67-7.63,(3H, m), 7.31,(1H, d), 3.20,(2H, t), 2.31,(3H, s), 1.06,(1H, m), 0.46,(1H, m), 0.27,(1H, m).
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[O:13][CH2:14][CH2:15][CH3:16])[CH3:3].Cl[C:18]1[N:19]=[N:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CN1C(=O)CCC1>[Br:12][C:10]1[CH:9]=[CH:8][C:7]([O:13][CH2:14][CH2:15][CH3:16])=[C:6]([CH:11]=1)[CH2:5][N:4]([C:18]1[N:19]=[N:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=1)[CH2:2][CH3:3]
Reactant: N#Cc1ccc(Cl)nn1
Reactant: CCCOc1ccc(Br)cc1CNCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCCOc1ccc(Br)cc1CN(CC)c1ccc(C#N)nn1
Temperature: 110 °C
Yield: 76.1 %

Procedure:
N-ethyl 2-propoxy-5-bromobenzylamine hydrochloride 2 (5.17 g, 16.8 mmol) and 3-chloro-6-cyanopyridazine (2.65 g, 16.8 mmol) were dissolved in NMP (25 ml) and sodium hydrogen carbonate added (3.54 g, 42.1 mmol). The mixture was heated at 110° C. under argon for 7.5 hours and then allowed to cool to ambient temperature. The mixture was poured into ethyl acetate (200 ml) washed with water (5×200 ml) and brine (200 ml), the organic phase dried over MgSO4 and concentrated in vacuo. The residue was purified by MPLC (20%ethyl acetate/hexane) and then crystallised from ether/hexane to give the title product (4.80 g, 76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[C:4]([F:29])[C:3]=1[CH2:30][C:31]([OH:33])=O.[NH:34]1[CH2:37][CH2:36][CH2:35]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:34]1([C:31](=[O:33])[CH2:30][C:3]2[C:2]([F:1])=[CH:7][C:6]([O:8][CH2:9][CH2:10][C@@H:11]3[CH2:13][C@@H:12]3[CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=4)[CH2:16][CH2:15]3)=[CH:5][C:4]=2[F:29])[CH2:37][CH2:36][CH2:35]1
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)O)c(F)c3)CC2)nc1
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)N4CCC4)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of {2,6-difluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy}phenyl]acetic acid (5.00 g, 10.8 mmol) in 8 ml anhydrous DMF at RT was added azetidine (0.928 g, 16.3 mmol) and N,N-diisopropylethylamine (3.78 ml, 21.7 mmol). o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (6.18 g, 16.3 mmol) was added to the solution and the mixture stirred at RT for 4 hrs. The residue was purified by preparative biotage reverse phase (C-18) (100 g column), eluting with Acetonitrile/Water+0.1% formic acid (35% to 90%). The solid was purified by column chromatography on silica gel (Biotage 40M), eluting with EtOAc/hexanes (30% to 90%). The product was further purified by preparative biotage Reverse phase (C-18)(100 g), eluting with Acetonitrile/Water+0.1% formic acid (35% to 90%) to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ 8.28 (s, 2H), 6.67 (d, J=9.4 Hz, 2H), 4.67 (t, J=13.9 Hz, 2H), 4.18 (m, 4H), 4.06 (m, 211), 3.85 (t, J=7.8 Hz, 2H), 3.38 (s, 2H), 3.23 (s, 3H), 2.85 (m, 2H), 2.20 (m, 211), 2.03 (m, 1H), 1.75 (t, J=14.2 Hz, 2H), 1.51 (m, 114), 1.21-1.25 (m, 3H), 0.87 (m, 1H), 0.57 (m, 2H), −0.08 (m, 1H). LC/MS (m/z): 501.4 (M+H)+. GPR119 Human EC50: 0.18 nM
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][CH3:35])=[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.[CH2:36]([C:38]1[C:39]([N:47]2[CH2:52][CH2:51][CH:50]([N:53]3[CH2:58][CH2:57][N:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:55][CH2:54]3)[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([CH:44]=1)[NH2:43])[CH3:37].Cl>C(O)C(F)(F)F>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[C:38]([CH2:36][CH3:37])[C:39]([N:47]4[CH2:48][CH2:49][CH:50]([N:53]5[CH2:54][CH2:55][N:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:57][CH2:58]5)[CH2:51][CH2:52]4)=[CH:40][C:41]=3[O:45][CH3:46])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCc1cc(N)c(OC)cc1N1CCC(N2CCN(S(C)(=O)=O)CC2)CC1
Agent: Cl
Solvent: OCC(F)(F)F
Product: CCc1cc(Nc2nccc(-c3c(-c4ccc(OC)c(C(=O)Nc5c(F)cccc5F)c4)nc4ccccn34)n2)c(OC)cc1N1CCC(N2CCN(S(C)(=O)=O)CC2)CC1
Temperature: 170 °C
Yield: 58.7 %

