Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-2].[Al+3].[O-2].[O-2].[Al+3].[N+:6]([C:9]1[CH:10]=[C:11]2[C:16](=[O:17])[NH:15][C:13](=[O:14])[C:12]2=[CH:18][CH:19]=1)([O-])=O.[H][H].[N+](C1C=CC=C2C(NC(=O)C=12)=O)([O-])=O>N.O[V](=O)=O.[Pd].O>[NH2:6][C:9]1[CH:10]=[C:11]2[C:16](=[O:17])[NH:15][C:13](=[O:14])[C:12]2=[CH:18][CH:19]=1
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: [H][H]
Agent: O=[V](=O)O
Agent: [Pd]
Agent: N
Solvent: O
Product: Nc1ccc2c(c1)C(=O)NC2=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.7 %

Procedure:
0.002 g of ammonium vanadate and 4 g of aluminium oxide granules containing 0.5% by weight of metallic palladium and having a particle size of 3.2 mm (as in Ex. 1) are added to a suspension consisting of 250 ml of water and 9.6 g of 4-nitrophthalimide. After displacing the air with nitrogen, the latter is replaced by hydrogen at atmospheric pressure and the suspension is stirred at room temperature for 20 hours. During this time, 100.6% of the theoretical amount of hydrogen, based on the nitrophthalimide used, is absorbed. The resulting suspension is then sieved through a sieve having a mesh width of 1 mm. The residue remaining on the sieve is washed with water and the combined aqueous phases are subsequently filtered through a paper filter. Drying at 80° C. under reduced pressure (125 mbar) gives 8.0 g (99%) of 4-aminophthalimide.
Reaction SMILES: [N:1](=[C:3]1[S:7][C:6]([CH3:9])([CH3:8])[N:5]=[C:4]1[CH3:10])[OH:2].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([N:21]([CH2:28][CH2:29][CH2:30][CH3:31])[S:22][N:23]([CH3:27])[C:24](F)=[O:25])[CH2:18][CH2:19][CH3:20]>C(#N)C>[CH2:17]([N:21]([CH2:28][CH2:29][CH2:30][CH3:31])[S:22][N:23]([CH3:27])[C:24]([O:2][N:1]=[C:3]1[S:7][C:6]([CH3:9])([CH3:8])[N:5]=[C:4]1[CH3:10])=[O:25])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN(CCCC)SN(C)C(=O)F
Reactant: CC1=NC(C)(C)SC1=NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN(CCCC)SN(C)C(=O)ON=C1SC(C)(C)N=C1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3.0 g (0.019 mol) of 5-oxo-2,2,4-trimethyl-3-thiazoline oxime are suspended in 10 ml of absolute acetonitrile. To the suspension at 0° C. there are successively added 5.5 g of anhydrous potassium carbonate and, dropwise, a solution of 4.52 g of N-(di-n-butylaminosulphenyl)-N-methylcarbamoyl fluoride in 10 ml of absolute acetonitrile. The reaction mixture is allowed to stir well at room temperature for 20 hours. Subsequently, the precipitated potassium salt is filtered off, and the filtrate is evaporated. Chromatography of the crude oily product on silica gel with ethyl acetate/toluene (1:3) as the eluent yields 5-oxo-2,2,4-trimethyl-3-thiazoline O-[N-(di-n-butylaminosulphenyl)-N-methylcarbamoyl]oxime, nD20 1.5200.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[C:12](=[O:19])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:4]=2[NH:3]1.[BH4-].[Na+]>CCO>[OH:19][CH:12]1[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2](=[O:1])[NH:3][C:4]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2
Reactant: O=C1c2ccccc2-c2[nH]c(=O)c3ccccc3c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c2c(c3ccccc13)C(O)c1ccccc1-2
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
To a stirred suspension of 2 (2.5 g, 0.01 mol) in EtOH (25 mL) was added NaBH4 (3.75 g, 0.1 mol) at room temperature in small portions over 30 min. The reaction mixture was stirred for an additional 2 h and then cooled to 0° C. where it was triturated with dilute HCl (10% soln.). The resulting solid precipitated was filtered and washed with water and MeOH to provide 3a (2.326 g, 92%). 1H NMR (DMSO-D6): δ 5.58 (d, J=8.1 Hz, 1H), 5.78 (d, J=8.7 Hz, 1H), 7.33-7.89 (m, 6H), 7.95 (d, J=7.8 Hz, 1W, 8.22 (d, J=7.8 Hz, 1H), 12.29 (s, 1H); 3C NMR (DMSO-D6): δ 77.44, 118.81, 120.15, 124.28, 125.04, 125.67, 126.34, 128.46, 128.64, 128.95, 133.27, 135.62, 136.12, 139.93, 148.55, 163.69.; MS (ES+): m/z 250.1 (M+1); Anal. Calcd for C16H11NO2: C, 77.10; H, 4.45; N, 5.62. Found: C, 77.01; H, 4.57, N, 5.59.
Reaction SMILES: [C:1]([N:11]([CH2:20][P:21]([O:25]Cl)([O:23]Cl)=[O:22])[CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:27]([SH:32])[CH2:28][CH2:29][CH2:30][CH3:31].C(Cl)Cl>C(OCC)C.C(N(CC)CC)C>[C:1]([N:11]([CH2:20][P:21]([O:25][S:32][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([O:23][S:32][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:22])[CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CCCCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)OCc1ccccc1
Reactant: CCCCCS
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCSOP(=O)(CN(CC(=O)OCCCC)C(=O)OCc1ccccc1)OSCCCCC
Reaction time: 16 h

