Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[NH2:3][C:4]1[C:9]2=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:33]=4[F:42])=[O:30])=[C:24]([F:43])[CH:23]=3)[C:11]([CH2:19][O:20][CH3:21])=[C:12]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:8]2[N:7]=[CH:6][N:5]=1.ClCCCl.[CH3:48][N:49]=[C:50]=[O:51]>O1CCCC1>[NH2:3][C:4]1[C:9]2=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[NH:31][C:32]4[CH:37]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:35]=[CH:34][C:33]=4[F:42])=[C:24]([F:43])[CH:23]=3)[C:11]([CH2:19][O:20][CH3:21])=[C:12]([CH:13]3[CH2:18][CH2:17][N:16]([C:50]([NH:49][CH3:48])=[O:51])[CH2:15][CH2:14]3)[N:8]2[N:7]=[CH:6][N:5]=1
Reactant: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1C1CCNCC1
Reactant: CN=C=O
Agent: N#N
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CNC(=O)N1CCC(c2c(COC)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c3c(N)ncnn23)CC1
Temperature: 0 °C
Yield: 32.8 %

Procedure:
To a flask charged with N2 was added 1-{4-[4-amino-6-(methoxymethyl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoro-methyl)phenyl]urea (Example 149) (30 mg, 0.052 mmol, 1.0 eq) and 1,2-dichloroethane (2 mL). Tetrahydrofuran was added dropwise until the reaction mixture was a complete solution. The solution was cooled to 0° C. and methyl isocyanate (5.2 μl, 1 eq) is added. The reaction mixture was allowed to gradually warm to rt over 17 hours. The reaction was concentrated and the residue dissolved in EtOAc. The organic phase was washed with saturated sodium bicarbonate solution (2×), brine (1×), separated and the organic layer dried (Na2SO4). The organic layer was filtered, concentrated and purified via flash column chromatography (tetrahydrofuran). The purified fractions were collected, concentrated, stirred in hexanes and filtered. The filtrate was placed under vacuum overnight to yield the title compound (18 mg, 32.8% yield). 1H-NMR (DMSO-d6) δ 9.44 (s, 1H), 9.29 (s, 1H), 8.65 (d, J=7.2 Hz, 1H), 8.29 (t, J=8.4 Hz, 1H), 7.88 (s, 1H), 7.51 (t, J=9.9 Hz, 1H), 7.41 (m, 1H), 7.2 (dd, J=12.1, 1.9 Hz, 1H), 7.1 (dd, J=8.5, 1.4 Hz, 1H), 4.22 (s, 2H), 4.06 (m, 2H), 3.42 (m, 1H), 3.15 (s, 3H), 2.73 (t, J=12.4 Hz, 2H), 2.57 (d, J=4.3 Hz, 3H) 2.17 (m, 2H), 1.59 (m, 2H); MS [M+H]+=633; LCMS RT=2.97 min.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][S:4]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([F:33])=[C:12]([C:15]([C:17]2[C:21]3[CH:22]=[C:23]([C:26]4[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=4)[CH:24]=[N:25][C:20]=3[NH:19][CH:18]=2)=[O:16])[C:13]=1[F:14])(=[O:6])=[O:5].[CH2:34]([S:36]([OH:39])(=[O:38])=[O:37])[CH3:35]>CC(C)=O>[CH3:1][CH2:2][CH2:3][S:4]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([F:33])=[C:12]([C:15]([C:17]2[C:21]3[CH:22]=[C:23]([C:26]4[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=4)[CH:24]=[N:25][C:20]=3[NH:19][CH:18]=2)=[O:16])[C:13]=1[F:14])(=[O:6])=[O:5].[S:36]([CH2:34][CH3:35])([O-:39])(=[O:38])=[O:37]
Reactant: CCS(=O)(=O)O
Agent: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Solvent: CC(C)=O
Product: CCS(=O)(=O)[O-]
Temperature: 2.5 °C

