Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][CH:3]=1.CO.[CH2:15]([NH2:17])[CH3:16]>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:17][CH2:15][CH3:16])=[N:4][CH:3]=1
Reactant: CCN
Reactant: Clc1ncc(Br)c2ccccc12
Solvent: CO
Product: CCNc1ncc(Br)c2ccccc12
Temperature: 50 °C
Yield: 88 %

Procedure:
To a suspension of 4-bromo-1 chloroisoquinoline (0.831 g, 3.43 mmol) in MeOH (10.3 mL, 254 mmol) was added ethylamine (70% in water, 1.1 mL). The mixture was heated at 50° C. for 16 h. The mixture was concentrated. The residue was partitioned between water (20 mL) and DCM (20 mL). DCM layer was separated. The aqueous layer was extracted with DCM (10 mL). The combined DCM solutions were dried (Na2SO4). Filtration and concentration gave 4-bromo-N-ethylisoquinolin-1-amine (0.761 g, 88%). LCMS: M+H+=251.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH2:13][CH:14]([S:16]([CH2:18][CH3:19])=[O:17])[CH3:15])[CH2:8][C:7]1=[O:20])(=O)[CH2:2][CH2:3][CH3:4].[CH2:21]([O:24][NH2:25])[CH:22]=[CH2:23]>C(O)C>[CH2:21]([O:24][NH:25][C:1](=[C:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH2:13][CH:14]([S:16]([CH2:18][CH3:19])=[O:17])[CH3:15])[CH2:8][C:7]1=[O:20])[CH2:2][CH2:3][CH3:4])[CH:22]=[CH2:23]
Reactant: C=CCON
Reactant: CCCC(=O)C1C(=O)CC(CC(C)S(=O)CC)CC1=O
Solvent: CCO
Product: C=CCONC(CCC)=C1C(=O)CC(CC(C)S(=O)CC)CC1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 67.6 %

Procedure:
6 g of 2-butyryl-5-(2-ethylsulfinylpropyl)-cyclohexane-1,3-dione was dissolved in 30 ml of ethanol. To the solution was added 1.6 g of allyloxyamine and the resulting solution was stirred at room temperature for 15 hours. After completion of the reaction, the reaction solution was treated as in Example 1 to obtain 4.8 g of the desired compound as colorless oily material.
Reaction SMILES: [CH:1](=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]=[C:12]1[O:16][C:14](=[O:15])[CH2:13]1.Cl.[CH:18]([OH:21])([CH3:20])[CH3:19]>ClCCl>[OH:10][CH:1](/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:11][C:12](=[O:16])[CH2:13][C:14]([O:21][CH:18]([CH3:20])[CH3:19])=[O:15]
Reactant: C=C1CC(=O)O1
Reactant: O=C/C=C/c1ccccc1
Reactant: CC(C)O
Agent: Cl
Solvent: ClCCl
Product: CC(C)OC(=O)CC(=O)CC(O)/C=C/c1ccccc1
Temperature: -25 °C
Yield: 14 %

Procedure:
In an atmosphere of argon, 10 ml of dichloromethane and 2.5 ml (5.0 mmol) of the above titanium dichlorodiiso-propoxide-dichloromethane solution were placed in a schlenk tube, and cooled to -25° C. with stirring. To the dichloromethane solution, 0.656 g (5.0 mmol) of E-cinnamaldehyde and 0.77 ml (10 mmol) of diketene were added, and were vigorously stirred at -25° C. over 69 hours to obtain a reaction mixture. To the reaction mixture, 1.5 ml of isopropyl alcohol was added, and was vigorously stirred at -25° C. over 1 hour. The reaction mixture was added to a mixed solution of 25 ml of 1N HCl and 25 ml of dichloromethane, and vigorously stirred at room temperature over 2 hours to give a solution. The solution was extracted with three portions of 5 ml of dichloromethane. The dichloromethane portions were combined, and dried by adding anhydrous magnesium sulfate. The solvent of the solution was removed by distillation in vacuo to obtain a concentrated solution. The concentrated solution was placed on a silica gel column and eluted with a mixture of hexane and ethyl acetate (hexane:ethyl acetate=7:3) to give 0.188 g of isopropyl E-5-hydroxy-3-oxo-7-phenyl-6-heptenoate (yield: 14% based on the amount of E-cinnamaldehyde).
Reaction SMILES: N[C:2]1C(C)=CC=CC=1C(OC)=O.[CH:13]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][CH:22]([N:26]([C:42](=[O:44])[CH3:43])[CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[C:21]2[CH:45]=[CH:46][CH:47]=[CH:48][C:20]1=2)=[O:18])([CH3:15])[CH3:14]>>[C:42]([N:26]([CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[C:30]([C:38]([F:39])([F:40])[F:41])[CH:29]=1)[CH:22]1[CH2:23][CH2:24][CH2:25][N:19]([C:17]([O:16][CH:13]([CH3:15])[CH3:14])=[O:18])[C:20]2[C:48]([CH3:2])=[CH:47][CH:46]=[CH:45][C:21]1=2)(=[O:44])[CH3:43]
Reactant: COC(=O)c1cccc(C)c1N
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccccc21
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(C)cccc21