Procedure:
A mixture of 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (0.60 g, 1.22 mmol), 5-ethyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (Example 206, Step B) (0.48 g, 1.22 mmol) and HCl (4N,1,4-Dioxane, 0.61 mL, 2.44 mmol) in trifluoroethanol (15 mL) was heated at 170° C. for 40 min in the microwave. The reaction mixture was concentrated onto silica gel and purified by flash column chromatography. Recrystallization from DCM and EtOH afforded the title compound N-(2,6-difluorophenyl)-5-(3-{2-[(5-ethyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamide (0.61 g, 56%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=[O:27]>C(Cl)Cl>[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:27]
Reactant: NCCCSc1ccncc1
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCSc1ccncc1)c1ccco1
Yield: 88.2 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.78 ml (19.9 mmol) of triethylamine in 40 ml of methylene chloride, 0.49 ml (4.98 mmol) of 2-furoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain powder. The powder was washed with ether and dried to obtain 960 mg of the desired compound (yield: 87.3% colorless powder)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:11]=[C:6]2[C:7](=[O:8])[O:9][CH2:12][C:5]2=[N:4][CH:3]=1
Reactant: COC(=O)c1cc(Cl)c[n+]([O-])c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1OCc2ncc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.9 %

Procedure:
A mixture of crude methyl 5-chloro-2-methylnicotinate 1-oxide (Organic letters, 2001, 3, 209, 2.29 mmol) and trifluoroacetic acid (453 μL, 3.21 mmol) in dichloromethane (20 mL) was stirred at room temperature for 2 days and heated at 45° C. for 1 hour. The mixture was partitioned between sat. aqueous sodium hydrogen carbonate (50 mL) and ethyl acetate (50 mL). The organic layer was washed with brine (50 mL), dried (sodium sulfate), and evaporated. The residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1/1) to afford 225 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[NH:12][CH2:11][CH2:10][S:9]2)[CH:5]=[CH:6][CH:7]=1.C1C=CC=CC=1.[Cl:19][CH:20]([Cl:24])[C:21](Cl)=[O:22]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([C:21](=[O:22])[CH:20]([Cl:24])[Cl:19])[CH2:11][CH2:10][S:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(C2NCCS2)c1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(C(Cl)Cl)N1CCSC1c1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
Five grams of 2-m-chlorophenyl thiazolidine was dissolved in 50 ml. of benzene and 2.6 g. of triethylamine and the mixture was stirred in a room temperature water bath, while 3.7 g. of dichloroacetyl chloride was added dropwise. After standing for about 30 minutes, the mixture was washed with water, separated and dried over magnesium sulfate and the benzene stripped under vacuum. There was obtained a yield of 7.2 g. of an oil, the title compound, ND30 = 1.5805.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[C:6]1(=[O:16])[NH:10][C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][CH:2]([F:5])[CH2:3][N:10]1[C:6](=[O:16])[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9]1=[O:11]
Reactant: FC(F)CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC(F)F
Temperature: 120 °C
Reaction time: 16 h
Yield: 77.9 %

Procedure:
An amount of 27.6 g (0.269 mol) of 2,2-difluoro-1-chloroethane and 20 g (0.135 mol) of phthalimide are dissolved in 95 g of N,N-dimethylformamide and treated with 56.3 g (0.403 mol) of potassium carbonate. The reaction mixture is stirred in an autoclave under pressure at 120° C. for 16 h. After the end of the reaction, cooling is carried out to ambient temperature and the solvent is exhaustively removed under vacuum. The remaining residue is treated with 100 ml of water and the solid is filtered off. The filter residue is washed twice with water and the product is dried under vacuum. An amount of 22.2 g of 2-(2,2-difluoroethyl)-1H-isoindole-1,3(2H)-dione with a purity of 98.4% is obtained. This corresponds to a yield of 77% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O:17]CC)=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[OH-].[Na+:31]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O-:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[Na+:31]
Reactant: CCOC(=O)c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1