Procedure:
Vemurafenib free-base (0.5 g) was suspended in 10 mL acetone at 30-35° C. Ethanesulfonic acid (0.11 g) was added at 30-35° C. and the mixture was cooled to 0-5° C. within 30 minutes. The resulting precipitate was isolated by filtration and washed with acetone (2 mL) The product was dried under reduced pressure (20 mbar) at room temperature to yield 0.57 g of Vemurafenib esylate as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:11]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:12]=[C:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]3)[CH:5]=[CH:6][C:7]=1[F:8].[CH:26]1([N:32]=[C:33]=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.CCN(CC)CC>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:10]2[N:11]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[N:12]=[C:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]3)[C:33]([NH:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:34])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(Nc2c3ccccc3nn2-c2ccc(Cl)cc2)cc1Cl
Reactant: O=C=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(NC1CCCCC1)N(c1ccc(F)c(Cl)c1)c1c2ccccc2nn1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 1.2, (3-chloro-4-fluoro-phenyl)-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in 1,2-dichloroethane in the presence of Et3N (3 eq.) for 4 d under reflux conditions to give the title compound as yellow oil. MS: m/e=496.9 [M+H+].
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:23][C:24]1[C:29]([C:30]#[N:31])=[CH:28][CH:27]=[CH:26][N:25]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C(Cl)=CC=C(Cl)C=1>[Cl:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:12])[C:5]=1[C:4]1[N:31]=[C:30]([C:29]2[C:24]([Cl:23])=[N:25][CH:26]=[CH:27][CH:28]=2)[N:2]([CH3:1])[N:3]=1
Reactant: CN(N=C(Cl)c1c(Cl)cccc1Cl)S(=O)(=O)c1ccccc1
Reactant: N#Cc1cccnc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccc(Cl)cc1
Product: Cn1nc(-c2c(Cl)cccc2Cl)nc1-c1cccnc1Cl
Yield: 37.3 %

Procedure:
In 50 ml of dichlorobenzene were dissolved 5.7 g of N-methyl-N-phenylsulfonyl-2,6-dichloro-benzohydrazonoyl chloride and 2.3 g of 2-chloro-3-cyanopyridine, to which was added 2.2 g of anhydrous aluminum chloride at room temperature with stirring. The resulting solution was raised to 120°-140° C. in an oil bath and stirred for 4 hours. After the completion of the reaction, the reaction solution was washed with a diluted alkali solution and further with a diluted hydrochloric acid solution. After the washing with water, the organic layer was dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The resulting concentrate was subjected to a chromatography of silica gel (trade mark: Wakogel C-200) using a mixed solution of hexane and ethyl acetate as a developing solvent to obtain 1.9 g (yield: 37.3%) of a desired light brown granular crystal (melting point: 133.0°-135.5° C.).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)(Cl)Cl.O>[Cl:22][CH2:23][C:24]([NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:25]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1Nc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccccc1Nc1ccccc1
Reaction time: 0.5 h
Yield: 106 %

Procedure:
In 100 ml of chloroform, 10.4 g of N-phenyl-1,2-benzenediamine and 12.1 g of triethylamine were dissolved, and the mixture was cooled to -5° C. to 0° C., and then 13.6 g of chloroacetyl chloride was added dropwise thereto, holding the temperature of the mixture at not higher than 20° C. The reaction nearly went to completion when the addition was finished. After stirring for further 30 minutes, the reaction mixture was diluted with 50 ml of water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The resulting solid was recrystallized from ethanol to give 15.6 g of crystals having a melting point of 112° C. to 113° C. Yield: 60.0%.
Reaction SMILES: CC(C)([O-])C.[Na+].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.[CH2:53]([O:55][C:56]([C:58]1[C:67](=[O:68])[C:66]2[C:61](=[CH:62][CH:63]=[C:64](I)[CH:65]=2)[N:60]([CH2:70][CH3:71])[CH:59]=1)=[O:57])[CH3:54].[C:72](=[NH:85])([C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH2:53]([O:55][C:56]([C:58]1[C:67](=[O:68])[C:66]2[C:61](=[CH:62][CH:63]=[C:64]([N:85]=[C:72]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[C:79]3[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=3)[CH:65]=2)[N:60]([CH2:70][CH3:71])[CH:59]=1)=[O:57])[CH3:54]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cn(CC)c2ccc(I)cc2c1=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(CC)c2ccc(N=C(c3ccccc3)c3ccccc3)cc2c1=O
Temperature: 80 °C
Yield: 90 %

