Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:11]=[C:12]4[C:16](=[C:17]([C:19]([NH2:21])=[O:20])[CH:18]=3)[NH:15][CH:14]=[C:13]4[CH:22]3[CH2:27][CH2:26][N:25]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH2:24][CH2:23]3)=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[C:33]1([S:39]([N:42]=[C:43]=[O:44])(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CS(C)=O>[CH2:31]([S:28]([N:25]1[CH2:26][CH2:27][CH:22]([C:13]2[C:12]3[C:16](=[C:17]([C:19]([NH2:21])=[O:20])[CH:18]=[C:10]([C:6]4[CH:5]=[C:4]5[C:9](=[CH:8][CH:7]=4)[CH2:1][N:2]([C:43]([NH:42][S:39]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)(=[O:41])=[O:40])=[O:44])[CH2:3]5)[CH:11]=3)[NH:15][CH:14]=2)[CH2:23][CH2:24]1)(=[O:29])=[O:30])[CH3:32]
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)CNC5)cc23)CC1
Solvent: CS(C)=O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)CN(C(=O)NS(=O)(=O)c4ccccc4)C5)cc23)CC1
Yield: 36.9 %

Procedure:
To a solution of 5-(2,3-dihydro-1H-isoindol-5-yl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.066 mmol) in DMSO (1.0 mL), was added benzenesulfonyl isocyanate (15 mg, 0.079 mmol). The resultant mixture was stirred overnight at room temperature. Mixture purified by Gilson Preparatory HPLC to give 15.5 mg of the title compound.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH:25]1[CH2:27][CH2:26]1>CC#N>[Br-:23].[CH:25]1([CH2:24][N+:1]23[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)([CH2:3][CH2:2]2)[CH2:7][CH2:8]3)[CH2:27][CH2:26]1
Reactant: BrCC1CC1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CC3CC3)(CC1)CC2
Product: [Br-]
Temperature: 60 °C
Yield: 39.6 %

Procedure:
To a solution of 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0552 g, 0.188 mmol) in 2 CH3CN/3CHCl3 (2.5 mL) was added (bromomethyl)cyclopropane (0.025 mL, 0.257 mmol). The solution was heated at 60° C. for 16 h, cooled down to room temperature and the solvents evaporated under vacuum. The residue was taken up in 2.5 mL of DMSO and purified by preparatory HPLC (without TFA) to give the title compound (0.0319 g, 39.9%). EI-MS m/z 348(M+) Rt (1.69 min).
Reaction SMILES: Br[CH2:2][CH:3]1[CH:7]([CH2:8]Br)[O:6][C:5](=O)[O:4]1.N12CCCNC1C=CCC[CH2:12]2.[CH2:22]([OH:24])[CH3:23].C(OCC)C.CCCCCC>C(Cl)Cl>[CH2:7]([O:6][C:5]([O:4][CH2:3][CH3:2])([CH3:12])[C:22](=[O:24])[CH3:23])[CH3:8]
Reactant: O=C1OC(CBr)C(CBr)O1
Reactant: CCO
Reactant: C1=CC2NCCCN2CCC1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOC(C)(OCC)C(C)=O
Temperature: 20 °C
Reaction time: 5 h
Yield: 9 %