Procedure:
Ethyl 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)methyl]-2-pyridinecarboxylate (421.4 mg, 0.97 mmol) was suspended in ethanol (4 ml) and 2M sodium hydroxide (1 ml) and heated at 90° C. for 1.75 hours. Reaction complete after about 1 hour.
Reaction SMILES: C(O)(=O)C(O)=O.[C:7]([O:11][C:12]([N:14]1[CH2:20][C:16]2([NH:19][CH2:18][CH2:17]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl>[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:19]2[C:16]3([CH2:15][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[CH2:20]3)[CH2:17][CH2:18]2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CC2(CCN2)C1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2(CCN2S(=O)(=O)c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 177.9 %

Procedure:
To a stirred solution of 6-(tert-butoxycarbonyl)-1,6-diaza-spiro[3.3]heptane oxalate (350 mg, 719 μmol) in dichloromethane (6 mL) was added at 0° C. triethylamine (221 μl, 1.58 mmol) followed by 4-fluorobenzene-1-sulfonyl chloride (294 mg, 1.51 mmol). The reaction mixture was stirred at ambient temperature for 15 h. Further 4-fluorobenzene-1-sulfonyl chloride (100 mg, 0.51 mmol) and triethylamine (200 μl, 1.4 mmol) were added, the reaction mixture was stirred at ambient temperature for another 3 h. The reaction mixture was then diluted with dichloromethane 10 mL) and quenched with water (10 mL). The aqueous phase was extracted with CH2Cl2, and the combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (SiO2; heptane:ethyl acetate 2:1) to give the title compound (456 mg, 89%) as a colorless oil. MS (EI) m/e: 357.1 (M+H)+.
Reaction SMILES: [OH-].[Na+].[C:3]([CH:6]1[CH2:11][CH2:10][C:9]([CH2:12][O:13]C(=O)C2C=C([N+]([O-])=O)C=C([N+]([O-])=O)C=2)=[CH:8][CH2:7]1)([CH3:5])=[CH2:4]>CO>[CH3:5][C:3]([C@@H:6]1[CH2:7][CH:8]=[C:9]([CH2:12][OH:13])[CH2:10][CH2:11]1)=[CH2:4]
Reactant: C=C(C)C1CC=C(COC(=O)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C(C)[C@@H]1CC=C(CO)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
Aqueous sodium hydroxide (3.23 g, 80.0 mmol, dissolved in 28 mL of water) was added to an ice cold solution of 3, 5-Dinitro-benzoic acid 4-isopropenyl-cyclohex-1-enylmethyl ester (14.0 g, 40.4 mmol) in methanol (140 mL) over a period of 0.25 h. The reaction mixture was allowed to warm to room temperature and then stirred for 3.0 h. The methanol was concentrated under vacuum and the resulting residue was suspended in water (60 mL) and extracted with ethyl acetate (2×100 mL). The organic layer was washed with water (2×100 mL) followed by brine (15%, 100 mL) and dried over sodium sulphate (30 g). The filtered organic layer was concentrated under vacuum to get pure (S)-perillyl alcohol (Weight: 5.84 g, Yield: 95% Purity: 99.4% by GC).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:24][C:25](=[O:27])[CH3:26])([CH2:22][OH:23])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:12]=2)[CH2:7][CH:6]=1.[Li+].[OH-]>CO.CCOCC>[OH:23][CH2:22][C:3]([NH:24][C:25](=[O:27])[CH3:26])([CH2:2][OH:1])[CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:12]=2)[CH2:7][CH2:6]1
Reactant: CCCCCCCCc1ccc2c(c1)CC=C2CC(CO)(CO)NC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: CCCCCCCCc1ccc2c(c1)CCC2CC(CO)(CO)NC(C)=O