Procedure:
A Pyrex tube was charged with sodium tert-butoxide (1.4 mmol), Pd2(dba)3 (0.00125 mmol), and BINAP (0.00375 mmol). The Pyrex tube was fitted with a septum and after the air atmosphere was replaced with argon, toluene (4 mL), 1-ethyl-6-iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (1.0 mmol), and benzophenone imine (1.2 mmol) were added by syringe. The reaction was sealed and heated to 80° C. with stirring until starting material was consumed as judged by GC analysis. The reaction mixture was cooled to room temperature, diluted with ether (40 mL), filtered, and concentrated. The crude reaction mixture was then recrystallized from MeOH to furnish the desired product in 90% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:18])[NH:9][N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.I[CH2:20][CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:18][CH2:20][CH3:21])=[N:9][N:10]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2cnc(Cl)cc21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nn(C(=O)OC(C)(C)C)c2cc(Cl)ncc12

Procedure:
tert-Butyl 6-chloro-3-oxo-2,3-dihydro-1H-pyrazolo[4,3-c]pyridine-1-carboxylate (1.19 g, 4.41 mmol), iodoethane (0.715 mL, 8.85 mmol), and cesium carbonate (4.36 g, 13.38 mmol) were stirred in DMF (15 mL) at room temperature for 16 h. Water was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (6-50% EtOAc-hexanes) gave tert-butyl 6-chloro-3-ethoxy-1H-pyrazolo[4,3-c]pyridine-1-carboxylate. MS ESI calc'd. For C13H16ClN3O3 [M+1]+ 298. found 298.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[NH:25]1[CH2:29][CH2:28][CH:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH2:26]1>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:25]3[CH2:29][CH2:28][CH:27]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[CH2:26]3)=[O:20])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: C1CC(N2CCOCC2)CN1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCC(N4CCOCC4)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 4-(pyrrolidin-3-yl)morpholine to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.84 (m, 1H) 2.04-2.20 (m, 1H) 2.29-2.39 (m, 1H) 2.39-2.48 (m, 5H) 2.77-2.97 (m, 1H) 3.24-3.35 (m, 1H) 3.37-3.84 (m, 8H) 7.65 (dd, J=8.08, 1.52 Hz, 1H) 7.72 (s, 1H) 7.78 (d, J=7.83 Hz, 1H) 8.13 (s, 1H) 8.19 (td, J=5.49, 2.40 Hz, 1H) 8.36 (br. s., 1H) 8.65 (s, 1H) 13.03 (br. s., 1H); ESI-MS m/z [M+H]+ 459.2.
Reaction SMILES: C1(S([CH2:9][C:10]2[CH2:29][C@@H:28]3[C@:15]([CH3:32])([CH2:16][CH:17]=[C:18]4[C@H:27]3[CH2:26][CH2:25][C:24]3[C@:19]4([CH3:31])[CH2:20][CH2:21][C:22](=[O:30])[CH:23]=3)[C:11]=2[C:12](=[O:14])[CH3:13])=O)C=CC=CC=1.C[O:34]P(OC)OC.C(Cl)Cl>C1(C)C=CC=CC=1.CO>[OH:34][C@:11]1([C@:15]2([CH3:32])[C@H:28]([C@H:27]3[C:18](=[CH:17][CH2:16]2)[C@:19]2([CH3:31])[C:24](=[CH:23][C:22](=[O:30])[CH2:21][CH2:20]2)[CH2:25][CH2:26]3)[CH2:29][C:10]1=[CH2:9])[C:12](=[O:14])[CH3:13]
Reactant: COP(OC)OC
Reactant: CC(=O)C1=C(CS(=O)c2ccccc2)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]12C
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: C=C1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]2(C)[C@@]1(O)C(C)=O

