Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([NH:24][C:25](=[O:30])[CH:26]=[CH:27][CH2:28]Br)[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1.CN(C)C=O>[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([NH:24][C:25](=[O:30])[CH:26]=[CH:27][CH2:28][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(C=CCBr)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CCNCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(CC)CC=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reaction time: 2 h
Yield: 59.6 %

Procedure:
A solution of 5.17 mL (3.65 g; 50 mmoles) of diethylamine in 20 mL of tetrahydrofuran was stirred and cooled in an ice bath, and a solution of 1.16 g (2.5 mmoles) of 4-Bromo-but-2-enoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide in 10 mL of tetrahydrofuran and 5 mL of N,N-dimethylformamide was added dropwise. After stirring for 2 hours, 45 mL of ethyl acetate and 30 mL of saturated aqueous sodium bicarbonate were added, and the layers were separated. The organic layer was extracted with 25 mL of brine, dried over sodium sulfate, and taken to an oil in vacuo. This was chromatographed on silica gel with 1:9 methanol methylene chloride to give 677 mg (59%) of the desired product, which melted at 196-199° C. Mass spectrum (m/e) M+2H 228.5.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[OH:9][C:10]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]([CH3:19])[N:11]=1.O>CN(C)C=O>[CH3:1][O:9][C:10]1[CH:14]=[C:13]([C:15]([F:16])([F:18])[F:17])[N:12]([CH3:19])[N:11]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(O)cc1C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(C(F)(F)F)n(C)n1
Reaction time: 15 h
Yield: 90.4 %

Procedure:
10.0 g (72.3 mmoles) of anhydrous potassium carbonate and 12.8 g (90.3 mmoles) of methyl iodide were added, at room temperature, to a solution of 10.0 g (60.2 mmoles) of 3-hydroxy-1-methyl-5-trifluoromethyl-1H-pyrazole dissolved in 50 ml of N,N-dimethylformamide. The mixture was stirred for 15 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 9.8 g (yield: 90.7%) of 3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazole.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[S:20][C:21]([C:24](O)=[O:25])=[CH:22][N:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[N:3]=1.[CH3:34][NH:35][CH3:36]>O1CCCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[S:20][C:21]([C:24]([N:35]([CH3:36])[CH3:34])=[O:25])=[CH:22][N:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)[N:3]=1
Reactant: CC1Cc2ccc(-c3ncc(C(=O)O)s3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CNC
Solvent: C1CCOC1
Product: CC1Cc2ccc(-c3ncc(C(=O)N(C)C)s3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 133 starting from 2-{2-[2-amino-6-(4-methylpiperazin-l-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1,3-thiazole-5-carboxylic acid and 2.0 M of dimethylamine in tetrahydrofuran solution. LCMS (M+H)+: m/z=493.2.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH3:18])[CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:18][CH:15]([CH2:16][CH3:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: CCC(C)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)CCCCCOc1ccc(O)cc1
Reaction time: 9.5 h

Procedure:
A 25 ml-flask was charged with 0.637 g of hydroquinone, 1 g of optically active 1-bromo-6-methyloctane, 0.667 g of anhydrous potassium carbonate and 4 ml of N,N-dimethylformamide, and reaction was carried out at 90° C. for 9.5 hours. After the reaction, insoluble substances were recovered by filtration and extracted with ether. The ether layer was washed with water and a saturated aqueous solution of sodium chloride and dried, and ether was removed by distillation under reduced pressure. The obtained crude product was purified by silica gel chromatography to obtain 0.32 g of optically active 4-(6'-methyloctyloxy)phenol.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:31][CH2:32][S:33][CH3:34])[C:13]([NH:15][C@H:16]1[CH2:25][CH2:24][C:19]2([O:23][CH2:22][CH2:21][O:20]2)[CH2:18][C@H:17]1[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][I:36]>>[I-:36].[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:13](=[O:14])[NH:15][C@H:16]1[CH2:25][CH2:24][C:19]2([O:20][CH2:21][CH2:22][O:23]2)[CH2:18][C@H:17]1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:31][CH2:32][S+:33]([CH3:35])[CH3:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CCOC(=O)[C@@H]1CC2(CC[C@@H]1NC(=O)[C@H](CCSC)NC(=O)OCc1ccccc1)OCCO2
Product: CCOC(=O)[C@@H]1CC2(CC[C@@H]1NC(=O)[C@H](CC[S+](C)C)NC(=O)OCc1ccccc1)OCCO2
Product: [I-]
Reaction time: 16.5 h

