Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])=[CH:11][CH:12]=2)[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH3:24])[CH2:6][C:5]1([CH3:32])[CH3:31])(=[O:3])[CH3:2].[CH3:33][C:34]1[O:38][N:37]=[C:36]([C:39](Cl)=[O:40])[CH:35]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][C:39]([C:36]3[CH:35]=[C:34]([CH3:33])[O:38][N:37]=3)=[O:40])=[CH:11][CH:12]=2)[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH3:24])[CH2:6][C:5]1([CH3:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(NC(=O)c3ccccc3O)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(NC(=O)c3ccccc3OC(=O)c3cc(C)on3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-(2-hydroxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (15 mg) with 5-methylisoxazole-3-carbonyl chloride (10 mg) and N,N-diisopropylethylamine (30 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: FC1C=C(F)C=CC=1C(Cl)=O.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][C:41]=1[F:47].C1(C)C=CC=CC=1>C(O)C>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([NH:22][C:23]([NH:44][C:43]1[CH:45]=[CH:46][C:40]([O:39][C:30]2[C:29]3[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=3)[N:33]=[CH:32][CH:31]=2)=[C:41]([F:47])[CH:42]=1)=[S:24])=[O:21]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1ccc(F)cc1F
Agent: O=C(N=C=S)c1ccc(F)cc1F
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(F)cc4F)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
2,4-Difluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-difluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2,4-Difluoro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (66 mg, yield 81%).
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][C@H:4]([NH:23]C(=O)OC(C)(C)C)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[CH:22]=1.Cl>ClCCl.O1CCOCC1>[NH2:23][C@@H:4]([CH2:3][CH:2]([CH3:31])[CH3:1])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[CH:22]=1
Reactant: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(C)c2c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)C[C@H](N)COc1ccc2c3ccncc3c(=O)n(C)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
To a solution of (S)-tert-butyl (4-methyl-1-((6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (190 mg, 0.447 mmol) in dichloromethane (4 mL) at 0° C. was added hydrogen chloride (81 mg, 0.558 mL, 2.233 mmol) in 1,4-dioxane (4 M) dropwise and the reaction mixture was stirred at 0° C. for 30 min then warmed to room temperature and allowed to stir for 2 h. The solvents were removed under reduced pressure to afford crude product which was purified by preparative HPLC (0.1% TFA in water) to afford (S)-8-((2-amino-4-methylpentyl)oxy)-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (51 mg, 0.157 mmol, 35% yield) as a yellow solid. LC/MS (ESI) m/e 326.2 [(M+H)+, calcd for C19H24N3O2 326.2]; LC/MS retention time (method A): tR=1.21 min; HPLC retention time (method A): tR=7.39 min; HPLC retention time (method B): tR=7.40 min. 1H NMR (400 MHz, CD3OD) δ ppm 9.48 (s, 1H), 8.77 (d, J=5.77 Hz, 1H), 8.43 (d, J=8.78 Hz, 1H), 8.26 (d, J=5.77 Hz, 1H), 7.09-7.16 (m, 2H), 4.20 (dd, J=9.41, 3.89 Hz, 1H), 4.02 (dd, J=9.29, 7.03 Hz, 1H), 3.81 (s, 3H), 3.35-3.39 (m, 1H), 1.81-1.91 (m, 1H), 1.41-1.56 (m, 2H), 0.98-1.05 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:49])=[C:4]([CH:9]2[O:14][C:13](=[O:15])[N:12]([C@@H:16]3[C:32]4=[N:33][C:29](=[CH:30][N:31]4COCC[Si](C)(C)C)[C:28]4[C:23](=[CH:24][C:25]([NH:42][C:43](=[O:46])[O:44][CH3:45])=[CH:26][CH:27]=4)[NH:22][C:21](=[O:47])[C@H:20]([CH3:48])[CH2:19][CH2:18][CH2:17]3)[CH2:11][CH2:10]2)[C:5]([F:8])=[CH:6][CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[Cl-].[Na+]>O1CCOCC1.CN(C1C=CN=CC=1)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:49])=[C:4]([C@@H:9]2[O:14][C:13](=[O:15])[N:12]([C@@H:16]3[C:32]4=[N:33][C:29](=[CH:30][NH:31]4)[C:28]4[C:23](=[CH:24][C:25]([NH:42][C:43](=[O:46])[O:44][CH3:45])=[CH:26][CH:27]=4)[NH:22][C:21](=[O:47])[C@H:20]([CH3:48])[CH2:19][CH2:18][CH2:17]3)[CH2:11][CH2:10]2)[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: COC(=O)Nc1ccc2c(c1)NC(=O)[C@H](C)CCC[C@H](N1CCC(c3c(F)ccc(Cl)c3F)OC1=O)c1nc-2cn1COCC[Si](C)(C)C
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)Nc1ccc2c(c1)NC(=O)[C@H](C)CCC[C@H](N1CC[C@H](c3c(F)ccc(Cl)c3F)OC1=O)c1nc-2c[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
Methyl N-[(10R,14S)-14-[6-(3-chloro-2,6-difluorophenyl)-2-oxo-1,3-oxazinan-3-yl]-10-methyl-9-oxo-16-{[2-(trimethylsilyl)ethoxy]methyl}-8,16,18-triazatricyclo[13.2.1.02,7]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]carbamate: To a solution of 10G (26 mg, 0.038 mmol) in dioxane (2 mL) was added CDI (60.9 mg, 0.376 mmol), TEA (0.262 mL, 1.878 mmol), DMAP (7.4 mg, 0.061 mmol) and sodium chloride (10.97 mg, 0.188 mmol). The reaction mixture was stirred at rt for 15 min. After 15 min, the reaction mixture was heated at 60° C. for 15 h. Aliquot LCMS shows the reaction mixture still contained the starting material and so the reaction mixture was heated at 70° C. for another 8 h. The reaction mixture was then cooled down to rt and diluted with EtOAc. The EtOAc layers were washed with water followed by brine and dried over MgSO4. The organic layers were concentrated and purified by silica gel chromatography. Desired fractions were pooled together and concentrated to yield the desired product (15 mg, 55%) as white solid product. MS (ESI) m/z: 718.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][N:5]=1.Br[CH2:14][CH2:15][CH3:16]>C1COCC1.O>[I:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:14][CH2:15][CH3:16])[N:5]=1
Reactant: Ic1n[nH]c2ccccc12
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCn1nc(I)c2ccccc21
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
NaH (60%, 197 mg, 4.92 mmol) was added to a solution of 3-iodoindazole (1.0 g, 4.1 mmol) in THF (20 mL) at 0° C., and the reaction stirred further for 30 min. Bromopropane (605 mg, 4.9 mmol) was added to the reaction at 0° C. The solution was heated to reflux and stirred overnight. It was then cooled, diluted with water, extracted with EtOAc (3×30 mL), and the organics were washed with brine, dried (Na2SO4), and concentrated. Purification by silica gel chromatography (10%-30% EtOAc/hexanes) gave 650 mg (56%) of the title compound as a yellow solid. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 0.93 (3H, t, J=7.2 Hz), 1.93-1.98 (2H, m), 4.35 (2H, t, J=7.2 Hz), 7.20 (1H, t, J=7.6 Hz), 7.36-7.49 (3H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH2:27]([S:29]([CH2:32][CH2:33][NH:34][C@@H:35]([C:37]1[N:46]([C:47]2[CH:52]=[CH:51][C:50]([O:53][CH2:54][C:55]([F:58])([F:57])[F:56])=[CH:49][CH:48]=2)[C:45](=[O:59])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=1)[CH3:36])(=[O:31])=[O:30])[CH3:28].C(N(CC)CC)C>ClCCl>[CH2:27]([S:29]([CH2:32][CH2:33][N:34]([C@@H:35]([C:37]1[N:46]([C:47]2[CH:48]=[CH:49][C:50]([O:53][CH2:54][C:55]([F:58])([F:57])[F:56])=[CH:51][CH:52]=2)[C:45](=[O:59])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=1)[CH3:36])[C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:12]([F:15])([F:14])[F:13])[CH:4]=1)(=[O:30])=[O:31])[CH3:28]
Reactant: CCS(=O)(=O)CCN[C@H](C)c1nc2ccccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)CCN(C(=O)Cc1ccc(F)c(C(F)(F)F)c1)[C@H](C)c1nc2ccccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86.6 %

Procedure:
4-Fluoro-3-trifluoromethylphenylacetic acid (164 mg, 0.74 mmol) was dissolved in dichloromethane and cooled to 0° C. Oxalyl chloride (64 μL, 0.74 mmol) was added, then after 5 min., N,N-dimethylformamide (5.7 μL, 0.07 mmol) was added. The reaction stirred at 0° C. for 30 min. and room temperature for 1 h. The solution was added slowly to a mixture of 12 (210 mg, 0.43 mmol) and triethylamine (182 μL, 1.30 mmol) in dichloromethane at −78° C. This stirred for 30 min., then was washed with saturated aqueous sodium bicarbonate and brine. It was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purified by reverse-phase HPLC to yield 256 mg of a colorless solid, 11. MS (ESI+): m/z=715.2 [M+H]+. 1H NMR (500 MHz; CDCl3; T=298 K): δ 9.10-8.95 (m, 1H), 8.66-8.58 (m, 1H), 7.78-7.57 (m, 1H), 7.47-7.36 (m, 3H), 7.24 (m, 1H), 7.13 (m, 3H), 5.03 (q, 1H, J=7.4 Hz), 4.43 (quint, 2H, J=8.0 Hz), 3.77 (s, 1H), 3.71 (m, 1H), 3.62-3.49 (m, 2H), 3.23-3.09 (m, 3H), 2.81 (d, 1H, J=12.9 Hz), 2.62-2.41 (m, 1H), 2.14-1.90 (m, 2H), 1.68 (broad s, 2H), 1.64-1.45 (m, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][NH:13][C:14]([NH:16][NH2:17])=[O:15].C(=O)(O)[O-].[Na+].C(=O)=O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][NH:13][C:14]([NH:16][NH2:17])=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NNC(=O)NN
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CCO
Product: NNC(=O)NNS(=O)(=O)c1ccc(Cl)cc1

Procedure:
211 (1.0 mole) p-chlorobenzenesulfonyl chloride was added to a suspension of 45 g (0.5 mole) carbohydrazide and 100 g sodium bicarbonate in 1000 ml ethanol in a 3 liter reaction flask. The mixture was stirred and heated gradually to gentle reflux (80° C) as carbon dioxide was evolved. Heating was continued until CO2 no longer evolved (3hours). The mix was cooled to 20 C and filtered. The mixture of product and sodium chloride was dried at 60° C. Yield = 227 g. The solid mixture was suspended in 2000 ml water, stirred to dissolve the sodium chloride, and then the insoluble product was filtered, washed and dried. Yield = 129 g, m.p. 239-240° C (dec.)