Procedure:
This compound was prepared utilizing the same methodology described in Example 1 wherein replacement of 2-amino-benzoic acid methyl ester with methyl 2-amino-3-methylbenzoate following the procedure of Example 1, Steps 1-8 for the synthesis of 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid isopropyl ester. CI MS 531 (M+H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[CH:7]=[C:8]([SH:13])[CH:9]=[C:10]([CH3:12])[CH:11]=1.[C:14](Cl)(=[O:18])[C:15](Cl)=[O:16]>C(Cl)Cl>[CH3:12][C:10]1[C:9]2[C:15](=[O:16])[C:14](=[O:18])[S:13][C:8]=2[CH:7]=[C:6]([CH3:5])[CH:11]=1
Reactant: Cc1cc(C)cc(S)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C)c2c(c1)SC(=O)C2=O
Temperature: 25 °C
Yield: 36.1 %

Procedure:
To a solution of aluminum chloride (AlCl3) (0.4 g, 3.6 mmol) in CH2Cl2 (4 mL) at −20° C. under nitrogen were added 3,5-dimethylbenzenethiol (1 g, 7.2 mmol) and oxalyl chloride (0.6 mL, 7.2 mmol) respectively. The solution was warmed to room temperature for 1 hour and was heated to 120° C. in a microwave reactor for 15 minutes. The solution was cooled down and was poured into crashed ice. The solution was extracted with CH2Cl2 and the organic layer was collected. The solution was dried with MgSO4 and was filtered. The filtrate was concentrated and the residue was purified by silica gel flash column chromatography with 5% EtOAc in Hexane as the eluent to afford the title compound (500 mg, 35%).
Reaction SMILES: N1C2C(=NC=CC=2)N([O:10][C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=O)N=1.[CH3:43][NH2:44]>CC(N(C)C)=O>[CH3:43][NH:44][C:11]([C:13]1[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]2\[C:21](=[O:41])[NH:22][C:23]3[C:28]\2=[CH:27][C:26]([S:29]([CH2:32][C:33]2[C:34]([Cl:40])=[CH:35][CH:36]=[CH:37][C:38]=2[Cl:39])(=[O:30])=[O:31])=[CH:25][CH:24]=3)[NH:15][C:14]=1[CH3:42])=[O:10]
Reactant: CN
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)On1nnc2cccnc21
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (100 mg, 0.162 mmol) in DMA (2 mL) was added methylamine (2 eq.). The mixture was stirred at rt for 2 hours. The reaction was concentrated, diluted with DCM, washed with sat. NaHCO3 and water, concentrated and triturated with methanol to give the titled compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1.Cl[C:20]1[N:30]=[C:29]2[C:23]([N:24]([CH3:35])[C:25](=[O:34])[CH2:26][CH2:27][N:28]2[CH:31]([CH3:33])[CH3:32])=[CH:22][N:21]=1.CCO.Cl>CO.O>[CH3:35][N:24]1[C:25](=[O:34])[CH2:26][CH2:27][N:28]([CH:31]([CH3:33])[CH3:32])[C:29]2[C:23]1=[CH:22][N:21]=[C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)=[O:7])=[CH:17][CH:18]=1)[N:30]=2
Reactant: CC(C)N1CCC(=O)N(C)c2cnc(Cl)nc21
Reactant: Nc1ccc(C(=O)NCCN2CCOCC2)cc1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCO
Product: CC(C)N1CCC(=O)N(C)c2cnc(Nc3ccc(C(=O)NCCN4CCOCC4)cc3)nc21
Temperature: 25 °C