Procedure:
Example 1, Alternative Step 9b: Methionine amide 2 (75.0 g, 0.15M) was dissolved in MeI (225 mL, 3 mL/g)—some off gassing was noted but no exotherm. The reaction mass was left to stir in the dark for 16.5 h. After this time a thick light yellow precipitate had formed. The flask was then evacuated to 200 mmHg and some of the MeI removed. The remaining material was slurried in TBMF (500 mL), after a 30 min stir-out the slurry was filtered, the cake washed with TBMF (500 mL). NMR analysis of this material indicated a small amount of MeI remaining. The cake was re-slurried in TBMF (500 mL), filtered, washed with TBMF (500 mL) and dried under vacuum to give [(3S)-3-benzyloxycarbonylamino-3-{(7R,8S)-7-ethoxycarbonyl-1,4-di-oxa-spiro[4.5]dec-8-ylcarbamoyl}-propyl]-dimethylsulfonium iodide 3 as a free flowing off-white solid (93.5 g, 97%, 99 area % purity). 1H-NMR: (300 MHz, CDCl3) δ 7.75 (d, J 9.0 Hz, 1H), 7.38-7.27 (m, 5H), 6.40 (d, J 7.0 Hz, 1H), 5.10 (s, 2H), 4.76-4.65 (m, 1H), 4.48-4.39 (m, 1H), 4.14-3.85 (m, 6H), 3.84-7.73 (m, 1H), 3.68-3.55 (m, 1H), 3.21 (s, 3H), 3.12 (s, 3H), 2.90-2.83 (s, 1H), 2.52-1.55 (m, 8H), 1.24 (t, J 7.0 Hz, 3H). HPLC: YMC-Pack Pro C18 5 μm 4.6×150 mm, 0.05% TFA (20% MeOH, 80% H2O), to 0.05% TFA (20% MeOH, 80% MeCN), 0-100% 10 min gradient. 2.45 min (I−), 8.14 min (Compound 3, 43.6 AP, I−54.6 AP). HRMS: m/z 509.2341 [Calc: C25H37N2O7S 509.2321].
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:17][C:16]3=[CH:18][N:19]=[C:20]([CH3:21])[N:15]3[C:14]2=[O:22])[CH2:9][CH2:8]1)=[O:6].C(N(CC)CC)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]=[C:44]=[O:45])=[C:39]([CH3:46])[CH:38]=1>C(#N)C>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([NH:3][CH:4]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:5]([N:7]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][C:16]4=[CH:18][N:19]=[C:20]([CH3:21])[N:15]4[C:14]3=[O:22])[CH2:9][CH2:8]2)=[O:6])=[O:45])=[C:39]([CH3:46])[CH:38]=1
Reactant: Cc1cc(Cl)ccc1N=C=O
Reactant: Cc1ncc2n1C(=O)N(C1CCN(C(=O)C(N)c3ccccc3)CC1)C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(Cl)ccc1NC(=O)NC(C(=O)N1CCC(N2Cc3cnc(C)n3C2=O)CC1)c1ccccc1
Yield: 64.3 %

Procedure:
2-(1-(2-Amino-2-phenylacetyl)-4-piperidinyl)-5-methyl-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride (0.21 g) obtained in Example 115a) was dissolved in acetonitrile (5.0 ml). Triethylamine (0.14 ml) and 4-chloro-2-methylphenyl isocyanate (80 mg) were added thereto, and mixed at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The reaction mixture was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with basic silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate). The product was crystallized from ethyl acetate-diethyl ether to obtain the title compound as colorless powder (0.16 g, 61%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][CH3:26])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]([CH3:26])[C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CNC1CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(c1ccc(F)cc1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1

