Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:10][C:9]2[NH:8][N:7]=[C:6]([C:11]3[NH:12][C:13]4[C:18]([CH:19]=3)=[CH:17][CH:16]=[C:15]([NH:20][CH3:21])[CH:14]=4)[C:5]=2[CH2:4][CH2:3]1.[N:23]1([C@@H:29]([CH3:33])[C:30]([OH:32])=O)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.Cl.C(N=C=NCCCN(C)C)C.C(Cl)(Cl)Cl>N1C=CC=CC=1.O>[CH3:1][C:2]1([CH3:22])[CH2:10][C:9]2[NH:8][N:7]=[C:6]([C:11]3[NH:12][C:13]4[C:18]([CH:19]=3)=[CH:17][CH:16]=[C:15]([N:20]([CH3:21])[C:30](=[O:32])[C@@H:29]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH3:33])[CH:14]=4)[C:5]=2[CH2:4][CH2:3]1
Reactant: C[C@@H](C(=O)O)N1CCOCC1
Reactant: CNc1ccc2cc(-c3n[nH]c4c3CCC(C)(C)C4)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: C[C@@H](C(=O)N(C)c1ccc2cc(-c3n[nH]c4c3CCC(C)(C)C4)[nH]c2c1)N1CCOCC1
Reaction time: 14 h
Yield: 78 %

Procedure:
To a solution of N-{2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl}-N-methylamine (45 mg, 0.15 mmol) in pyridine (1 ml) were added (S)-2-(morpholin-4-yl)propionic acid obtained in Reference Example 3 (110 mg, 0.69 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (106 mg, 0.55 mmol) at room temperature, and the mixture was stirred for 14 hr. To the reaction mixture were added chloroform and water, and the organic layer was separated. The organic layer was dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Then, the residue was dissolved in a mixed solvent of tetrahydrofuran (1 ml) and methanol (1 ml). To the solution was added 2 N aqueous sodium hydroxide solution (0.35 ml) at room temperature, and the mixture was stirred for 20 min. To the reaction mixture were added chloroform and water, and the organic layer was separated. The organic layer was dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography to give the title compound (52 mg, yield 78%).
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(=CC=3)C(=O)N([C@@H](C(C)C)C(O)=O)C4)=CC=2)=CC=1.[CH3:35][CH:36]([CH3:72])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[C:47]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:66]=[CH:65][C:64]([C:67]([F:70])([F:69])[F:68])=[CH:63][CH:62]=4)=[O:59])=[CH:53][CH:52]=3)[CH:48]=2)[C:43]1=[O:71])[C:38]([O:40]C)=[O:39]>>[CH3:35][CH:36]([CH3:72])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[C:47]([C:51]3[CH:52]=[CH:53][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:62]=[CH:63][C:64]([C:67]([F:70])([F:68])[F:69])=[CH:65][CH:66]=4)=[O:59])=[CH:55][CH:56]=3)[CH:48]=2)[C:43]1=[O:71])[C:38]([OH:40])=[O:39]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)cc3)ccc2C1=O
Yield: 96 %

Procedure:
The compound of example 245 was prepared analogous to compound of example 225 by hydrolysis of compound of example 244.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.C(N(CC)CC)C.[C:35](Cl)(=[O:38])[O:36][CH3:37]>ClCCl>[CH3:37][O:36][C:35](=[O:38])[NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][N:13]([C:12]3[C:7]4[O:6][CH2:5][O:4][C:8]=4[CH:9]=[CH:10][CH:11]=3)[CH2:14][CH2:15]2)[CH2:22][CH2:23]1
Reactant: COC(=O)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Temperature: 0 °C

Procedure:
The title compound was prepared from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25 mg, 0.068 mmol) and triethylamine (20.6 mg, 28.4 μl, 204 μmol) in dichloromethane (1 mL). Methyl carbonochloridate (7.06 mg, 5.78 μl, 0.075 μmol) was added to the mixture stirring at 0° C. The ice bath was removed and the reaction mixture was stirred for 1 hour at room temp. The reaction was diluted with dichloromethane and quenched with sat NaHCO3 (4 mL). The aqueous layer was extracted with DCM (1×5 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 15% MeOH in dichloromethane) to yield the title compound as a white solid (9 mg, 34%), MS (ISP) m/z=390.3 [(M+H)+].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C1COCCN1
Product: CC(C)(C)c1ccc(N2CCOCC2)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 95 %