Procedure:
4-amino-N-(2-morpholin-4-ylethyl)benzamide (Buttpark; 188 mg, 0.75 mmol) and 10-chloro-6-methyl-2-propan-2-yl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 76; 160 mg, 0.63 mmol) were heated together in 1:3 EtOH:water (8 ml) in the presence of concentrated hydrochloric acid (126 ul) for 24 hours. The reaction was cooled to ambient temperature and then loaded onto an SCX-2 (5 g) column pre-wet with methanol. The product was eluted with 2M NH3/MeOH and the solvent evaporated to give product as a brown gum. This was purified by reverse phase HPLC to give the title compound a white solid. (125 mg, 42%)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26](O)=[O:27])[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][NH:36][CH2:37][CH2:38][CH2:39][OH:40]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)[CH2:25][C:26]([N:36]([CH2:37][CH2:38][CH2:39][OH:40])[CH2:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)=[O:27])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3ncccc3c2)cc1
Reactant: OCCCNCc1ccccn1
Product: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)N(CCCO)Cc2ccccn2)c2ccc3ncccc3c2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-acetic acid with 3-[(pyridin-2-ylmethyl)-amino]-propan-1-ol
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C:10](=[O:14])[C@@H:9]1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([Mg]Cl)[CH:23]=[CH2:24]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@:10]([OH:14])([CH2:24][CH:23]=[CH2:22])[C@@H:9]1[C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OCCN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Reactant: C=CC[Mg]Cl
Solvent: C1CCOC1
Product: C=CC[C@@]1(O)OCCN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(3S)-4-Benzyl-3-(4-fluorophenyl)-2-morpholinone (13.6 g, 47.6 mmol) was dissolved in anhydrous tetrahydrofuran (200 ml) and cooled to below -70° C. under an inert atmosphere. Allyl magnesium chloride (26.2 ml of a 2.0M solution in tetrahydrofuran; 52.4 mmol) was added dropwise over 15 minutes, maintaining the temperature below -70° C. After 30 minutes, the reaction was quenched by the addition of a saturated solution of ammonium chloride and allowed to warm to room temperature. The resulting suspension was extracted with ethyl acetate (3×100 ml), and the combined organic extracts dried (MgSO4) and concentrated in vacuo to yield the tide compound in ~3:1 mixture of the lactols as a light yellow oil (15.3 g, 98%), which was used without further purification. MS (ES+) m/z 328 (M+1, 22%), 310 (M--OH, 61), 269 (100).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[OH:15])[C:8]([O:10][CH3:11])=[O:9])#[N:4].BrCCO[Si]([C:23](C)([CH3:25])[CH3:24])(C)C>CN(C=O)C.CCOC(C)=O>[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH:23]([CH3:25])[CH3:24])[C:8]([O:10][CH3:11])=[O:9])#[N:4]
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Reaction time: 1.5 h
Yield: 84.2 %