Procedure:
A mixture of 4,5-dibromomethyl-1,3-dioxolan-2-one (2.07 g, 7.6 mmole) and 1,8-diazabicyclo[5.4.0]undec-5-ene (2.26 ml, 15.2 mmole) in CH2Cl2 (20 ml) was stirred at 20° C. for 5 h, then anhydrous ethanol (5.0 ml, 85 mmole) was added, and the resulting mixture was stirred at 20° C. for 10 h. Flash chromatography (ethyl ether-hexane eluent) of the reaction mixture yielded 3,3-diethoxy-2-butanone as a colorless liquid (110 mg, 10%): IR (AgCl) 2965, 1722, 1350, 1253, 1133, 1050, 954 cm-1 ; 'H NMR (CDCl3) 1.23 (m, 9 H), 2.28 (s, 3 H), 3.50(q, J=7.5 Hz, 4 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](O)=O)[CH:6]=[CH:7][CH:8]=1.C[N:14]([CH3:17])C=O.[C:18](Cl)(=O)[C:19]([Cl:21])=[O:20]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[CH2:18][CH2:17][NH:14][CH2:10][CH2:9][C:5]=2[CH:4]=1.[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:18][C:19]([Cl:21])=[O:20])[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C=O
Reactant: COc1cccc(CC(=O)O)c1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCNCC2
Product: COc1cccc(CC(=O)Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The title compound was synthesized by referring to the synthetic method of EP285287. To a solution of (3-methoxyphenyl)acetic acid (16 g) in tetrahydrofuran (150 ml) were sequentially added N,N-dimethylformamide (0.1 ml) and oxalyl chloride (10 ml) under a nitrogen atmosphere, the solution was stirred for 5 hours at room temperature, and then the reaction mixture was concentrated in vacuo to provide (3-methoxyphenyl)acetyl chloride (18.8 g). To a solution of aminoacetaldehyde dimethylacetal (11 g) and triethylamine (11 g) in chloroform (150 ml) was added (3-methoxyphenyl)acetyl chloride (18.8 g) on an ice bath, and the solution was stirred for 9.5 hours at room temperature. Water was added thereto, the solution was stirred, extracted with ethyl acetate, then sequentially washed with water and brine, and the solvent was evaporated in vacuo. Obtained by purifying the residue by NH silica gel column chromatography (hexane-ethyl acetate system), a solution of N-(2,2-dimethoxyethyl)-2-(3-methoxyphenyl)acetamide (24.9 g) in acetic acid (75 ml) was added dropwise to concentrated hydrochloric acid (50 ml), and the solution was stirred overnight at room temperature. The reaction mixture was poured into an ice water, ethyl acetate and tetrahydrofuran were sequentially added thereto, insoluble material was removed by filtration, then the filtrate was concentrated in vacuo. To the residue was added water, the resulting solid was filtered and collected. To a solution of the resulting 8-methoxy-1,3-dihydrobenz[d]azepin-2-one (6.3 g) in acetic acid (100 ml) was added 10% palladium-activated charcoal (1.5 g), and the solution was stirred for 23 hours at room temperature under a hydrogen atmosphere at 4 atmospheric pressures. After filtration through celite pad, the solvent was evaporated in vacuo, was neutralized by sequentially adding water and aqueous ammonia. The resulting solid was filtered to provide 8-methoxy-1,3,4,5-tetrahydrobenz[d]azepin-2-one (5.6 g). To a suspension of this compound (1.5 g) in tetrahydrofuran (15 ml) was added dropwise borane-tetrahydrofuran complex (1.0 M solution in tetrahydrofuran) (15 ml), and the solution was refluxed for 2 hours. 5N hydrochloric acid (5 ml) was added thereto on an ice bath, the solution was refluxed for 45 minutes, and then neutralized with aqueous ammonia. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (752 mg).
Reaction SMILES: O[CH2:2][C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1CCCCC1.[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[CH2:28][CH3:29])[CH:23]=[O:24].CO>O>[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[CH:28]([CH3:2])[CH3:29])[CH:23]=[O:24]
Reactant: CCc1ccc(C=O)cc1Br
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Solvent: CO
Solvent: O
Solvent: C1CCCCC1
Product: CC(C)c1ccc(C=O)cc1Br
Temperature: 41.79999923706055 °C
Yield: 207.7 %