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([Cl:15])=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:16]#[N:17])=[CH:4][N:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+].[CH3:70][C@H:71]1[C@H:80]([NH2:81])[CH2:79][CH2:78][C:73]2([O:77][CH2:76][CH2:75][O:74]2)[CH2:72]1>CCOC(C)=O.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].COCCOC>[Cl:15][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[C:2]([NH:81][C@@H:80]4[CH2:79][CH2:78][C:73]5([O:74][CH2:75][CH2:76][O:77]5)[CH2:72][C@H:71]4[CH3:70])=[N:3][CH:4]=[C:5]([C:16]#[N:17])[C:6]=3[NH:7][C:8]=2[CH:9]=1
Reactant: C[C@@H]1CC2(CC[C@H]1N)OCCO2
Reactant: N#Cc1cnc(Cl)c2c1[nH]c1cc(Cl)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: C[C@@H]1CC2(CC[C@H]1Nc1ncc(C#N)c3[nH]c4cc(Cl)ccc4c13)OCCO2
Temperature: 85 °C

Procedure:
A flask containing 1,7-dichloro-5H-pyrido[4,3-b]indole-4-carbonitrile (Example 1 Step 4, 140 mg, 0.53 mmol), BINAP (50 mg, 0.08 mmol), Pd2(dba)3 (24 mg, 0.03 mmol), and NaOtBu (164 mg, 1.71 mmol) was evacuated and refilled with nitrogen (×3). Degassed DME (10 mL) and (7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decan-8-amine (183 mg, 1.07 mmol) were added to the mixture. The reaction mixture was heated to 85° C. overnight, cooled to room temperature, diluted with EtOAc, and washed with water and brine. The organic layer was dried (sodium sulfate), concentrated, and purified by flash chromatography to afford the title compound. LRMS (APCI) calc'd for (C21H21ClN4O2) [M+H]+, 397.1. found 397.0.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[CH3:33][NH:34][CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>>[CH3:33][N:34]([CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)[C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([C:11]2[O:12][C:8]([CH3:7])=[C:9]([CH2:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[N:10]=2)=[CH:14][CH:15]=1
Reactant: CNCc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)N(C)Cc4cccnc4)cc3)oc2C)cc1
Yield: 67.7 %

Procedure:
Method E. Reaction of oxalyl chloride (132 λL, 1.5 mmol) and benzoic acid 4 (376 mg, 1.0 mmol) with subsequent coupling to N-methyl-N-(3-pyridinylmethyl)amine (51 mg, 1.1 mmol) gave benzamide 11 (322 mg, 67%) as a white powder: mp (EtOAc) 77-80° C.; 1H NMR δ 8.59 (br s, 1 H, H-2′), 8.52 (br d, J=4.5Hz, 1 H, H-6′), 7.87 (br d, J=7.6Hz, 2 H, H-2, H-6), 7.77 (br s, 1 H, H-4′), 7.66 (br d, J=8.2Hz, 2 H, H-2″, H-6″), 7.58 (br s, 2 H, H-3, H-5), 7.38-7.44 (m, 3 H, H-5′, H-3″, H-5″), 4.71 (br s, 2 H, CH2N), 4.62 (s, 2 H, CH2SO2), 2.90 (s, 3 H, NCH3), 2.39 (s, 3H, CH3), 2.11 (s, 3 H, CH3); 13C NMR δ 169.7, 158.0, 149.7, 149.1, 148.6, 144.5, 137.6, 135.6, 135.5, 132.9, 129.6 (2), 128.2 (2), 127.8 (2), 127.4, 125.9, 125.5 (2), 123.7, 52.9, 47.8, 37.0, 21.0, 9.6; MS m/z 476.7 (MH+, 100%). Anal. calcd for C26H25N3O4S: C, 65.67; H, 5.30; N, 8.84. Found: C, 65.46; H, 5.37; N, 8.67%.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:21]([O:28][C:29](=[O:36])[C:30]([CH2:32][CH2:33][O:34][CH3:35])=[CH2:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>O1CCCC1>[CH2:21]([O:28][C:29](=[O:36])[CH:30]([CH2:32][CH2:33][O:34][CH3:35])[CH2:31][C:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C=C(CCOC)C(=O)OCc1ccccc1
Reactant: O=C(O)C1CCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COCCC(CC1(C(=O)O)CCCC1)C(=O)OCc1ccccc1
Temperature: -73 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