Procedure:
Butyl N-carbobenzoxy-N-(dichlorophosphonomethyl)glycinate (13.25 g., 0.34 mole) and pentanethiol (6.96 g., 0.67 mole) were dissolved in 100 ml. of diethyl ether and 50 ml. of methylene chloride. Triethylamine (6.76 g) dissolved in 100 ml. of diethyl ether was then added. The reaction mixture was stirred for 16 hours at ambient temperatures and then filtered. The filtrate was washed with 3% ammonium hydroxide, then with brine, then with 5% hydrochloric acid and then the brine and the ether solution dried over sodium sulfate and then evaporated in vacuo to yield a crude product. The crude product was chromatographed through a silica gel column employing methylene chloride as the eluant. Evaporation of the methylene chloride yielded n-butyl N-carbobenzoxy-N-[di-(n-pentylthio)phosphonomethyl]glycinate as a yellow oil, ND25 =1.5218 and having the following analysis.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6](/[CH:10]=[CH:11]\[C:12]2[CH:13]=[C:14]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[C:21](Cl)[N:20]=3)[CH:15]=[CH:16][CH:17]=2)[CH:5]=1.C(N(CC)CC)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:25][C:24]1[CH:23]=[N:22][C:21]2[NH:3][C:4]3[CH:9]=[CH:8][N:7]=[C:6]([CH:5]=3)[CH:10]=[CH:11][C:12]3[CH:13]=[C:14]([NH:18][C:19]=1[N:20]=2)[CH:15]=[CH:16][CH:17]=3
Reactant: Nc1ccnc(/C=C\c2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Clc1cnc2nc1Nc1cccc(c1)C=Cc1cc(ccn1)N2

