Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Si:21]([O:28][CH2:29][C@H:30]([C:32]1[CH:33]=[N:34][C:35]([CH3:38])=[N:36][CH:37]=1)[NH2:31])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(#N)C.C(N(CC)C(C)C)(C)C>[Si:21]([O:28][CH2:29][C@@H:30]([NH:31][C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:32]1[CH:37]=[N:36][C:35]([CH3:38])=[N:34][CH:33]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: Cc1ncc([C@H](N)CO[Si](C)(C)C(C)(C)C)cn1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(N[C@H](CO[Si](C)(C)C(C)(C)C)c4cnc(C)nc4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (420 mg, 1.48 mmol) and (S)-2-(tert-butyldimethylsilyloxy)-1-(2-methylpyrimidin-5-yl)ethanamine (742 mg, 2.78 mmol) in acetonitrile (8 mL) and N,N-diisopropylethylamine (1 mL) was subjected to microwave irradiation at 185° C. for 3 h. The reaction mixture was concentrated and the residue was purified by silica-gel column to yield the product as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](Cl)(=[O:18])[CH3:17]>ClCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([C:16](=[O:18])[CH3:17])[CH3:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)Cl
Agent: ClCl
Product: CC(=O)N(C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.2 %

Procedure:
To a solution of 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester (616 mg, 2.9 mmol) in CH2 Cl2 (25 ml), was added acetyl chloride (215 μl, 3.02 mmol, 1.05 eq.) dropwise. The reaction mixture was stirred at RT for 16 hrs. The crude reaction mixture was extracted with CH2 Cl2 (2×50 ml) and washed with water (10 ml) and with brine (10 ml). The solvent was removed under reduced pressure to give the expected 4-(Acetyl-methyl-amino)-piperidine-1-carboxylic acid tert-butyl ester (708 mg, 96% yield).
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1C(=O)C2=CC=CC=C2C1=O>>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCCBr
Reactant: Sc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NCCCCCCCCSc1nc2ccccc2o1
Temperature: 60 °C

Procedure:
To a round bottom flask with 2-mercaptobenzoxazole (2.14 g, 14.2 mmol) andDMF (100 mL) at room temperature was added K2CO3 (2.61 g, 18.9 mmol) followed by N-(8-bromooctyl)phthalimide (4.00 g, 11.8 mmol). The resulting solution was heated to 60° C. for 0.5 h and then cooled back to room temperature. At this point, the reaction mixture was quenched with H2O (100 mL) and then diluted with EtOAc (600 mL). The organic layer was washed with 1 N HCl (60 mL), sat. aq. NaHCO3 (60 mL), and brine (60 mL) and then dried (MgSO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (10 to 20% EtOAc/petroleum ether gradient) to afford the thioether intermediate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([OH:14])=[O:13])=[CH:6]2.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)[C:7]([C:12]([OH:14])=[O:13])=[CH:6]2
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)n2c(C(=O)O)cc3cc(OC)ccc32)cc1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of commercially available 5-methoxyindole-2-carboxylic acid (6.69 g, 35 mmol) and triethylamine (10 mL, 71.7 mmol) in anhydrous CH2Cl2 (70 mL) containing catalytic amount of DMAP was added dropwise a solution of 4-methoxybenzoyl chloride (6.20 g, 36.34 mmol) in CH2Cl2 (15 mL) at 0° C. The reaction mixture was stirred at this temperature for 15 min and then at room temperature for 4 hours. The reaction mixture was washed successively with 5% aqueous KHSO4 solution (2×20 mL), brine (25 mL), dried over Na2SO4, and evaporated under reduced pressure to dryness. The solid residue was recrystallized from methanol to yield 5-methoxy-1-(4′-methoxybenzoyl)-1H-indole-2-carboxylic acid as a white solid (7.4 g, 65%): mp 185-187° C.; 1H NMR (DMSO-d6) δ 3.80 and 3.85 (each 3H, s, 2×OMe), 7.02 (1H, dd, J=2.5 Hz and J=9.0 Hz, ArH), 7.07 (2H, d, J=8.9 Hz, 2×ArH), 7.28 (1H, d, J=2.5 Hz, ArH), 7.33 (1H, s, ArH), 7.38 (1H, d, J=9.0 Hz, ArH), 7.59 (2H, d, J=8.9 Hz, 2×ArH), 13.2 (1H, brs, exchangeable, OH). Anal. Calcd. for C18H15NO5.0.1H2O: C, 65.73; H, 4.65; N, 4.25. Found: C, 65.77; H, 4.61; N, 4.24.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([O:7][C:8]2[C:9]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:10][C:11]([C:18]([OH:20])=[O:19])=[CH:12][C:13]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[CH:5][CH:6]=1.[C:26]([O:30][CH2:31]Cl)(=[O:29])[CH2:27][CH3:28].C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[NH2:17][S:14]([C:13]1[CH:12]=[C:11]([CH:10]=[C:9]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:8]=1[O:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:18]([O:20][CH2:31][O:30][C:26]([CH2:27][CH3:28])=[O:29])=[O:19])(=[O:16])=[O:15]
Reactant: CCC(=O)OCCl
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)OCOC(=O)c1cc(N2CCCC2)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
In a similar manner to Example 13, piretanide can be reacted with chloromethyl propionate, triethylamine and sodium iodide in DMF to yield ethylcarbonyloxymethyl 3-aminosulfonyl-4-phenoxy-5-(1-pyrrolidinyl)benzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:25])=[CH:22][CH:21]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2ccc3[nH]c4c(c3c2)CC(N(C)C)CC4)cc1
Yield: 41.3 %