Procedure:
A mixture of 16-(phenylsulfinylmethyl)pregn-4,9(11),16-triene-3,20-dione (VIA, Example 14, 100 mg) in toluene (1 ml) and methanol (0.14 ml) containing 53 μl of trimethylphosphite was heated for 16 hrs at 65° in a sealed vial. TLC showed the reaction to be complete. Methylene chloride was added, the reaction mixture washed with water, the organic phase separated, dried and concentrated under reduced pressure to give the title compound. NMR (CDCl3) 0.77, 1.35, 2.31, 5.10, 5.27, 5.57 and 5.75 δ.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH:18][C:19]2[CH:28]=[CH:27][C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:20]=2[C:29]([O:31]C)=[O:30])(=[O:17])=[O:16])[CH2:3][CH2:2]1.[CH2:33]([CH:35]([CH2:38][CH3:39])[CH:36]=O)[CH3:34].C([BH3-])#N.[Li+].[OH-]>CN(C=O)C.C(O)(=O)C>[CH2:33]([CH:35]([CH2:38][CH3:39])[CH2:36][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH:18][C:19]2[CH:28]=[CH:27][C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:20]=2[C:29]([OH:31])=[O:30])(=[O:17])=[O:16])[CH2:3][CH2:2]1)[CH3:34]
Reactant: CCC(C=O)CC
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2NCC2CCNCC2)ccc2c1CCCC2
Agent: [BH3-]C#N
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCC(CC)CN1CCC(CNc2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)CCCC3)CC1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 20.5 %

Procedure:
A mixture of Example 557B (0.026 g, 0.06 mmol) in DMF (2.5 mL) was treated with acetic acid (0.01 mL) and 2-ethylbutanal (0.025 g, 0.06 mmol). The mixture was shaken at 50° C. for 20 minutes, treated with macroporous polystyrene bound cyanoborohydride resin (85 mg, 0.2 mmol), shaken at 70° C. for 5 hours, and filtered. The filtrate was concentrated, dissolved in 1 mL 2:1 dioxane water, treated with LiOH (25 mg, 0.6 mmol) and heated to 160° C. for 30 minutes in a microwave reactor. The reaction mixture was concentrated and the residues purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product (6.5 mg). MS (ESI(+)) m/e 528 (M+H)+; (ESI(−)) m/e 526 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.51 (dd, 1H), 7.38 (dt, 1H), 6.94 (d, 1H), 6.84 (d, 1H), 6.62 (m, 2H), 6.07 (m, 1H), 3.13 (m, 2H), 2.95-2.80, (m, 4H), 2.66 (m, 4H), 1.83 (m, 3H), 1.66 (m, 5H), 1.34 (m, 6H), 0.85 (t, 6H).
Reaction SMILES: Cl[CH2:2][C:3]([Cl:5])=[O:4].[CH2:6]([NH:13][C@H:14]([CH3:17])[CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:6]([NH:13][C@H:14]([CH3:17])[CH2:15][O:16][CH2:2][C:3]([Cl:5])=[O:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[C@H](CO)NCc1ccccc1
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[C@H](COCC(=O)Cl)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Chloroacetyl chloride (11.6 mL, 120 mmol) was added dropwise at 0° C. to a solution of (R)-2-(benzylamino)propan-1-ol (19.9 g, 120 mmol) and triethylamine (30.5 mL) in toluene (600 mL). The cooling bath was removed and the reaction mixture was stirred at room temperature for 18 h. The reaction was concentrated under reduced pressure and the recovered solids dissolved in EtOAc (500 mL) and then washed with saturated bicarbonate (2×250 mL), H2O (250 mL) and saturated brine (250 mL). The organic phase was then dried (Na2SO4), filtered and concentrated to afford (R)-2-(2-(benzylamino)propoxy)acetyl chloride: MS consistent.
Reaction SMILES: [CH2:1]([Sn:4](Cl)([CH3:6])[CH3:5])[CH:2]=[CH2:3].C(CC[Mg]I)(C(C(C(C(C(F)(F)F)(F)F)(F)F)(F)F)(F)F)(F)F.[C:31]([CH2:50][CH2:51]I)([C:34]([C:37]([C:40]([C:43]([C:46]([F:49])([F:48])[F:47])([F:45])[F:44])([F:42])[F:41])([F:39])[F:38])([F:36])[F:35])([F:33])[F:32].[Mg]>>[CH2:1]([Sn:4]([CH3:6])([CH3:5])[CH2:51][CH2:50][C:31]([F:32])([F:33])[C:34]([F:36])([F:35])[C:37]([F:38])([F:39])[C:40]([F:42])([F:41])[C:43]([F:44])([F:45])[C:46]([F:47])([F:48])[F:49])[CH:2]=[CH2:3]
Reactant: C=CC[Sn](C)(C)Cl
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Agent: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CC[Mg]I
Agent: [Mg]
Product: C=CC[Sn](C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 46.9 %