Procedure:
To a mixture of N-{3-[(Z)-2-(4-aminopyridin-2-yl)vinyl]phenyl}-2,5-dichloropyrimidin-4-amine dihydrochloride (34.6 mg, 0.08 mmol) and triethylamine (0.034 mL, 0.24 mmol) in dry 1,4-dioxane (0.70 mL) was added (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.8 mg, 0.0048 mmol), palladium acetate (0.7 mg, 0.003 mmol) and cesium carbonate (52.3 mg, 0.16 mmol). The mixture was degassed by bubbling N2 through the solution. The sealed tube was then microwaved at 150° C. for 30 min. The reaction mixture was diluted with THF/MeOH, filtered and concentrated to give the residue, which was then triturated with MeOH/EtOAc/THF to provide the desired product as a light yellow powder (9 mg, 35%). LCMS for C17H13ClN5 (M+H)+: m/z=322.0. 1H NMR (300 MHz, DMSO-d6): δ 9.81 (s, 1H), 9.33 (s, 1H), 9.15 (s, 1H), 8.49 (s, 1H), 8.26 (m, 1H), 8.19 (s, 1H), 7.33 (m, 1H), 7.24 (m, 1H), 7.08 (d, J=5.7 Hz, 1H), 6.93 (dd, J=5.7, 2.1 Hz, 1H), 6.83 (m, 1H), 6.58 (d, J=13.5 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+].Br[C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1>COCCOC>[C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)NC(=O)C2
Yield: 71.6 %

Procedure:
1-t-Butoxycarbonylpyrrol-2-ylboronic acid (1.5 g, 7.1 mmol) and a saturated aqueous solution of sodium hydrogen carbonate (25 ml) were added to a solution of 6-bromooxindole (1.1 g, 5.2 mmol), (prepared as described for the starting material in Example 62), in 1,2-dimethoxyethane (75 ml). The reaction mixture was degassed and placed under argon and tetrakis(triphenylphosphine)palladium(0) (50 mg) was added and the mixture heated at reflux for 6 hours. The organic solvent was removed by evaporation and the reaction mixture partitioned between ethyl acetate and water. The organic phase was separated and the aqueous phase was re-extracted twice with ethyl acetate. The organic phases were combined, washed with brine, dried (MgSO4), and the solvent removed by evaporation. The residue was triturated with ether/isohexanes (1/1) and collected by filtration to give 6-(1-t-butoxycarbonylpyrrol-2-yl)oxindole (1.11 g, 71%).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]#[C:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.C1(NC2CCCCC2)CCCCC1.S(Cl)([Cl:42])=O>ClCCl>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]#[C:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([Cl:42])=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: O=S(Cl)Cl
Reactant: CC1(C)CCC(C)(C)c2cc(CC#Cc3ccc(C(=O)O)cc3)ccc21
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(CC#Cc3ccc(C(=O)Cl)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.9 g (8.3 mmol) of 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid and 100 ml of dichloromethane are introduced into a round-bottomed flask under a stream of nitrogen and 2.4 ml (12.1 mmol) of dicyclohexylamine are added dropwise. The mixture is stirred at room temperature for one hour, 1.2 ml (11.7 mmol) of thionyl chloride are added dropwise and the mixture is stirred for one hour. The reaction medium is evaporated to dryness, the residue is taken up in ethyl ether, the dicyclohexylamine salt is filtered off and the filtrate is evaporated. 3 g (100%) of the crude acid chloride are collected, which product will be used in its current state for the rest of the synthesis.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH:24]1([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH:2]([C:7]3[CH:12]=[CH:11][C:10]([O:13][C:14]4[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=4)=[CH:9][CH:8]=3)[C:3]([O:5][CH3:6])=[O:4])=[CH:34][CH:35]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: COC(=O)C(Br)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: Oc1ccc(C2CCCCC2)cc1
Product: COC(=O)C(Oc1ccc(C2CCCCC2)cc1)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Yield: 68.5 %

Procedure:
In a manner similar to Example 16, 7.62 g of methyl α-bromo-α-[p-(α,α,α-trifluoro-m-tolyloxy)phenyl]acetate was reacted with 4.4 g of p-cyclohexylphenol to give 6.5 g of product as an amber oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:10][CH2:11][CH2:12][CH3:13])=[C:7]([OH:9])[CH:8]=1.C(N(CC)CC)C.[Br:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[NH:27][C:26](=[O:33])/[C:25]/2=[CH:34]/OC.O>CN(C)C=O>[Br:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[NH:27][C:26](=[O:33])/[C:25]/2=[CH:34]\[NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:10][CH2:11][CH2:12][CH3:13])=[C:7]([OH:9])[CH:8]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CCCOc1ccc(CN)cc1O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.2 %