Procedure:
Compound 19 (18 mg, 0.047 mmol) is dissolved in methanol (0.50 mL) and LiOH (0.04 g, 0.60 mmol) is added. The reaction is heated and maintained at reflux for 2 hours, diluted with ether (5 mL). The organic layer is washed with water (1×5 mL) and brine (1×5 mL). The combined organic layer is concentrated in vacuo then purified by silica gel chromatography eluding with 75% methanol and 25% methylene chloride.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[Br:6][CH:7]([CH3:10])[CH2:8][OH:9]>C(Cl)(Cl)(Cl)Cl>[Br:6][CH:7]([CH3:10])[CH2:8][O:9][P:1]([Cl:5])([Cl:3])=[O:2]
Reactant: CC(Br)CO
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)COP(=O)(Cl)Cl
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of 42 g of phosphorous oxychloride in 110 ml of carbon tetrachloride was added dropwise with stirring a solution of 25 g of 2-bromo-1-propanol in 25 ml of carbon tetrachloride. This mixture was stirred overnight, then taken to dryness, evaporated twice from toluene and dried. The residue was distilled on a Kugelrohr 75° C., 0.05 mm, giving 26.1 g of the desired compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:14]=[N:15][CH:16]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2S(C1C=CC=CC=1)(=O)=O.N1C=CC=CC=1.[CH3:42][C:43]1[S:44][CH:45]=[C:46]([C:48](Cl)=[O:49])[N:47]=1>C(Cl)Cl>[CH3:42][C:43]1[S:44][CH:45]=[C:46]([C:48]([NH:1][C:2]2[CH:10]=[C:9]([C:11]3[CH:16]=[N:15][CH:14]=[C:13]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:12]=3)[CH:8]=[C:7]3[C:3]=2[CH:4]=[N:5][NH:6]3)=[O:49])[N:47]=1
Reactant: Nc1cc(-c2cncc(NS(=O)(=O)c3ccccc3)c2)cc2c1cnn2S(=O)(=O)c1ccccc1
Reactant: Cc1nc(C(=O)Cl)cs1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(C(=O)Nc2cc(-c3cncc(NS(=O)(=O)c4ccccc4)c3)cc3[nH]ncc23)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.7 %

Procedure:
N-{5-[4-Amino-1-(phenylsulfonyl)-1H-indazol-6-yl]-3-pyridinyl}benzenesulfonamide (100 mg) was dissolved in DCM (5 ml) and pyridine (0.024 ml) was added. The reaction was stirred at RT for 2 min before 2-methyl-1,3-thiazole-4-carbonyl chloride (35 mg) was added. The reaction was stirred at RT for 18 h. Further 2-methyl-1,3-thiazole-4-carbonyl chloride (10 mg) was added and stirring continued for 2 h at RT. Further 2-methyl-1,3-thiazole-4-carbonyl chloride (35 mg) was added and the reaction stirred at RT for 18 h before being quenched with water. DCM was added and the reaction was passed through a hydrophobic frit and evaporated to dryness. The residue was dissolved in DMSO:MeOH (1:1, v/v, 1 ml) and purified by MDAP (method E). The desired dried intermediate was dissolved in MeOH and 2M NaOH (1 ml) was added. The reaction was stirred at RT for 30 min. The reaction was neutralised with 2M HCl (aq) then evaporated to dryness. The residue was dissolved in MeOH and loaded onto a SCX-2 SPE cartridge pre-conditioned with MeOH. After eluting with MeOH then 10% NH3 in MeOH, the basic fraction was evaporated to dryness to give the title compound (22 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)[CH2:11][CH:12]=[C:13]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:8]2=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[N:9]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)[CH2:11][CH:12]=[C:13]([CH2:14][C:15]([OH:17])=[O:16])[C:8]2=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2CC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2CC(=O)O
Temperature: 25 °C

Procedure:
To a solution of biphenyl indolizinyl tert-butyl ester (0.039 mmol, the title compound of Example 3231) in 0.5 mL of chloroform is added 0.25 mL of TFA, and the progress of the reaction is monitored by 1H NMR. The resulting solution is stirred at room temperature until the reaction is complete. The mixture is quenched with methanol and concentrated in vacuo. The residue is purified to give the title compound of Example 3232.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][C:13]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:15][C:14]1[CH:16]=[CH:17][CH:18]=[C:19]([C:20]([F:21])([F:22])[F:23])[C:13]=1[CH3:12])=[O:9]
Reactant: Cc1c(N)cccc1C(F)(F)F
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: Cc1c(NC(=O)c2cc(Cl)ccc2O)cccc1C(F)(F)F
Yield: 14.5 %

Procedure:
Using 5-chlorosalicylic acid and 2-methyl-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.