Procedure:
4-tert-Butyl-2-nitrochlorobenzene (19 g.; 68 mmoles) and morpholine (30 g.; 340 mmoles) were heated at 90° C. for 40 hours. The mixture was then poured into ice water. The yellow solid precipitate was collected by filtration (95% yield) and found to melt at 58°-60° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)=[O:9])[CH:3]=1.[CH:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]([OH:24])[CH:16]=1.CCN(C(C)C)C(C)C.CN1CCCC1=O>O>[CH:12]1([CH2:11][NH:10][C:8]([C:4]2[CH:3]=[C:2]([O:24][C:17]3[CH:16]=[CH:15][C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=3)[CH:7]=[CH:6][N:5]=2)=[O:9])[CH2:14][CH2:13]1
Reactant: O=C(NCC1CC1)c1cc(Cl)ccn1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(NCC1CC1)c1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1

Procedure:
4-Chloro-2-[(cyclopropylmethyl)aminocarbonyl]pyridine (1.5 g), p-nitrophenol (2.0 g), Hunig's base (3.1 ml) and 1-methyl-2-pyrrolidinone (6.2 ml) were stirred together at 160° C. for 3 hours. Water was added, extraction was performed with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=4:1, followed by 2:1) using NH type silica gel to obtain 0.35 g of the target substance as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:19][CH2:20][CH2:21][C:22](OCC)=[O:23])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Br:1][C:2]1[N:3]([CH2:19][CH2:20][CH2:21][CH:22]=[O:23])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CCOC(=O)CCCn1c(Br)c(Cc2ccc(Cl)cc2)c2ccccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: O=CCCCn1c(Br)c(Cc2ccc(Cl)cc2)c2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
To a vigorously stirred solution of 0.3 g of the product from Step 3 in 5 mL of THF cooled at −78° C. was added dropwise a solution of diisobutylaluminum hydride (4 mL, 1 M in hexane). After stirring for 30 minutes at −78° C., the reaction was quenched with 1 mL of acetone followed by 10 mL of 20% aqueous solution of potassium sodium tartrate. The mixture was extracted with 20 mL of 1:1 hexane/EtOAc and the extract was dried over Na2SO4 and concentrated. The residue was purified by silica gel flash chromatography eluted with 8:1 hexane/EtOAc to give 0.19 g of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4](Cl)[N:3]=1.[O:25]1[CH2:30][CH2:29][C@@H:28]([NH2:31])[C@@H:27]([NH2:32])[CH2:26]1.CCN(C(C)C)C(C)C>C(#N)C>[NH2:32][C@@H:27]1[C@H:28]([NH:31][C:4]2[N:3]=[C:2]([Cl:1])[C:7]3[C:8](=[O:22])[N:9]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=4[O:20][CH3:21])[CH2:10][C:6]=3[C:5]=2[F:23])[CH2:29][CH2:30][O:25][CH2:26]1
Reactant: N[C@@H]1CCOC[C@@H]1N
Reactant: COc1ccc(CN2Cc3c(F)c(Cl)nc(Cl)c3C2=O)c(OC)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCOC[C@@H]4N)nc(Cl)c3C2=O)c(OC)c1
Temperature: 85 °C
Reaction time: 72 h
Yield: 9.6 %