Procedure:
Beginning with 10.6 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.8 μL (0.063 mMol) 4-methoxybenzoyl chloride, 6.9 mg (41%) of the title compound were recovered as a light brown foam.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=1[CH:23]=[CH:24][N+:25]([O-])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:25][CH2:24][CH2:23][C:10]1[C:11]([C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:12][C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:14][C:9]=1[OH:8]
Reactant: CC(C)(C)c1cc(OCc2ccccc2)c(C=C[N+](=O)[O-])c(C(C)(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1cc(O)c(CCN)c(C(C)(C)C)c1

Procedure:
To a solution of 0.183 g (0.5 mmol) of the product of Step B in 10 mL of methanol was added 0.1 g of 10% palladium on carbon catalyst and the reaction mixture was stirred in Parr shaker under 40 psig of hydrogen overnight. The reaction mixture was then filtered through Celite filter aid and the filtrate was evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with mixtures of CH2Cl2/MeOH/conc. NH4OH of the following compositions: 97/3/0.3; 95/5/0.5; and 90/10/1. Combination of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [F:1][C:2]([F:16])([CH3:15])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][C:6]=1[CH3:14].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[F:1][C:2]([F:16])([CH3:15])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:12])=[CH:7][C:6]=1[CH3:14]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(OCC(C)(F)F)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OCC(C)(F)F
Yield: 61 %