Procedure:
2,5-Difluoronitrobenzene (2.69 ml, 24.84 mmol), 1-benzyl-4-methylaminopiperidine (EXAMPLE 9, 5.00 g, 24.84 mmol), and potassium carbonate (4.12 g, 29.81 mmol) are refluxed in acetonitrile for 21 hr. The mixture is then poured into water and extracted with chloroform. The extract is dried over sodium sulfate, filtered and concentrated. The concentrate is chromatographed (silica gel; ethyl acetate/hexane) to give the title compound, NMR (300 MHz, CD3OD) 7.45, 7.37, 7.29, 3.46, 2.99, 2.87, 2.64, 1.98 and 1.67δ.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:41](=[O:48])([O:45][CH2:46][CH3:47])[O:42][CH2:43]Cl>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CCOC(C)=O>[C:41](=[O:48])([O:45][CH2:46][CH3:47])[O:42][CH2:43][N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CCOC(=O)OCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)OCC)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.1 g, 0.2 mmol) and Et3N (114 μL, 0.8 mmol) in DMF (0.6 mL) was added a solution of TBAB (132 mg, 0.4 mmol) in DMF (0.2 mL). The reaction was stirred at 10° C. for 30 min, followed by dropwise addition of a solution of chloromethyl ethyl carbonate (34 mg, 0.25 mmol) in DMF (0.2 mL). The mixture was stirred at 10° C. for another 3 h, then diluted with EtOAc (40 mL) and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=2/1) to afford the title compound as a white solid (85 mg, 73%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.[CH2:24]([O:26][C:27]([C:29]1[N:30]=[C:31](Cl)[O:32][CH:33]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1[N:30]=[C:31]([NH:2][C:3]2[CH:23]=[CH:22][CH:21]=[C:5]([CH2:6][NH:7][C:8]3[C:17]4[C:12](=[C:13]([C:18](=[O:19])[NH2:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][N:9]=3)[CH:4]=2)[O:32][CH:33]=1)=[O:28])[CH3:25]
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Reactant: CCOC(=O)c1coc(Cl)n1
Agent: Cl
Product: CCOC(=O)c1coc(Nc2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2)n1