Procedure:
A mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2 H)-one (2.5 g, 6.74 mmol), (3R,4R)-tetrahydro-2H-pyran-3,4-diamine (0.711 g, 6.12 mmol), and DIPEA (5.35 mL, 30.6 mmol) in ACN (30 mL) was stirred at 85° C. for 3 d in a sealed tube. Additional (3R,4R)-tetrahydro-2H-pyran-3,4-diamine (0.356 g, 3.06 mmol) and DIPEA (2.14 mL, 12.2 mmol) were added and the mixture was heated at 100° C. overnight. The mixture was concentrated and purified via preparative HPLC. The fractions corresponding to the desired regioisomer were collected to give the title compound (265 mg, 9.60%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.65 (m, 1 H), 1.80-1.82 (s, 1 H), 3.40 (td, J=11.47, 2.44 Hz, 1 H), 3.53 (dd, J=11.23, 1.95 Hz, 1 H), 3.67 (dd, J=11.47, 2.20 Hz, 1 H), 3.71-3.73 (m, 1 H), 3.75 (s, 3 H), 3.77-3.79 (m, 1 H), 3.81 (s, 3 H), 4.09-4.11 (m, 1 H), 4.33 (s, 2 H), 4.50 (s, 2 H), 6.48 (dd, J=8.30, 2.44 Hz, 1 H), 6.58 (d, J=2.44, 1 H), 6.90 (br s, 1 H), 7.06 (d, J=8.30 Hz, 1 H). [M+H] calc'd for C21H24ClFN4O4, 451; found, 451.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)=[CH:12][CH:11]=1)[CH2:2]2.CC(O)=O.[Br:27]N1C(=O)CCC1=O>CC#N>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([Br:27])[CH:17]=3)=[CH:12][CH:11]=1)[CH2:2]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)nn2)cc1
Solvent: CC(=O)O
Solvent: CC#N
Product: Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)nn2)cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The product of Example 29F (150 mg, 0.5 mmol) was treated with HOAc (36 μL, 36 mg, 0.6 mmol) in MeCN (5 mL) at ambient temperature for 5 min. N-bromosuccinimide (Aldrich, 100 mg, 0.55 mol) in MeCN (5 mL) was then added to the above solution at 0° C. and stirred at 0° C. for 1 h. It was then concentrated under reduced pressure. The title compound was purified by preparative HPLC (Xterra™, column, Xterra RP-18 5 μm, 30×100 mm. Eluting Solvent, MeCN/H2O (NH4HCO3, 0.1 M, pH=10) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) (100 mg, yield, 53%). 1H NMR (300 MHz, CD3OD) δ 1.45-1.65 (m, 1H), 1.65-1.94 (m, 2H), 1.93-2.16 (m, 1H), 2.19-2.39 (m, 1H), 2.67-3.11 (m, 5H), 3.37-3.54 (m, 1H), 5.18-5.35 (m, 1H), 6.91 (d, J=8.5 Hz, 1H), 7.19 (d, J=9.2 Hz, 1H), 7.70 (dd, J=8.5, 2.0 Hz, 1H), 7.95 (d, J=9.5 Hz, 1H), 8.03 (d, J=2.0 Hz, 1H) ppm. MS (DCl/NH3): 375 (M+H)+, 377 (M+H)+.
Reaction SMILES: C12BC(CCC1)CCC2.[CH2:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:11]=[CH2:12].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:29]12([CH2:39][NH:40][C:41](=[O:50])[C:42]3[C:47]([Cl:48])=[CH:46][N:45]=[C:44](Cl)[CH:43]=3)[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2>O.CN(C)C=O>[C:29]12([CH2:39][NH:40][C:41](=[O:50])[C:42]3[C:47]([Cl:48])=[CH:46][N:45]=[C:44]([CH2:12][CH2:11][CH2:10][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH:43]=3)[CH2:30][CH:31]3[CH2:32][CH:33]([CH2:34][CH:35]([CH2:37]3)[CH2:36]1)[CH2:38]2
Reactant: C=CCO[Si](C)(C)C(C)(C)C
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Cl)ncc1Cl
Agent: B1C2CCCC1CCC2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Temperature: 60 °C
Yield: 248.6 %