Procedure:
To a suspension of NaH (0.39 g, 9.3 mmol) in DMF (15 mL) was added a solution of 3 (1.9 g, 6.5 mmol) in DMF (10 mL) at 0° C. under nitrogen. The reaction was stirred for 1.5 h, and then (2-bromoethoxy)-tert-butyldimethylsilane (2.09 mL, 9.7 mmol) was added. The reaction mixture was stirred overnight, diluted with EtOAc, quenched with aqueous ammonium chloride solution, and extracted with EtOAc (3×50 mL). The organic layers were combined and dried over Na2SO4. Purification with over silica gel (EtOAc) gave the product 4 (1.2 g, 41%) as a light yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][C:15]([S:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[CH:9]\[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:34]=[C:33](OC/C=C(/C2C=CC(C#CCN3CCOCC3)=CC=2)\C2C=CC=CC=2)[CH:32]=[CH:31][C:25]=1[O:26][CH2:27][C:28]([OH:30])=[O:29].[C:60]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[I:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][C:15]([S:18][C:19]([F:22])([F:20])[F:21])=[CH:14][CH:13]=2)=[CH:9]\[CH2:10][O:11][C:33]2[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([O:30][CH3:60])=[O:29])=[C:24]([CH3:23])[CH:34]=2)=[CH:4][CH:3]=1
Reactant: OC/C=C(\c1ccc(I)cc1)c1ccc(SC(F)(F)F)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1cc(OC/C=C(\c2ccccc2)c2ccc(C#CCN3CCOCC3)cc2)ccc1OCC(=O)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(SC(F)(F)F)cc2)cc1C
Temperature: 0 °C
Reaction time: 5 h

Procedure:
The above allyl alcohol (1.09 g, 2.4 mmol), methyl (4-hydroxy-2-methylphenoxy)acetate (0.549 g, 27.9 mmol; example 2) and triphenylphosphine (0.755 g, 28.8 mmol) were dissolved in a mixture of anhydrous toluene (20 mL) and tetrahydrofuran (10 mL). The mixture was cooled to 0° C., kept under argon and a degassed solution of diisopropyl azodicarboxylate (0.56 mL, 28.8 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise during 30 min. The reaction mixture was allowed to warm up the ambient temperature with the bath and then was stirred for 5 h. The solvents were evaporated in vacuo and the residue was submitted to flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 10:1) affording methyl (Z)-[4-[3-(4-iodophenyl)-3-[4-(trifluoromethyl-sulfanyl)phenyl]allyloxy]-2-methylphenoxy]acetate as solid mass.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]1[CH2:53][CH2:52][C:47]2([O:51][CH2:50][CH2:49][O:48]2)[CH2:46][CH2:45]1)=O>>[O:51]1[C:47]2([CH2:52][CH2:53][N:44]([CH2:42][CH2:41][O:39][C:38]3[CH:37]=[CH:36][C:4]([CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]4[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=4[CH:16]4[CH2:25][CH2:24][C:23]5[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=5[CH2:17]4)=[CH:3][C:2]=3[F:1])[CH2:45][CH2:46]2)[O:48][CH2:49][CH2:50]1
Reactant: O=C(CCl)N1CCC2(CC1)OCCO2
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCC4(CC3)OCCO4)c(F)c2)C(C)C)c1
Yield: 21.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-1-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethanone (21 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.2 mg) was obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]1)[C:12]([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[CH2:11]([N:16]1[CH2:21][CH2:20][CH:19]([CH:22]=[O:23])[CH2:18][CH2:17]1)[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)CN1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)CN1CCC(C=O)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a solution of oxalyl chloride (490 μL, 5.6 mmol) in DCM (10 mL) at −78° C. was added DMSO (796 μL, 11.2 mmol) dropwise followed by the addition of a solution of 20b (943 mg, 5.6 mmol) in DCM (2 mL). The mixture was stirred at −78° C. for 30 min and TEA (3.6 mL, 25.5 mmol) was added. The reaction was stirred at −78° C. for 5 min, warmed to rt and stirred at rt for 30 min. The reaction was quenched with water and extracted with DCM. The organic layers were combined and washed with water, dried over magnesium sulfate to give 20c as a yellow semi-solid (880 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:9]2[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH:15]([CH3:17])[CH3:16])[S:5]1(=[O:19])=[O:18].[F:20][C:21]1[CH:29]=[C:28]2[C:24]([C:25]([C:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH:31]=3)=[CH:26][NH:27]2)=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>O>[F:14][C:10]1[C:9]2[N:4]([CH2:3][CH2:2][N:33]3[CH2:34][CH2:35][C:30]([C:25]4[C:24]5[C:28](=[CH:29][C:21]([F:20])=[CH:22][CH:23]=5)[NH:27][CH:26]=4)=[CH:31][CH2:32]3)[S:5](=[O:19])(=[O:18])[N:6]([CH:15]([CH3:17])[CH3:16])[CH2:7][C:8]=2[CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)N1Cc2cccc(F)c2N(CCCl)S1(=O)=O
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)N1Cc2cccc(F)c2N(CCN2CC=C(c3c[nH]c4cc(F)ccc34)CC2)S1(=O)=O
Temperature: 100 °C