n-Butyl lithium (2.5M in hexane, 18.16 ml, 45.4 mmole) was added dropwise under nitrogen to a stirred solution of diisopropylamine (4.59, 45.4 mmole) in dry tetrahydrofuran (20 ml) keeping the temperature between -40° and -20° C. Stirring was continued at -20° C. for half an hour and cyclopentane carboxylic acid (2.59 g, 22.7 mmole) in dry tetrahydrofuran (10 ml) was added over five minutes, keeping the temperature at -20° C. The mixture was allowed to attain room temperature over one and a half hours, stirred for a further one hour and then cooled to -73° C. 2-(2-Methoxyethyl)propenoic acid benzyl ester (5.0 g, 22.7 mmole) in dry tetrahydrofuran (10 ml) was added dropwise keeping the temperature below -70° C. After two hours at -77° C., the mixture was quickly warmed to 0° C., acidified with 5N hydrochloric acid, and extracted with hexane. The hexane extract was washed (×7) with a mixture of water and saturated aqueous sodium bicarbonate (1:1 by volume) to remove unreacted cyclopentane carboxylic acid. The extract was washed with water, dried (MgSO4) and evaporated under vacuum to give a pale yellow oil (6.3 g) which was chromatographed on silica gel (600 g). Gradient elution starting with a mixture of ethyl acetate and hexane (3:7 by volume) changing to neat ethyl acetate gave the required product as a colourless oil (4.0 g, 53%). Found: C,68.39 ; H,7.99. C19H26O5 requires C,68.24; H,7.84%. On prolonged standing the material solidified and when recrystallized from hexane gave a white solid, m.p. 41°-2° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]([NH2:19])[CH:12]=[CH:13][C:14]=2[C:15]([F:18])([F:17])[F:16])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=1.C(N1CCC(OC2C=C(C(F)(F)F)C=C(NC(C3C(Cl)=NC=CC=3)=O)C=2)CC1)(OC(C)(C)C)=O>>[Cl:20][C:21]1[N:22]=[CH:23][CH:24]=[CH:25][C:26]=1[C:27]([NH:19][C:11]1[CH:12]=[CH:13][C:14]([C:15]([F:17])([F:18])[F:16])=[C:9]([O:8][CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:10]=1)=[O:28]
Reactant: Nc1ccc(C(F)(F)F)c(OCCN2CCCC2)c1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: CC(C)(C)OC(=O)N1CCC(Oc2cc(NC(=O)c3cccnc3Cl)cc(C(F)(F)F)c2)CC1
Product: O=C(Nc1ccc(C(F)(F)F)c(OCCN2CCCC2)c1)c1cccnc1Cl

Procedure:
2-Chloro-N-[3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenyl]-nicotinamide was prepared from 3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenylamine and 2-chloropyridine-3-carbonyl chloride by a procedure similar to that described in the preparation of 1-Boc-4-{3-[(2-chloro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9]2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:40]([O:44][CH2:45][CH3:46])(=[O:43])[CH:41]=[CH2:42].C(N(CCCC)CCCC)CCC>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:45]([O:44][C:40](=[O:43])[CH:41]=[CH:42][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9]2)=[CH:4][CH:3]=1)[CH3:46]
Reactant: O=C(N1CCc2ccc(Br)cc2C1)C(F)(F)F
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)C=Cc1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Reaction time: 8 h

Procedure:
A solution of 7-bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (2.6 g, Reference Example 7), tri-o-tolylphosphine (0.37 g), palladium (II) acetate, ethyl acrylate (1.6 mL) and tributylamine (8.01 mL) in dry dimethylformamide (25 mL), under argon, was heated at 155° C. for 3 hours then stood at room temperature overnight. The reaction mixture was evaporated and the resulting black oil was partitioned between ethyl acetate (200 mL) and hydrochloric acid (200 mL, 2M). The organic phase was washed with hydrochloric acid (200 mL, 2M), then with water (100 mL), then with brine (100 mL), then dried over magnesium sulfate and then evaporated. The residual yellow oil was subjected to flash chromatography on silica under gradient elution conditions with a mixture of ethyl acetate and pentane (from 3:97 to 10:90, v/v) to give the title compound. LC-MS: RT=4.05 minutes; no molecular ion observed.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]([C:10]1([CH2:15][C:16](OC)=[O:17])[O:14][CH2:13][CH2:12][O:11]1)([CH3:9])[CH3:8]>C1COCC1>[CH:7]([C:10]1([CH2:15][CH2:16][OH:17])[O:14][CH2:13][CH2:12][O:11]1)([CH3:9])[CH3:8]