Procedure:
According to the general procedure of example 129, an amount of 100 mg (0.55 mmol) of 5-(aminomethyl)-2-propoxyphenol is dissolved in N,N-dimethylformamide (5 mL). 228 μl (1.65 mmol) of triethylamine is added followed by 171 mg (0.607 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione. After the mixture is stirred at room temperature for 30 min, water (3 mL) is added and the reaction mixture is stirred for 3 hours. The precipitate is filtered and washed several times with anhydrous ether. The crude solid is then purified by high performance liquid chromatography to give 67 mg of a white solid. MS (ESI) m/z 430.8 (M+1).
Reaction SMILES: Br[C:2]1[C:6](=[O:7])[C:5]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[O:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.CC1(C)C(C)(C)OB([C:26]2[CH:43]=[CH:42][C:29]([O:30][CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=3)=[CH:28][CH:27]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:15]1[CH:16]=[CH:17][C:12]([C:3]2[O:4][C:5]3([CH2:11][CH2:10][CH2:9][CH2:8]3)[C:6](=[O:7])[C:2]=2[C:26]2[CH:27]=[CH:28][C:29]([O:30][CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=3)=[CH:42][CH:43]=2)=[CH:13][CH:14]=1
Reactant: O=C1C(Br)=C(c2ccncc2)OC12CCCC2
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C(c2ccncc2)OC12CCCC2
Yield: 6.6 %

Procedure:
A mixture of 3-bromo-2-(pyridin-4-yl)-1-oxaspiro[4.4]non-2-en-4-one (0.2 g, 0.68 mmol), 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl) quinoline (0.25 g, 0.82 mmol), and Cs2CO3 (1.25 g, 6.68 mmol) in toluene (10 mL) and water (2 mL) was degassed, Pd(dppf)Cl2 (0.05 g, 0.014 mmol) was added under an inert atmosphere and again degassed. Then the reaction was refluxed for 3 h. and was filtered through a pad of Celite®, the filtrate was diluted with EtOAc (50 mL), washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 2-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1-oxaspiro[4.4]non-2-en-4-one (20 mg, 5%) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.68 (d, J=8.5 Hz, 2H), 8.44 (d, J=7.9 Hz, 1H), 8.02 (t, J=8.4 Hz, 2H), 7.80 (t, J=8.2 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.63 (t, J=8.5 Hz, 1H), 7.48 (d, J=8.5 Hz, 2H), 7.18 (d, J=7.4 Hz, 2H), 7.12 (d, J=7.5 Hz, 2H), 5.42 (s, 2H), 2.08-1.82 (m, 8H). MS: [M+H]: m/z=449.2. HPLC: 96.9% (RT-2.24 min), Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13]C1.CC(N(C)C)=O>CCOC(C)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N:11]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: C1CCNCC1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Br)cc1N1CCCC1
Temperature: 120 °C
Yield: 96679.6 %