Procedure:
Freshly prepared allyldimethyltin chloride (2.86 g, 12.7 mmol) was added dropwise to the Grignard reagent of C6F13CH2CH2MgI, which was prepared from C6F13CH2CH2I (6.0 g, 12.7 mmol) and magnesium powder (0.37 g, 15.2 mmol). The reaction mixture was refluxed overnight (16 h) before quenching with 1N HCl. The crude product was purified by vacuum distillation (112° C./water pump) to give pure 2a as a colorless oil (3.20 g, 35%). 1H NMR (CDCl3) δ 5.95-5.86 (m, 1H), 4.85-4.80 (dd, J=16.8, 1.4 Hz, 1H), 4.73-4.69 (dd, J=11.8, 1.8 Hz, 1H), 2.30-2.12 (m, 2H), 1.83 (d, J=8.5 Hz, 2H), 1.00-0.92 (m, 2H), 0.15 (s, JSn-H=26.3 Hz, 6H); 13C NMR (CDCl3) δ 136.8, 121.8-107.2 (m), 27.9 (t), 16.9, −1.8, −12.2; 19F NMR (CDCl3) δ −81.3 (3F), −117.2 (2F), −122.5 (2F), −123.4 (2F), −123.9 (2F), −126.7 (2F); 119Sn NMR (C6D6): δ −1.4; HRMS: calc. 496.9597 (M+-Me), found: 496.9583. IR (thin film): 1626 cm−1.
Reaction SMILES: [CH:1]1([C:9](=[O:12])[CH2:10][CH3:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.[BH4-].[Na+]>C(O)C>[CH:1]1([CH:9]([OH:12])[CH2:10][CH3:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: CCC(=O)C1CC=CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCC(O)C1CC=CCCCC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 82.2 %

Procedure:
1-cyclooct-3-enylpropan-1-one (84.0 g, 0.5 mol) was slowly added to a solution of sodium borohydride (11.9 g, 0.3 mol) in ethanol (330 ml) at 0° C. (ice bath), and stirring was continued at room temperature for 4 h. The reaction mixture was poured into ice-cold 2N HCl (500 ml) and extracted with MTBE (2×200 ml). After washing with brine (3×200 ml), drying (MgSO4) and evaporation of solvents, the yellowish oily residue (86.6 g) was distilled over a 20 cm Widmer column (66-80° C./0.7-0.8 mbar) to give 69.2 g of 1-cyclooct-3-enylpropan-1-ol (colourless oil, 68% yield). It consisted of >90% of a 1:1 mixture of two diastereomeric racemates of 1-cyclooct-3-enylpropan-1-ol. An analytical sample was purified by flash chromatography (hexane/MTBE 3:1).
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([NH:12][C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:23])=[O:11])[CH2:6][CH2:5]1.[Cl:32][C:33]1[N:38]=[CH:37][CH:36]=[CH:35][N:34]=1>>[ClH:31].[ClH:32].[N:34]1[CH:35]=[CH:36][CH:37]=[N:38][C:33]=1[NH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([NH:12][C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:23])=[O:11])[CH2:6][CH2:5]1
Reactant: Clc1ncccn1
Reactant: N[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Agent: Cl
Product: O=C(Nc1ccc(Cl)cn1)c1oc2ccccc2c1NC(=O)[C@H]1CC[C@H](Nc2ncccn2)CC1