Procedure:
A one liter four-necked cylindrical shaped reaction flask equipped with a Dean-Stark trap, condenser, thermometer, nitrogen inlet, and a mechanical stirrer was charged with 42 g of D-sorbitol (0.23 mole), 700 mL of cyclohexane, 105 g of 3-bromo-4-ethylbenzaldehyde (0.46 moles), 80 mL of methanol, and 2.5 g of water. The system was then flushed with argon and heated in an oil bath with stirring. The mixture was then heated to a vapor temperature of 41.8° C., at which time 3.0 g of p-toluenesulfonic acid in 40 mL of methanol was slowly added. The reaction was seeded with 1.0 g of 3,4-dimethylbenzylidene sorbitol in 20 mL of methanol. The reaction was then stirred and heated (to about 120° C.) under reflux with removal of water through the Dean Stark trap as cyclohexane was returned to the system. Heating was then recommenced until the vapor temperature reached 70° C., at which time 40 mL of methanol were added slowly. The reaction mixture was allowed to heat up to the same vapor temperature and methanol was added slowly again, and repeated another 5 times. The reaction product (a white gel) was then cooled, neutralized with potassium hydroxide (7 g in 40 mL of methanol), and stripped of the resultant cyclohexane layer (by azeotrope with water). The gel remaining was then filtered and purified in boiling water and boiling methanol, giving 3-bromo-4-isopropylbenzaldehyde as a white solid (108.5 g, 78% yield)(as determined through standard analyses) exhibiting a peak melting transition of 216.3° C. by DSC at 20° C./min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[Cl:31]>CO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:24][C:25]1[CH:26]=[C:27]([C:2]2[CH:3]=[CH:4][C:5]([F:10])=[C:6]([C:7]#[N:8])[CH:9]=2)[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1cc(-c2ccc(Cl)c(Cl)c2)ccc1F
Temperature: 105 °C
Yield: 90.2 %

Procedure:
A mixture of 5-bromo-2-fluorobenzonitrile (400 mg, 2.000 mmol) and (Ph3P)4Pd (116 mg, 0.100 mmol) were mixed in a microwave tube (20 mL) and flushed with nitrogen. Toluene (5 mL), 2 M aqueous sodium carbonate (2.270 mL, 4.54 mmol) and a solution of 3,4-dichlorophenylboronic acid (519 mg, 2.72 mmol) in MeOH (3 mL) were added. The mixture was heated in an oil bath at 105° C. for 4.5 h. After cooling to room temperature, the reaction was diluted with water (10 mL) and the two phases were separated. The aqueous phase was extracted with ethyl acetate (20 mL), and combined organic phases were washed with water (2×10 mL), 5% aqueous NH4OH (10 mL), and brine (10 mL). The organic phase was dried over Na2SO4 and the solvent was removed. The residue was chromatographed on silica gel eluting with hexane containing 0, 2, 3% ethyl acetate to afford 480 mg of product as a white solid which was about 76% pure by LC/MS. This was used as such in the next step.
Reaction SMILES: [CH:1]1[NH:2][C:3]2[N:9]=[C:8]([NH2:10])[N:7]=[C:6]([Cl:11])[C:4]=2[N:5]=1.[CH3:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.CC(C)=O>CN(C=O)C>[Cl-:11].[NH2:10][C:8]1[N:9]=[C:3]2[C:4]([NH:5][CH:1]=[N:2]2)=[C:6]([N+:13]2([CH3:12])[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:7]=1
Reactant: CN1CCCC1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: C[N+]1(c2nc(N)nc3nc[nH]c23)CCCC1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.1 %