Procedure:
A 20 mL screwtop vial was charged with 4-bromo-2-fluorobenzaldehyde (200 mg, 0.985 mmol), piperadine (116 μL, 1.19 mmol), and DMA (1 mL). The reaction was heated to 120° C. for 3 h. The reaction was diluted in EtOAc and extracted with brine (3×). The organics were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (0% to 20% EtOAc in hexanes) and yielded 4-bromo-2-(pyrrolidin-1-yl)benzaldehyde (242 g, 92%). 1H NMR 400 MHz (CDCl3) δ 10.21 (s, 1H), 7.66 (dd, J=8.3, 2.4 Hz, 1H), 7.31-7.17 (m, 2H), 4 (m, 4H), 1.78 (m, 4H), 1.71-1.60 (m, 2H). LCMS (ESI, m/z): 268 [M+H]+.
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([O:8][C:9]([C:11]1[CH:15]=[CH:14][N:13]([CH:16]([CH3:18])[CH3:17])[C:12]=1[CH:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[CH3:28])O)=[O:10])[CH3:7].N1C=CC=CC=1.[Cl:35][C:36]1[C:37]([F:43])=[C:38]([NH2:42])[CH:39]=[CH:40][CH:41]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.O1CCOCC1.CCOC(C)=O>[CH2:6]([O:8][C:9]([C:11]1[CH:15]=[CH:14][N:13]([CH:16]([CH3:18])[CH3:17])[C:12]=1[CH:19]([NH:42][C:38]1[CH:39]=[CH:40][CH:41]=[C:36]([Cl:35])[C:37]=1[F:43])[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[CH3:28])=[O:10])[CH3:7]
Reactant: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(Cl)cc1C
Reactant: Nc1cccc(Cl)c1F
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)c1ccn(C(C)C)c1C(Nc1cccc(Cl)c1F)c1ccc(Cl)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Methanesulfonyl chloride (10.62 mmol) was added to a mixture of 2-[(4-chloro-2-methyl-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step A4) (4.09 mmol), pyridine (14.01 mmol) and DMAP (1.226 mmol) in CH2Cl2 (70 mL). After stirring for 20 h, the reaction mixture was diluted with CH2Cl2 and washed with a saturated aqueous solution of NH4Cl (2×). The combined aqueous phases were back-extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and concentrated. A mixture of the crude intermediate and 3-chloro-2-fluoro-phenylamine [2106-04-9] (11.64 mmol) in dioxane (90 mL) was stirred at 90° C. for 11 h. After cooling to rt, the reaction mixture was diluted with EtOAc and successively washed with 10% w/w aqueous citric acid and brine. The combined aqueous phases were back-extracted with EtOAc. The combined organic phases were dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a yellow solid. tR: 9.08 min (HPLC 2); ESI-MS: tR=1.54 min, [M]+318/320 (i.e. fragmented pyrrolium ion) (LC-MS 1); TLC: Rf=0.45 (1:4 EtOAc/hexanes).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]([F:15])([F:14])[F:13])[CH:9]=2)[NH:4][N:3]=1.[CH3:16]C([O-])(C)C.[K+].CI>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]([F:14])([F:13])[F:15])[CH:9]=2)[N:4]([CH3:16])[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: FC(F)(F)Oc1ccc2[nH]nc(I)c2c1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2cc(OC(F)(F)F)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
To a solution of 3-iodo-5-(trifluoromethoxy)-1H-indazole (178 mg, 543 μmol) in THF (5 mL) at 0° C. was added KOtBu (85.2 mg, 760 μmol) and the mixture stirred at 0° C. for 30 min then MeI (108 mg, 47.5 μL, 760 μmol) was added. The reaction mixture was stirred at 0° C. for 30 min then warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride in water and extracted with dichloromethane (3×30 mL). The combined organics were dried over MgSO4 and concentrated to a clear oil. Purification by chromatography (40 g column, 50 μm from Analogix, 0-20% EtOAc in hexanes over 20 min) gave 3-iodo-1-methyl-5-(trifluoromethoxy)-1H-indazole (141 mg, 412 μmol, 76%) as a white solid. MS (M+H)+=342.8; 1H NMR (CDCl3) δ: 7.36-7.43 (m, 1H), 7.23-7.36 (m, 2H), 4.12 (s, 3H); LCMS ESI+ TIC MS showed 100% purity, [M+H]+=342.8. The regioisomer, 3-iodo-2-methyl-5-(trifluoromethoxy)-2H-indazole, (29 mg, 84.8 μmol, 16%) was also obtained as a waxy off-white solid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[NH:9][CH:8]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[Cl:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:6][CH2:5][CH2:4][NH2:1]
Reactant: [N-]=[N+]=NCCCc1c[nH]c2ccc(Cl)cc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCCc1c[nH]c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 22 h
Yield: 33.6 %