Procedure:
The title compound was prepared according to Example 684 starting 4-(3-Amino-benzylamino)-quinazoline-8-carboxylic acid amide hydrochloride and 2-Chloro-oxazole-4-carboxylic acid ethyl ester at 120° C.:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:21])[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1)(=[O:11])=[O:10].O.O.[Sn](Cl)Cl>CO.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:21])[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1)(=[O:11])=[O:10]
Reactant: CN(c1ccccc1Cl)S(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(c1ccccc1Cl)S(=O)(=O)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-(2-chlorophenyl)-N-methyl-(3-nitrophenyl)sulfonamide (2.6 mmol, 848 mg) and tin (II) chloride dihydrate (10.4 mmol, 2.35 g) were heated for 4 hr at reflux in 15 mL of methanol. The reaction mixture was cooled to room temperature and diluted with 20 mL of ethyl acetate and 10 mL of a saturated solution of aqueous sodium carbonate. Heavy gas evolution was observed upon addition of aqueous sodium carbonate to the reaction mixture. The reaction mixture was stirred 1 hr and then filtered through a plug of Celite®. The layers were separated and the organic layer was extracted once with a saturated solution of aqueous sodium carbonate, once with brine, and then dried with sodium sulfate. The crude product was purified using flash chromatography (0-5% ethyl acetate/methylene chloride) to give N-(2-chlorophenyl)-N-methyl-(3-aminophenyl)sulfonamide as an off white foam. 1H NMR (300 MHz) 3.13 (s, 3H), 3.80 (br s, 2H), 6.80-6.87 (m, 1H), 7.02-7.25 (m, 6H), 7.30-7.38 (m, 1H). MS (ESI): m/e 297.2, 299.2 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([OH:15])=O)[CH2:2][CH:3]=[CH2:4].C(Cl)(=O)C(Cl)=O.[NH:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH2:23].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([NH:23][NH:22][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:15])[CH2:2][CH:3]=[CH2:4]
Reactant: CC(C)(C)OC(=O)NN
Reactant: C=CCCOc1ccccc1CC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCCOc1ccccc1CC(=O)NNC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a solution of 2-(2-(but-3-en-1-yloxy)phenyl)acetic acid (0.22 g, 1.06 mmol, 1 equiv) in DCM (11 mL) was added one drop DMF followed by oxalyl chloride (0.19 mL, 2.11 mmol, 2 equiv). Gas evolution observed. After 1 h, the reaction was concentrated in vacuo to provide the crude acid chloride. The acid chloride was taken up in DCM (5 mL) and added slowly to a solution of tert-butyl hydrazinecarboxylate (168 mg, 1.27 mmol, 1.2 equiv) and DIPEA (0.55 mL, 3.17 mmol, 3 equiv) in DCM (11 mL). After stirring 1 h, the reaction was diluted with DCM, washed with saturated aqueous NaHCO3, dried (MgSO4), and concentrated in vacuo. The crude product was purified via flash column chromatography (0-100% EtOAc/hexane) to provide the product (0.28 g, 83%) as a viscous tan oil. 1H NMR (400 MHz, CDCl3) δ 7.62 (br. s., 1H), 7.31-7.23 (m, 2H), 7.00-6.87 (m, 2H), 6.48-6.26 (m, 1H), 5.99-5.85 (m, 1H), 5.23 (dd, J=17.1, 1.5 Hz, 1H), 5.17 (d, J=10.3 Hz, 1H), 4.14-4.09 (m, 2H), 3.61 (s, 2H), 2.61 (q, J=6.4 Hz, 2H), 1.48-1.36 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][N:38]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:25]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][N:38]=1)=[O:27]
Reactant: Nc1ccc(Cl)cn1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccc(Cl)cn4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline 50 mg) was dissolved in chloroform (5 ml) and triethylamine (1 ml), and a solution of triphosgene (45 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, 2-amino-5-chloropyridine (23 mg) was added to the reaction solution, and the mixture was stirred at 60° C. for additional one hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 39 mg (yield 53%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][C:11](=O)[CH:12]=[CH2:13].[NH2:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]1[N:25]([C:22]2[CH:23]=[CH:24][C:19]([S:16]([NH2:15])(=[O:17])=[O:18])=[CH:20][CH:21]=2)[C:11]([CH3:10])=[CH:12][CH:13]=1
Reactant: O=Cc1ccccc1F
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: C=CC(C)=O
Product: Cc1ccc(-c2ccccc2F)n1-c1ccc(S(N)(=O)=O)cc1

Procedure:
2-Fluorobenzaldehyde and but-3-en-2-one were treated according to the procedure outlined in General Procedure C followed by subjecting the resulting product to conditions outlined in General Procedure D along with p-aminosulfonyl phenylamine to obtain the titled compound. 1H NMR (CDCl3) δ ppm 2.18 (3H), 4.71 (2H), 6.13 (1H), 6.34 (1H), 7.05-7.90 (8H); MS (ESI) m/z 331 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:28][CH2:29][N:30]3[C@H:35]4[CH2:36][CH2:37][C@@H:31]3[CH2:32][CH:33]([N:38]3[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=5[N:40]=[C:39]3[CH3:47])[CH2:34]4)[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]([NH:20]C(=O)OC(C)(C)C)[CH:17]([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:28][CH2:29][N:30]3[C@H:31]4[CH2:37][CH2:36][C@@H:35]3[CH2:34][CH:33]([N:38]3[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=5[N:40]=[C:39]3[CH3:47])[CH2:32]4)[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]([NH2:20])[CH:17]([CH3:18])[CH3:19])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)CC1
Agent: Cl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H](N)C(C)C)CC1
Yield: 98.8 %