Procedure:
1.0 g (5.9 mmol) 6-Chloroguanine is dissolved in 40 mL DMF at 40° C. After cooling to room temperature, 1.4 mL 1-methylpyrrolidine (13.2 mmol) is added, and the reaction mixture is stirred for 18 h. 2 mL of acetone are added to complete precipitation. The solid is filtered, washed with ether and dried in vacuo, yielding 1.03 g 27 (3.9 mmol, 66%).
Reaction SMILES: [OH2:1].[OH-].[Li+].[CH3:4][O:5][C:6]1[C:7]([NH:13][S:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])=[N:8][CH:9]=[C:10]([CH3:12])[N:11]=1.CO.O.[O:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[C:30]([CH:29]=[CH:28][C:27]1[CH:20]=[CH:21][C:22]([C:18]2[C:17]([S:14]([NH:13][C:7]3[C:6]([O:5][CH3:4])=[N:11][C:10]([CH3:12])=[CH:9][N:8]=3)(=[O:15])=[O:16])=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:17][CH:18]=1)([OH:26])=[O:1]
Reactant: O
Reactant: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(C=CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Lithium hydroxide monohydrate (87 mg) was added to a solution of N-isobutoxycarbonyl-2-14-(2-[methoxycarbonyl]vinyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (250 mg) in tetrahydrofuran (6.2 ml) followed by methanol (2.5 ml) and water (2.5 ml). The reaction mixture was stirred at ambient temperature for 18 hours then evaporated to dryness. The residue was dissolved in water (50 ml), washed with ethyl acetate (50 ml), acidified with 8% aqueous citric acid to pH 3-4 and extracted with ethyl acetate (100 ml). The organic layer was extracted with saturated sodium bicarbonate solution (50 ml) and the aqueous phase separated, acidified with 8% aqueous citric acid and extracted with ethyl acetate (3×30 ml). The combined organic extracts were dried (MgSO4) and evaporated to give 2-[4-(2-carboxyvinyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (108 mg) as a solid, m.p. 233°-235° C.: 1H NMR (d6 -DMSO): 2.2 (s, 3 H), 3.8 (s, 3 H), 6.55 (d, 1 H), 7.35 (br s, 1 H), 7.45 (d, 2 H), 7.55-7.75 (m, 4 H), 8.45 (dd, 1 H), 8.8 (dd, 1 H), 10.1 (br s, 1 H); mass spectrum (+ve ESP) 427 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:16][O:17][C:18](=[O:25])[CH:19]([CH3:24])[C:20]([NH2:23])([CH3:22])[CH3:21]>>[Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([NH:23][C:20]([CH3:22])([CH3:21])[CH:19]([CH3:24])[C:18]([O:17][CH3:16])=[O:25])=[O:10])=[N:6][CH:7]=1
Reactant: COC(=O)C(C)C(C)(C)N
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Product: COC(=O)C(C)C(C)(C)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and 3-amino-2,3-dimethyl-butanoic acid methyl ester (CAN 89855-37-8) as starting materials and isolated (126 mg, 81%) as colorless oil; LC-MS (UV peak area, m/z) 100%, 355.1427 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][CH2:13]C[C:11]2=[O:17])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(=O)NCCCC1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][CH2:13][C:11]2=[O:17])=[O:9])=[CH:18][CH:19]=1)([O-:3])=[O:2]
Reactant: O=C1CCCCCN1C(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C1CCCCN1
Product: O=C1CCCCN1C(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
Synthesized as for N-(4-nitrobenzoyl)caprolactam (Example XXIII) using valerolactam (Aldrich) in place of caprolactam.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)C1C=CC=CC=1.C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>C(Cl)Cl>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:27]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.42 g of benzylpiperazine are dissolved in 35 ml of methylene chloride and there are added thereto 2.1 g of triethylamine and then, dropwise and while cooling with ice, 3.4 g of 3-methoxybenzoyl chloride in 30 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature and then washed with H2O. After being dried over sodium sulphate, the solution is concentrated to dryness by evaporation in vacuo. The oily 1-benzyl-4-(3-methoxybenzoyl)-piperazine is dissolved in 150 ml of fine spirit and debenzylated over 0.5 g of Pd-C. When the hydrogenation is complete, the catalyst is filtered off from the mixture and the filtrate is concentrated to dryness by evaporation in vacuo. The oily N-(3-methoxybenzoyl)-piperazine so obtained is placed in a sulphonating flask with 3.8 g of p-chlorophenethyl bromide and heated to 100°. At 60° a slight exothermic reaction takes place. After 3 hours at 100° , the mixture is cooled and dissolved in 400 ml of methylene chloride, and then 2N NaOH is added thereto; the whole is extracted by shaking and the methylene chloride phase is washed twice with H2O. The organic phase is dried over Na2SO4 and concentrated to dryness by evaporation in vacuo. The oily 1-[2-(4-chlorophenyl)-ethyl]-4-(3-methoxybenzoyl)piperazine is dissolved in isopropanol, and hydrochloric acid is added thereto. After the addition of ether, the hydrochloride, which has a melting point of 230°-232°, crystallises.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH:11]=[N:12][N:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:14]=2)[O:4]1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([N:18]1[CH2:19][CH2:20][CH:15]([N:13]2[CH:14]=[C:10]([B:5]3[O:6][C:7]([CH3:8])([CH3:9])[C:3]([CH3:21])([CH3:2])[O:4]3)[CH:11]=[N:12]2)[CH2:16][CH2:17]1)(=[O:32])=[O:31]
Reactant: CC1(C)OB(c2cnn(C3CCNCC3)c2)OC1(C)C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2cnn(C3CCN(S(C)(=O)=O)CC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine hydrochloride (315 mg, 1.0 mmol) and triethylamine (303 mg, 3.0 mmol) in DCM (15 mL) was added methanesulfonyl chloride (230 mg, 2.0 mmol) dropwise, the mixture was stirred at room temperature for 1 hour. Then the mixture was extracted with EA, wash with brine, dried and purified by flash column chromatography, eluting with EA/MeOH, to give product as light yellow solid. MS (m/z): 356 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[S:20][CH:21]=[CH:22][C:23]=3[CH3:24])=[O:18])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.C([Si]([O:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH:51]2[CH2:53][O:52]2)=[CH:45][CH:44]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[OH:52][C@H:51]([CH2:50][O:49][C:46]1[CH:47]=[CH:48][C:43]([OH:42])=[CH:44][CH:45]=1)[CH2:53][NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]([C:19]3[S:20][CH:21]=[CH:22][C:23]=3[CH3:24])=[O:18])[CH2:15][CH2:16]2)=[CH:6][CH:5]=1
Reactant: Cc1ccsc1C(=O)N1CCC(Sc2ccc(CCN)cc2)CC1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Product: Cc1ccsc1C(=O)N1CCC(Sc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 59.6 %