Procedure:
A suspension of 1-(2-chloroethyl)-3,4-dihydro-8-fluoro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide (1.35 g), 4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine (31.45 g, 6.7 mmol) and Na2CO3 (3.6 g, 34.6 mmol) in water (8 ml) was heated at 100° C. under argon atmosphere for 30 hours. After cooling to room temperature the product was extracted with dichloromethane. The organic phase was dried over Na2SO4 and evaporated to dryness. The crude mixture was purified by flash chromatography using as eluent CH2Cl2 /MeOH (97:3) yielding 3,4-dihydro-8-fluoro-1-{2-[4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl]-1-ethyl}-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide as a pale brown solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:9][CH:8]=[C:7]([O:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=1)[CH3:3].[CH3:15][S:16]([Cl:19])(=[O:18])=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[ClH:19].[CH3:15][S:16]([O:14][CH2:13][CH2:12][CH2:11][O:10][C:7]1[CH:6]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[S:9][CH:8]=1)(=[O:18])=[O:17]
Reactant: CN(C)Cc1cc(OCCCO)cs1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)Cc1cc(OCCCOS(C)(=O)=O)cs1
Product: Cl
Temperature: 0 °C

Procedure:
A solution of 3-[5-(dimethylaminomethyl)-3-thienyloxy]-1-propanol (0.25 g) and methanesulphonyl chloride (0.1 ml) in dry dichloromethane (10 ml) at 0°-5° was stirred for 1 h. The mixture was poured onto an ice cold 4% aqueous solution of sodium carbonate (50 ml). The solution was extracted with dichloromethane (20 ml). The organic extract was evaporated to give the title compound (0.05 g) as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([OH:12])[CH2:6][C:5]1([CH3:14])[CH3:13].[C:15]([C:17]1[C:18]([F:40])=[CH:19][C:20](F)=[C:21]([NH:23][C:24]2[N:29]=[C:28]([NH:30][CH:31]3[CH2:33][CH2:32]3)[C:27]3=[N:34][CH:35]=[C:36]([C:37]#[N:38])[N:26]3[N:25]=2)[CH:22]=1)#[N:16]>CN(C=O)C>[NH3:4].[C:15]([C:17]1[C:18]([F:40])=[CH:19][C:20]([O:12][CH:7]2[CH2:8][C:9]([CH3:10])([CH3:11])[N:4]([CH3:3])[C:5]([CH3:14])([CH3:13])[CH2:6]2)=[C:21]([NH:23][C:24]2[N:29]=[C:28]([NH:30][CH:31]3[CH2:33][CH2:32]3)[C:27]3=[N:34][CH:35]=[C:36]([C:37]#[N:38])[N:26]3[N:25]=2)[CH:22]=1)#[N:16]
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Reactant: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(C)(C)CC(Oc2cc(F)c(C#N)cc2Nc2nc(NC3CC3)c3ncc(C#N)n3n2)CC1(C)C
Product: N
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 52.5 %
Yield: 1 %

Procedure:
NaH (60% in mineral oil, 18 mg, 0.45 mmol) added to a solution of 1,2,2,6,6-pentamethylpiperidin-4-ol (73 mg, 0.43 mmol) in dry DMF (1 mL) at RT. This was left stirring for 30 min and then solid 2-((5-cyano-2,4-difluorophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 414) (50 mg, 0.14 mmol) was added. The reaction was left stirring at RT for 3/4 hr and then heated at 55° C. for 7 hr. It was quenched with sat. aq. NH4Cl solution (0.5 mL) and diluted with DCM. After washing with water (3×), the organic phase was dried with sodium sulfate. The solvent was removed and radial silica gel chromatography with DCM containing 0 to 3% MeOH and then 1 to 4% 2N NH3 in MeOH afforded the title compound (37 mg) as a glass.
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[CH2:5]1[O:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[O:6]1>>[CH2:2]([O:14][C:11]1[CH:12]=[CH:13][C:7]2[O:6][CH2:5][O:9][C:8]=2[CH:10]=1)[CH2:3][CH3:4]
Reactant: CCCI
Reactant: Oc1ccc2c(c1)OCO2
Product: CCCOc1ccc2c(c1)OCO2