Procedure:
To a solution of 3-(3-azidopropyl)-5-chloro-1H-indole (0.299 g; 1.27 mmol) in tetrahydrofuran (9 mL) were added triphenylphosphine (0.354 g; 1.34 mmol) and water (0.6 mL). The reaction mixture was stirred at room temperature for 22 hours and was then evaporated to dryness. The residue was dissolved in dichloromethane (10 mL) and 10 mL of 6N hydrochloric acid were added. After separation, the aqueous layer was further extracted with dichloromethane (2×10 mL) and the pH was adjusted to 14 with a solution of sodium hydroxide 6N. This basic solution was extracted with dichloromethane (3×20 mL) and the combined organic layer was dried over magnesium sulfate, and evaporated to afford 0.089 g (34%) of 3-(5-chloro-1H-indol-3-yl)propan-1-amine as a white solid.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Cl:32][C:33]1[CH:40]=[CH:39][C:38]([N:41]2[CH:45]=[CH:44][CH:43]=[N:42]2)=[CH:37][C:34]=1[CH:35]=[O:36]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([CH:35]([C:34]3[CH:37]=[C:38]([N:41]4[CH:45]=[CH:44][CH:43]=[N:42]4)[CH:39]=[CH:40][C:33]=3[Cl:32])[OH:36])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=Cc1cc(-n2cccn2)ccc1Cl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(O)c1cc(-n2cccn2)ccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (356 mg, 0.68 mmol) in THF was added isopropylmagnesium chloride (0.75 mL, 1.5 mmol) slowly at 0° C. One hour later 2-chloro-5-pyrazol-1-yl-benzaldehyde (140 mg, 0.68 mmol) was added and warmed up the reaction mixture to RT for 2 hours, quenched with water, extracted with ethyl acetate, concentrated and purified by flash column to give 4-chloro-N-{5-chloro-2-[(2-chloro-5-pyrazol-1-yl-phenyl)-hydroxy-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16](Cl)=[O:17].S(O)(O)(=O)=O.[NH2:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1>>[NH:26]1[CH:27]=[CH:28][N:29]=[C:25]1[NH:24][C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:15])([F:14])[F:13])=[O:17]
Reactant: O=C(Cl)c1cnc2c(C(F)(F)F)cccc2c1O
Reactant: Nc1ncc[nH]1
Agent: O=S(=O)(O)O
Product: O=C(Nc1ncc[nH]1)c1cnc2c(C(F)(F)F)cccc2c1O
Yield: 39.7 %

Procedure:
Using the procedure of Example 1, 11.57 g of 4-hydroxy-8-trifluoromethyl-quinoline-3-carboxylic acid chloride were reacted with 5.52 g of 2-aminoimidazole sulfate to obtain 3.9 g of N-(1H-imidazol-2-yl)-4-hydroxy-8-trifluoromethyl-quinoline-3-carboxamide melting at 211° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15][CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:22]([O:26][C:27](=[O:33])[CH2:28][S:29](Cl)(=[O:31])=[O:30])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27](=[O:33])[CH2:28][S:29](=[O:30])(=[O:31])[N:15]([C:12]1[S:13][CH:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[N:11]=1)[CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)CS(=O)(=O)Cl
Reactant: CC(C)c1ccc(-c2csc(NCc3cccs3)n2)cc1
Product: CC(C)c1ccc(-c2csc(N(Cc3cccs3)S(=O)(=O)CC(=O)OC(C)(C)C)n2)cc1

Procedure:
[4-(4-Isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amine, chlorosulfonyl-acetic acid tert-butyl ester were combined according to general procedure C (method 2) to provide {[4-(4-isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-sulfamoyl}-acetic acid tert-butyl ester. LCMS m/z: 494 (M+1)+.