Procedure:
A solution of 9-borabicyclo[3.3.1]nonane at 0.5 M in tetrthydrofuran (2.78 mL, 1.39 mmol) was added to neat (allyloxy)(tert-butyl)dimethylsilane (0.15 mL, 0.69 mmole). The mixture was heated to 60° C. for 2 hours under nitrogen. The reaction was subsequently cooled to room temperature and a solution of potassium phosphate (0.37 g) in water (1 mL) was added slowly. A solution of N-(1-adamantylmethyl)-2,5-dichloroisonicotinamide (0.20 g, 0.59 mmol; prepared as described in WO 01/94338) in dimethylformamide (3 mL) was added followed by tetrakis(triphenyphosphine)palladium (0) (7 mg). The solution was heated to 70° C. for 2 hours; allowed to cool to room temperature then partitioned between ethyl acetate (20 mL) and brine (10 mL). The aqueous phase was further extracted with ethyl acetate (2×20 mL) and the combined organics were washed with brine (20 mL); dried over magnesium sulphate; filtered and evaporated under vacuum to give the crude product (0.70 g) as a yellow oil, which was used, as such, without any further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](Cl)(=[O:29])[C:26](Cl)=[O:27].[CH2:31]([OH:33])[CH3:32]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:25](=[O:29])[C:26]([O:33][CH2:31][CH3:32])=[O:27])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(Cl)C(=O)Cl
Reactant: Fc1ccc(-c2ccc3c(ccn3Cc3ccccc3)c2)cc1Cl
Product: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(F)c(Cl)c3)cc12
Yield: 67 %

Procedure:
Ethyl [1-benzyl-5-(3-chloro-4-fluorophenyl)-1H-indol-3-yl](oxo)acetate was prepared from 1-benzyl-5-(3-chloro-4-fluorophenyl)-1H-indole (0.705 g, 2.10 mmol), oxalyl chloride (0.73 mL, 8.4 mmol), and ethanol (6 mL) according to the procedure described in Step 3 of Example 1. Purification by flash chromatography (Biotage apparatus) using 5-10% ethyl acetate in hexane as an eluant afforded the title compound as a yellow solid (0.616 g, 67%), mp: 148-149° C. Mass spectrum (+APCI, [M+H]+) m/z 436; 1HNMR (400 MHz, DMSO-d6): δ 8.75 (s, 1H), 8.4 (d, 1H, J=2.0 Hz), 7.85 (dd, 1H, J=7.1 Hz and 2.4 Hz), 7.6-7.7 (m, 3H), 7.5 (t, 1H, J=8.9 Hz), 7.25-7.35 (m, 5H), 5.65 (s, 2H), 4.35 (q, 2H, J=7.1 Hz), and 1.35 ppm (t, 3H, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11]([S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:10]1[C:9](=[O:26])[CH2:8][CH2:7][CH2:6][C:5]2=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:37]NS(C1C=CC=CC=1)(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11]([S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:10]1[C:9](=[O:26])[CH:8]([F:37])[CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4cc(Cl)c(Cl)cc42)CCCC3=O)cc1
Reactant: O=S(=O)(NF)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c3c(c4cc(Cl)c(Cl)cc42)CCC(F)C3=O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
6,7-Dichloro-9-tosyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (intermediate 1c) (420 mg, 1.02 mmol) dissolved in anhydrous THF (10 mL) and cooled to −78° C. was mixed with LiHMDS (1.13 mL, 1.1 mmol, 1M solution in THF). The reaction mixture was slowly warmed to 0° C., stirred for an additional 30 min. at 0° C., then cooled to −78° C. and N-fluoro benzene sulfonamide (0.31 g, 1.3 mmol) was added. The resulting mixture was slowly warmed to room temperature and stirred for 15 min., quenched with saturated NH4Cl and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4, the solvent was removed under reduced pressure to give the crude compound which was purified by column chromatography [EtOAc-hexane (7:93) as eluant] to obtain the title compound (160 mg, 37%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.53 (s, 1H), 8.082 (d, J=8.0 Hz, 2H), 7.69 (s, 1H), 7.35 (d, J=8.5 Hz, 2H), 5.26-5.13 (m, 1H), 3.14-3.11 (m, 1H), 3.01-2.95 (m, 1H), 2.62-2.55 (m, 1H), 2.42 (s, 3H), 2.38-2.41 (m, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[C:12](\[C:15]2[CH:24]=[CH:23][C:18]3[N:19]([CH3:22])[CH:20]=[N:21][C:17]=3[CH:16]=2)/[CH2:13][CH3:14])=[CH:7][CH:6]=1.[CH3:32][NH2:33]>CO>[CH3:22][N:19]1[C:18]2[CH:23]=[CH:24][C:15](/[C:12](/[CH2:13][CH3:14])=[C:11](/[C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)\[C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:33][CH3:32])=[CH:6][CH:7]=3)=[CH:16][C:17]=2[N:21]=[CH:20]1
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2c(c1)ncn2C
Reactant: CN
Solvent: CO
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCNC)cc1)c1ccc2c(c1)ncn2C
Temperature: 85 °C