Procedure:
Starting from commercially available iodopropane and sesamol the title compound is obtained as colorless oil.
Reaction SMILES: [SiH:1]([OH:4])([OH:3])[OH:2].Cl[SiH3].C[Si](C)(C)C1([Si](O)(O)O)C=CC=C1.C[Si](C)(C)C1([Si](Cl)(Cl)Cl)C=CC=C1.N[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(OCC)C>[C:34]1([Si:1]([OH:4])([OH:3])[OH:2])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Nc1ccccc1
Reactant: O[SiH](O)O
Agent: C[Si](C)(C)C1([Si](Cl)(Cl)Cl)C=CC=C1
Agent: C[Si](C)(C)C1([Si](O)(O)O)C=CC=C1
Agent: [SiH3]Cl
Solvent: CCOCC
Product: O[Si](O)(O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
In general, silanetriol is synthesized by hydrolyzing chlorosilane or alkoxysilane. As a typical example of using chlorosilane, Jutzi et al. reported synthesis of (1-trimethylsilylcyclopenta-2,-4-dienyl)silanetriol with a yield of 98% by dissolving (1-trimethylsilylcyclopenta-2,-4-dienyl)trichlorosilane, a chlorosilane with large steric hindrance, in ethyl ether, slowly adding an aniline aqueous solution and stirring at 0° C. for 3 hours, removing the resulting aniline salt through filtration and then removing ethyl ether under reduced pressure [Organometallics 1997, 16, 5377]. However, this method involves a complicated process of removing a large amount of salts and is limited in that it is applicable only to silanes having substituents with large steric hindrance. As a typical example of using alkoxysilane, Ishida et al. obtained cyclohexylsilanetriol by mixing cyclohexyltrimethoxysilane in an aqueous solution of acetic acid and stirring for 2 hours at room temperature [J. Polym. Sci. 1979, 17, 1807]. In addition, Korkin et al. reported that they obtained phenylsilanetriol with a yield of 68% by adding phenyltrimethoxysilane dropwise to an acetic acid aqueous solution, stirring for 4 hours while maintaining temperature at 5-10° C. and removing impurities from the resulting white solid through filtration [J. Organomet. Chem. 2003, 686, 313]. However, the method of using alkoxysilane is limited in that the resultant silanetriol should be insoluble in water.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25](Br)[N:26]=3)[N:21](COCC[Si](C)(C)C)[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].C(C1CCN(C(=O)[C@H](NC(C2C3C(=NC=C(Br)N=3)N(COCC[Si](C)(C)C)C=2)=O)C2CC2)CC1)#N.[CH3:72][O:73][C:74]1[CH:79]=[CH:78][N:77]=[C:76]([Sn](CCCC)(CCCC)CCCC)[CH:75]=1.C(C1C=CN=C([Sn](CCCC)(CCCC)CCCC)C=1)(C)(C)C>>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:76]4[CH:75]=[C:74]([O:73][CH3:72])[CH:79]=[CH:78][N:77]=4)[N:26]=3)[NH:21][CH:20]=2)=[O:18])[C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(OC)ccn1
Reactant: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CCC(C#N)CC1
Agent: CCCC[Sn](CCCC)(CCCC)c1cc(C(C)(C)C)ccn1
Agent: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Product: COc1ccnc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CCC(C#N)CC4)C(C)(C)C)c3n2)c1

Procedure:
Prepared according to the procedure outlined in Example 111, steps 4-5 substituting 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide for 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide and 4-methoxy-2-tributylstannanyl-pyridine for 4-tert-butyl-2-(tributylstannyl)pyridine. MS: (M+H)+=476.