Procedure:
2-chloro-N-{(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2-methylpropyl}acetamide was obtained from treating 1,1-dimethylethyl {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-2-methylpropyl}carbamate (0.614 g, 0.95 mmol) with HCl as outlined in the procedure for Example 890 to form {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-2-methylpropyl}amine (0.512 g, 99%). {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-2-methylpropyl}amine (0.050 g, 0.09 mmol), Chloro-acetyl chloride (0.011 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2-chloro-N{(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2-methylpropyl}acetamide (0.037 g, 66%) as an oil. ES-LCMS m/z 622 (M+1).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH:6]=[C:5]([CH2:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>C(Cl)Cl.O>[S:10]1[CH:11]=[CH:12][N:13]=[C:9]1[CH2:8][C:5]1[CH2:4][CH2:3][N:2]([C:21](=[O:24])[CH:22]=[CH2:23])[CH2:7][CH:6]=1
Reactant: C1=C(Cc2nccs2)CCNC1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CC=C(Cc2nccs2)CC1
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 25.6 %

Procedure:
To a stirred suspension of 2-((1,2,3,6-tetrahydropyridin-4-yl)methyl)thiazole hydrochloride (Intermediate-2) (1.57 g, 5.34 mmol) in anhydrous CH2Cl2 (20 mL) was added triethylamine (4.4 mL, 32.0 mmol), followed by acryloyl chloride (1.3 mL, 16.0 mmol) at 0° C. and the reaction mixture was allowed to stir at 20-35° C. for 16 h. Then the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was rotary evaporated under vacuum to get residue which was purified by column chromatography using a mixture of 20% ethyl acetate/hexane as an eluent to get the desired compound as a light brown liquid (320 mg, 26%); 1H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J=3.4 Hz, 1H), 7.60 (d, J=2.9 Hz, 1H), 6.88-6.70 (m, 1H), 6.14-6.08 (m, 1H), 5.72-5.60 (m, 2H), 4.12-4.08 (m, 1H), 4.06-3.96 (m, 1H), 3.74-3.70 (m, 2H), 3.66-3.54 (m, 2H), 2.12-2.02 (m, 2H); ES-MS: 235.1 (M+1)+.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[N:5][N:4]=[CH:3]1.C(#N)C.[Br:10][CH2:11][CH:12]1[CH2:14][CH2:13]1.NN1C=NN=C1.C(#N)C>C(O)(C)C.C(OCC)C>[Br-:10].[CH3:11][C:12]1([N+:5]2[N:4]=[CH:3][N:2]([NH2:1])[CH:6]=2)[CH2:14][CH2:13]1
Reactant: Nn1cnnc1
Reactant: BrCC1CC1
Solvent: CC#N
Solvent: CC(C)O
Solvent: CCOCC
Product: CC1([n+]2cn(N)cn2)CC1
Product: [Br-]
Temperature: 50 °C

Procedure:
4-amino-1,2,4-triazole 3.2154 g, 38.2 mmoles, was weighed out and dissolved into 100 ml of acetonitrile in three necked, round bottomed 250 ml flask equipped with an overhead stirrer. Bromomethylcyclopropane, 10.7539 g, 79.6 mmoles, was weighed out and added slowly to the vigorously stirred 4-amino-1,2,4-triazole/acetonitrile solution. Reaction mixture was heated to 50° C. for 5 days, at which time, thin layer chromatography revealed that no 4-amino-1,2,4-triazole remained. The reaction solution was then cooled, and transferred to a large round bottomed flask and the solvent and excess bromomethylcyclopropane rotary evaporated away. The oil was transferred to a preweighed Schlenk flask using a minimal amount of acetonitrile three 10 ml aliquots. The flask and its contents were evacuated for 20 hours at ambient temperature to leave a beige crystalline solid. This solid was then transferred to a 500 ml round bottom flask, and dissolved in hot isopropanol 200 ml. The flask was then placed in a refrigerator overnight to cool. The next day the solution was layered with 100 ml of diethyl ether and returned to cold storage. Upon standing, a large crop of white crystals were formed of 1-methylcyclopropyl-4-amino-1,2,4-triazolium bromide which were washed with three 50 ml aliquots of cold isopropyl alcohol and vacuum dried to a constant weight of 4.8167 g, 22 mmoles. Melting point: 61-63° C.; DSC onset: 150-155° C.