Procedure:
(4-{[4-(2-Aminoethyl)phenyl]sulfanyl}-1-piperidinyl)(3-methyl-2-thienyl)methanone (0.57 g, 1.58 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenylsilane (0.58 g, 1.44 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.656 g, 0.858 mmol).
Reaction SMILES: [CH3:1][CH:2]1[N:7]([C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[CH2:6][C:5]([C:14]([O:16]C)=O)=[CH:4][CH2:3]1.Br[CH2:19][Cl:20].C([Li])CCC.CCCCCC.P([O-])([O-])([O-])=O>C1COCC1.C(OCC)(=O)C>[Cl:20][CH2:19][C:14]([C:5]1[CH2:6][N:7]([C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[CH:2]([CH3:1])[CH2:3][CH:4]=1)=[O:16]
Reactant: ClCBr
Reactant: C=CCOC(=O)N1CC(C(=O)OC)=CCC1C
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCOC(=O)N1CC(C(=O)CCl)=CCC1C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 53.1 %

Procedure:
To a solution of 1-allyl 3-methyl 6-methyl-5,6-dihydro-1,3(2 H)-pyridinedicarboxylate (0.44 g, 1.85 mmol) and bromochloromethane (0.18 ml, 2.8 mmol) in THF (15 ml) was added −90 to −80° C. a solution of n-butyllithium in hexane (1.59M, 1.75 ml, 2.8 mmol) over a 15 minute period. After stirring for additional 40 minutes, the reaction mixture was poured into a mixture of ice (10 g) and phosphate buffer (pH 7.0, 10 ml). After ethyl acetate was added and the mixture was separated with a separating funnel, the aqueous layer was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride, dried over magnesium sulfate and the organic solvent was removed under reduced pressure. The residue was purified by silica gel (25 g) chromatography to give allyl 5-(chloroacetyl)-2-methyl-3,6-dihydro-1(2 H)-pyridinecarboxylate (253 mg, 53%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]([NH:8][CH2:9][C:10]([O:12]CC)=O)=[N:6][CH:7]=1.BrC1[C:25]([NH:31]CC(OCC)=O)=[N:26][CH:27]=[C:28](Br)N=1.O1[CH2:43][CH2:42][CH:41]([CH2:44][NH2:45])[CH2:40]C1.C(N(CC)C(C)C)(C)C>CO.CS(C)=O>[NH2:31][C:25]1[NH:26][C:27]2[CH:28]=[C:43]([C:2]3[N:3]=[C:4]4[N:15]([CH2:16][CH:17]5[CH2:18][CH2:19][O:20][CH2:21][CH2:22]5)[C:10](=[O:12])[CH2:9][NH:8][C:5]4=[N:6][CH:7]=3)[CH:42]=[C:41]([CH3:40])[C:44]=2[N:45]=1
Reactant: CCOC(=O)CNc1ncc(Br)nc1Br
Reactant: NCC1CCOCC1
Reactant: CCOC(=O)CNc1ncc(Br)nc1NCC1CCOCC1
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2cnc3c(n2)N(CC2CCOCC2)C(=O)CN3)cc2[nH]c(N)nc12
Temperature: 150 °C