Procedure:
Trans-3-[4-aminocyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide dihydrochloride (350 mg) obtained in Example 219 and 2-chloropyrimidine (99 mg) are treated in a similar manner to Example 373 to give the title compound (65 mg).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:9]([CH3:20])[CH:8]=1.S(=O)=O.[S:24](Cl)([Cl:27])(=[O:26])=[O:25]>O1CCCC1.CCCCCC>[CH3:13][C:11]1[CH:12]=[C:7]([S:24]([Cl:27])(=[O:26])=[O:25])[CH:8]=[C:9]([CH3:20])[C:10]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(Br)cc(C)c1-c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Agent: O=S=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)Cl)cc(C)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
2.5 M n-butyllithium, in tetrahydrofuran, (0.46 ml, 1.17 mmol, 1.1 equiv.) was added dropwise to a solution of 4-bromo-2,6-dimethylbiphenyl (0.28 g, 1.06 mmol, 1.0 equiv.) in dry tetrahydrofuran (5 ml), under nitrogen at −78° C. and the mixture stirred for 15 minutes. This solution was added, by canula, to a solution of sulfur dioxide (3 mL) and tetrahydrofuran (3 ml) under nitrogen at −78° C. The solution was allowed to warm to room temperature while stirring for 16 hours. The solvent was evaporated under reduced pressure and the residue suspended in hexane (4 ml) and dichloromethane (4 ml). The suspension was cooled to 0° C., a solution of sulfuryl chloride (0.14 g, 1.06 mmol, 1.0 equiv.) in hexane (2 ml) was added and the mixture was allowed to warm to room temperature while stirring for 1.5 hours. The hexane and dichloromethane were evaporated under reduced pressure to afford crude 2,6-dimethylbiphenyl-4-sulfonyl chloride, 0.22 g (74% yield) as a red gum, this material was used in the next step without further purification.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[N:3]=1.[CH:11]([NH2:14])([CH3:13])[CH3:12]>C(#N)C>[F:10][C:4]1[C:5]([F:9])=[CH:6][C:7]([F:8])=[C:2]([NH:14][CH:11]([CH3:13])[CH3:12])[N:3]=1
Reactant: Fc1cc(F)c(F)nc1F
Reactant: CC(C)N
Solvent: CC#N
Product: CC(C)Nc1nc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.2 %

Procedure:
To 20 ml of acetonitrile were added 6.0 g of 2,3,5,6-tetrafluoropyridine and 6.0 g of isopropylamine, and the mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. After adding 40 ml of chloroform, the solution was washed with 50 ml of 3% aqueous solution of potassium carbonate. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 1.9 g of the title compound as a colorless oil.
Reaction SMILES: [N:1]1[C:2]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl[CH2:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[CH3:24].C(O)(=O)C(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C(C)(C)C.[Pd+2].C([O-])(=O)C(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)C=CC=CC=1>[CH3:24][C:18]1[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=1[CH2:16][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][C:2]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: Cc1ccc(C)c(CCl)c1
Reactant: CCOC(=O)c1cn2ccccc2n1
Agent: [Pd+2]
Agent: CC(C)(C)C(=O)O
Agent: CC(C)(C)C(=O)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc2ccccn2c1Cc1cc(C)ccc1C
Temperature: 110 °C
Yield: 54 %

Procedure:
A mixture of ethyl imidazo[1,2-a]pyridine-2-carboxylate (0.48 g, 2.5 mmoL), 2-(chloromethyl)-1,4-dimethylbenzene (0.6 mL, 3.75 mmol), palladium pivalate (15 mg, 0.05 mmol), 2-(diphenylphosphino)-2′-(N,N-dimethylamino)biphenyl (38 mg, 0.1 mmol), pivalic acid (51 mg, 0.5 mmol) and cesium carbonate (1.22 g, 3.75 mmol) in toluene (5 mL) was degassed and flushed with N2 three times. The reaction mixture was heated with stirring at 110° C. until TLC or LCMS analysis indicated that the reaction was complete. The reaction mixture was allowed to cool to room temperature and evaporated in vacuo. The crude residue was suspended in EtOAc (30 mL) and washed with water. The aqueous phases were extracted with further EtOAc (4×30 mL), then the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by chromatography (SiO2; 2-60% EtOAc in DCM) to afford the title compound (420 mg, 55%) as a pale orange solid. δH (400 MHz, CDCl3) 7.74 (d, J 9.2 Hz, 1H), 7.66 (d, J 7.0 Hz, 1H), 7.20-7.26 (m, 1H), 7.11 (d, J 7.7 Hz, 1H), 6.94 (d, J 7.6 Hz, 1H), 6.75 (t, J 6.9 Hz, 1H), 6.39 (s, 1H), 4.70 (s, 2H), 4.50 (q, J 7.1 Hz, 2H), 2.41 (s, 3H), 2.12 (s, 3H), 1.44 (t, J 7.1 Hz, 3H). LCMS (ES+) (M+H)+ 308, RT 2.31 minutes.