Procedure:
To a stirred solution of (Z)-4-(1-(4-(2-chloroethoxy)phenyl)-2-(1-methyl-1H-benzo[d]imidazol-5-yl)but-1-enyl)phenol (20 mg, 1.0 eq) in 10 mL MeOH was added 5 mL CH3NH2 (aq) and heated at 85° C. for 72 h. The organic solvent was removed in vacuo, water was added to the residue, and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the desired (Z)-product. 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.60 (s, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 2H), 7.01 (d, J=9.2 Hz, 1H), 6.80 (d, J=8.4 Hz, 2H), 6.75 (d, J=8.8 Hz, 2H), 6.45 (d, J=8.4 Hz, 2H), 3.89 (t, J=5.2 Hz, 2H), 3.80 (s, 3H), 2.88 (t, J=5.2 Hz, 2H), 2.52 (q, J=7.2 Hz, 2H), 2.46 (s, 3H), 0.88 (t, J=7.2 Hz, 3H); m/z=428[M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([S:20](=[O:23])(=[O:22])[NH2:21])[CH:17]=2)[O:12][CH2:11]1)=[O:8].[OH-].[Na+].[CH3:31][NH:32][C:33](=[O:38])C(Cl)(Cl)Cl.C>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([S:20]([NH:21][C:33]([NH:32][CH3:31])=[O:38])(=[O:22])=[O:23])[CH:17]=2)[O:12][CH2:11]1)=[O:8]
Reactant: CNC(=O)C(Cl)(Cl)Cl
Reactant: COc1ccc(F)cc1C(=O)NC1COc2cc(OC)c(S(N)(=O)=O)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CNC(=O)NS(=O)(=O)c1cc2c(cc1OC)OCC(NC(=O)c1cc(F)ccc1OC)C2
Temperature: 0 °C

Procedure:
1.64 g (4 mmol) of 3-(5-fluoro-2-methoxybenzamido)-6-sulfamoyl-7-methoxychroman were heated at 80° C. for 30 minutes in 10 ml of dry DMSO after addition of 0.4 g (10 mmol) of freshly powdered sodium hydroxide and 1.05 g (6 mmol) of N-methyltrichloroacetamide. The cooled reaction mixture was introduced into ice-water, clarified with active charcoal and acidified to pH 1. The precipitate was filtered off with suction, dried and recrystallized from ethanol. The product had a melting point of 260° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[OH:8][CH2:9][C:10]([NH:12][CH2:13][C@H:14]([O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[C:19]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH3:35])[CH:29]=1)=[N:20][CH:21]=[N:22]2)[CH3:15])=[O:11]>>[OH:8][CH2:9][C:10]([NH:12][CH2:13][C@H:14]([O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[C:19]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:2][C:3]3[N:4]=[CH:5][S:6][CH:7]=3)=[C:30]([CH3:35])[CH:29]=1)=[N:20][CH:21]=[N:22]2)[CH3:15])=[O:11]
Reactant: ClCc1cscn1
Reactant: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CNC(=O)CO)c23)ccc1O
Product: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CNC(=O)CO)c23)ccc1OCc1cscn1
Yield: 13 %