Procedure:
Ethyl 2-(5-bromo-3-((tetrahydro-2H-pyran-4-yl)methylamino)pyrazin-2-ylamino)acetate. Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (2.00 g, 5.90 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (0.713 g, 6.19 mmol), N,N -diisopropylethylamine (3.08 mL, 17.70 mmol) and dimethylsulfoxide (4 mL) were combined in a microwave vial with a stirbar and heated in a Biotage Emrys Optimizer microwave reactor at 150° C. for 1 h. The resulting mixture was transferred to a round bottom flask with methanol. The methanol and N,N-diisopropylethylamine were removed under reduced pressure and the residue purified using Biotage flash chromatography (5-100% ethyl acetate in hexane). Fractions containing the desired product were combined in a reparatory funnel and washed twice with water and once with brine. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dried under high vacuum at 50° C. to give impure desired product (1.578 g) as an amber waxy solid which was taken on to the next step without further purification. MS (ESI) m/z 373.4 [M]+, 375.4 [M+2]+.
Reaction SMILES: [OH-].[Na+].[C:3](#[N:6])[CH:4]=[CH2:5].[CH:7](=[O:11])[CH:8]([CH3:10])[CH3:9]>>[CH3:9][C:8]([CH3:10])([CH2:5][CH2:4][C:3]#[N:6])[CH:7]=[O:11]
Reactant: CC(C)C=O
Reactant: C=CC#N
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C=O)CCC#N

Procedure:
Starting Materials: 50% caustic soda solution; reaction temp.; choice between 20° to 50° C.; mole ratio acrylonitrile:isobutyraldehyde as 1.1:1. Feed of acrylonitrile and isobutyraldehyde/hour: 280 ml.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11]1[C:19]2[N:14]([CH:15]=[CH:16][C:17](=O)[CH:18]=2)[CH2:13][CH:12]=1>>[CH2:11]1[CH:19]2[N:14]([CH2:15][CH:16]=[C:17]([C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][CH:6]=3)[CH2:18]2)[CH2:13][CH2:12]1
Reactant: O=c1ccn2c(c1)C=CC2
Reactant: Fc1ccc2[nH]ccc2c1
Product: Fc1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1

Procedure:
The 5-fluoro-1H-indole (910 mg, 6.7 mmol) and 7-indolizinone (1.40 g, 10.1 mmol) were converted to product by the procedure of Example 2 to give 1.22 g. (70.9%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[C:11]([F:27])[CH:10]=1)#[N:2].[O:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH:34][C:35]2[NH:39][CH:38]=[N:37][N:36]=2)[CH2:29]1>>[F:27][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:14]=[CH:13][C:12]=1[CH2:15][C:16]1[C:17](=[O:18])[N:34]([CH:30]2[CH2:31][CH2:32][CH2:33][O:28][CH2:29]2)[C:35]2[N:36]([N:37]=[CH:38][N:39]=2)[C:22]=1[CH2:23][CH2:24][CH3:25]
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Reactant: c1nnc(NC2CCCOC2)[nH]1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCCOC2)c2ncnn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 60.6 %

Procedure:
A mixture of ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (0.42 g) and N-(tetrahydro-2H-pyran-3-yl)-4H-1,2,4-triazol-3-amine (0.1 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.17 g, 60%).