Reactant: COC(=O)CC1(C(C)C)OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C1(CCO)OCCO1
Temperature: 0 °C
Yield: 66.5 %

Procedure:
In a flame-dried three neck flask equipped with an addition funnel, magnetic stirring bar, rubber septum, and a nitrogen inlet, was placed LiAlH4 (3.12 g, 82.1 mmol) and THF (700 mL). After being cooled at 0° C., a solution of methyl 2-(2-isopropyl-1,3-dioxolan-2-yl)acetate (12 g, 63.8 mmol) in THF (160 mL) was added dropwise with stirring. The mixture was warmed to rt, and stirred for 24 hours. The reaction was quenched by adding water (5 mL), 15% aqueous NaOH (10 mL), and water (5 mL) slowly. The organic layer was separated, and the residue was extracted with EtOAc (3×100 mL). The combined organic phase was dried over Na2SO4, and concentrated to afford the crude product, which was purified by column chromatography to give 2-(2-isopropyl-1,3-dioxolan-2-yl)-ethanol (6.8 g, 67%). 1H NMR (CDCl3): δ 0.90 (d, J=6.8 Hz, 6H), 1.87-1.96 (m, 3H), 2.81 (br, 1H), 3.69-3.72 (m, 2H), 3.92-4.01 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([CH3:14])[N:6]=[C:5]([C:15]2[CH:16]=[N:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)[CH:4]=1.C1C(=O)N([Br:32])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)(Cl)Cl>[Br:32][CH2:14][C:7]1[N:6]=[C:5]([C:15]2[CH:16]=[N:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(OC)cc(-c2cnc(OC)c(OC)c2)nc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(OC)cc(-c2cnc(OC)c(OC)c2)nc1CBr
Temperature: 65 °C
Reaction time: 24 h

Procedure:
As shown in step 9-iv of Scheme 9, Compound 2032 (200 mg, 0.628 mmol) and NBS (112 mg, 0.63 mmol) were added to 15 mL of CCl4 and the solution purged with nitrogen for 5 minutes. Benzoyl peroxide (20 mole %) was added and the reaction mixture heated at 65° C. under nitrogen for 16 hours. An additional equivalent of NBS and 0.3 equivalents of benzoyl peroxide were added and heating continued for an additional hour. Potassium carbonate (1.0 g) was added as an acid scavenger and heating continued for an additional 24 hours. The reaction mixture was cooled and filtered through a cotton plug and the volatiles removed under reduced pressure. The residue was taken up in DCM and passed through a plug of silica gel, which was eluted with additional DCM. Elution with EtOAc recovered crude product, which was further purified by silica gel chromatography (DCM—1:1 EtOAc/DCM to give ethyl 6-(bromomethyl)-4,5′,6′-trimethoxy-2,3′-bipyridine-5-carboxylate (Compound 2033, 87 mg of white solid: ESMS (M+1) 397/399.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]2=[N:4][CH:3]=1.[N:12]1([C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=2)[CH:16]=[CH:15][CH:14]=[N:13]1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:11][C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([N:12]4[CH:16]=[CH:15][CH:14]=[N:13]4)[CH:22]=3)=[CH:3][N:4]=[C:5]2[CH:10]=1
Reactant: Clc1ccn2c(Br)cnc2c1
Reactant: OB(O)c1cccc(-n2cccn2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Clc1ccn2c(-c3cccc(-n4cccn4)c3)cnc2c1

Procedure:
3-Bromo-7-chloro-imidazo-[1,2-a]-pyridine (1 eq, 2.59 mmol, 600 mg) and 3-(1H-pyrazolyl)-phenylboronic acid (1.2 eq, 1.04 mmol, 195 mg) are dissolved in DME (5 ml) and water (1.5 ml) and Na2CO3 (0.65 eq, 1.68 mmol, 209 mg) is added. PdCl2(PPh3)2 (0.04 eq, 0.104 mmol, 72.8 mg) is added and the reaction mixture is heated using microwave radiation at 120° C. for 10 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield 7-chloro-3-(3-pyrazol-1-yl -phenyl)-imidazo[1,2-a]pyridine as a brown solid; [M+H]+=295