Procedure:
The procedure described in Example 3 was repeated using 4-(chloromethyl)-1,3-thiazole and 2-hydroxy-N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]acetamide (obtained as described in Example 82, preparation of starting materials) to give the title compound as a white solid in 13% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 2.21 (s, 3H), 3.42 (dt, 1H), 3.71 (dt, 1H), 3.79 (d, 2H), 4.95 (m, 1H), 5.24 (s, 2H), 5.48 (t, 1H), 7.09 (d, 1H), 7.23 (d, 1H), 7.29 (d, 1H), 7.54 (d, 1H), 7.62 (dd, 1H), 7.68 (t, 1H), 7.77 (d, 1H), 8.16 (t, 1H), 8.44 (s, 1H), 9.14 (d, 1H), 9.95 (s, 1H); Mass spectrum MH+ 480.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[O:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1.CI>O1CCCC1>[CH3:1][C:16]1([C:19]([OH:21])=[O:20])[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1
Reactant: [Li]CCCC
Reactant: O=C(O)C1CCOCC1
Solvent: C1CCOC1
Solvent: CI
Solvent: CC(C)NC(C)C
Product: CC1(C(=O)O)CCOCC1
Temperature: 25 °C
Reaction time: 84 h

Procedure:
Butyllithium (21.1 ml, 33.8 mmol, 1.6 M in hexanes) was added dropwise over 10 minutes to a stirred solution of diisopropylamine (4.7 ml, 33.8 mmol) in anhydrous tetrahydrofuran (40 ml) under an atmosphere of nitrogen at <10° C. Upon addition, tetrahydropyran-4-carboxylic acid (J. Am. Chem. Soc., 1993, 115, 8407) was added in anhydrous tetrahydrofuran (20 ml) under nitrogen at <5° C. The mixture was stirred at room temperature for one hour after which methyl iodide (2.4 ml, 38.4 mmol) was added dropwise at <5° C. The resultant solution was stirred at <50° C. for 30 minutes, allowed to warm to room temperature and stirred for a further 3.5 days. The solvent was removed by evaporation and the residue dissolved in dichloromethane (100 ml) and 2N hydrochloric acid (100 ml) added. The aqueous layer was extracted with dichloromethane (3×100 ml) and the combined organic layers were washed with water (100 ml), brine (100 ml), dried (MgSO4), filtered and evaporated to yield the title product (1.4 g) which was used in the next step without purification. Data for the title compound: 1H NMR (250 MHz, CDCl3) δ1.00 (3H, s), 1.47-1.58 (2H, m), 2.06-2.11 (2H, m), 3.49-3.60 (2H, m), 3.78-3.86 (2H, m).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:31])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH2:29][CH3:30])[N:17]=2)[CH2:9]1.[CH2:32]([O:34][C:35]([CH:37]1[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([CH:37]1[CH2:42][CH2:41][CH:40]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:31])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH2:29][CH3:30])[N:17]=3)[CH2:11]2)[CH2:39][CH2:38]1)=[O:36])[CH3:33]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: CCn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCC(N2CC(NC(=O)CNc3nn(CC)c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-ethyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 67, Step A) and 4-oxo-cyclohexanecarboxylic acid ethyl ester using the procedure described in Step E of Example 1.
Reaction SMILES: [CH2:1]([S:7][CH2:8][CH2:9]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CSCCCl.C(SCC[S:25][C:26]#[N:27])CCCCC>>[CH2:1]([S:7][CH2:8][CH2:9][N:27]=[C:26]=[S:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCSCCCl
Reactant: CCCCCCSCCSC#N
Agent: CSCCCl
Product: CCCCCCSCCN=C=S

Procedure:
Example 1 is repeated with the exception that n-C6H13SCH2CH2Cl is used as a reagent instead of CH3SCH2CH2Cl and the reaction is allowed to proceed for seventy-five minutes. The product is isolated by distillation at reduced pressure and analyzed by gas chromatography/mass spectrometry which shows that the product is 0.7 percent n-C6H13SCH2CH2SCN and 97.0 percent n-C6H13SCH2CH2NCS.