Procedure:
The title compound is prepared in 61% yield (481 mg, colorless oil) from 1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethanone (545 mg, 2.38 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (346 mg, 2.85 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [Br:1][CH2:2]/[C:3](/[CH3:14])=[CH:4]\[C@@H:5]([CH3:13])[C@H:6]([OH:12])[C@@H:7]([O:10][CH3:11])[CH:8]=[CH2:9].N1C(C)=CC=CC=1C.[Si:23](OS(C(F)(F)F)(=O)=O)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl>[Br:1][CH2:2]/[C:3](/[CH3:14])=[CH:4]\[C@@H:5]([CH3:13])[C@H:6]([O:12][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C@@H:7]([O:10][CH3:11])[CH:8]=[CH2:9]
Reactant: C=C[C@H](OC)[C@@H](O)[C@H](C)/C=C(/C)CBr
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=C[C@H](OC)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](C)/C=C(/C)CBr
Temperature: -15 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of secondary alcohol 12 (5.04 g, 19.23 mmol) in CH2Cl2 (150 mL) at −15° C. was added 2,6-lutidine (3.4 mL, 28.85 mmol) and TBSOTf (6.2 mL, 26.92 mmol). After stirring at −15° C. for 1 h, the reaction mixture was quenched with MeOH (20 mL) at −15° C. The mixture was treated with saturated NH4Cl aqueous solution. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. Purification of the crude product by flash chromatography (EtOAc-hexanes, 1:9) to afford bromide 13 (6.6 g, 91%) as a yellow oil. [α]20D 2.76 (c 1.5, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 5.61 (m, 1 H), 5.35 (d, 1 H, J=9.8 Hz), 5.23 (m, 2 H), 3.88 (s, 2H), 3.48 (dd, 1 H, J=3.0, 7.1 Hz), 3.30 (t, 1 H, J=7.5 Hz), 3.15 (s, 3H), 2.53 (m, 1H), 1.75 (s, 3H), 0.88 (m+s, 12 H), 0.05 (s, 3H), 0.02 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 136.8, 135.6, 130.1, 119.2, 86.5, 78.0, 56.6, 35.1, 32.8, 26.5, 22.3, 18.9, 13.9, −3.4, −4.4; HRMS (ESI) calcd for [C17H33BrO2Si+Na]+: 399.1331. found: 399.1321.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21]1([CH2:27][N:28]=[C:29]=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:29]([NH:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:30])[C:3]1=[O:20]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C=NCc1ccccc1
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)NCc2ccccc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and phenylmethylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: 240°-242° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[Br:10][C:11]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[CH:16][C:12]=1[NH:13][CH2:14][CH3:15].C(N(C(C)C)CC)(C)C>O1CCOCC1>[Br:10][C:11]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[CH:16][C:12]=1[N:13]([CH2:14][CH3:15])[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1
Reactant: CCNc1ccc(C(C)C)cc1Br
Reactant: Cc1nc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCN(c1nc(C)nc(Cl)n1)c1ccc(C(C)C)cc1Br
Yield: 67.7 %

Procedure:
Part B: 2,4-Dichloro-6-methyl-1,3,5-triazine (3 g, 18.29 mmol), 2-bromo-N-ethyl-4-isopropylaniline (6.07 g, 25.07 mmol) and diisopropylethylamine (3.2 g, 25.07 mmol) were dissolved in dioxane (60 mL) under N2 and refluxed three hours. The solvent was stripped and the residue was purified using flash chromatography (CH2Cl2, silica). to provide N-(2-bromo-4-isopropylphenyl)-N-ethyl-4-chloro-6-methyl-1,3,5-triazine-2-amine (4.58 g) as a clear oil in 68% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])(=[O:22])=[O:21])[CH2:16][CH2:15]1.O1CCOCC1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[C:44]([CH:47]=[O:48])[S:45][CH:46]=2)O1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH:47]([C:44]1[S:45][CH:46]=[C:42]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])(=[O:22])=[O:21])[CH2:16][CH2:15]2)[CH:43]=1)=[O:48]
Reactant: CC1(C)OB(c2csc(C=O)c2)OC1(C)C
Reactant: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Temperature: 150 °C
Yield: 60.7 %

Procedure:
To 5-bromo-3-(1-{[3-(methyloxy)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (170 mg, 0.37 mmol) in mixture of dioxane (4.5 mL) and water (1.5 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (265.2 mg, 1.11 mmol), potassium carbonate (309 mg, 2.22 mmol) and Pd(PPh3)4 (44.2 mg, 0.04 mmol) were added. The reaction mixture was heated by microwave at 150° C. for 20 minutes. Then all the solvent was evaporated. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The water layer was extracted with ethyl acetate (2×50 mL). The combined organic phase washed with brine (50 mL) and dried with Mg2SO4 and concentrated. The crude product was purified by Combiflash (dichloromethane/methanol, 1%-40% methanol, 25 min.) to give title compound (110 mg, 61%).
Reaction SMILES: Cl[C:2]1[C:12]2[C:11]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:10]=3[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:8][CH2:7][C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1.[H-].[Na+].[CH3:27][SH:28]>CN(C)C=O.O>[Cl:17][C:15]1[CH:14]=[CH:13][C:11]2[C:12]3[C:2]([S:28][CH3:27])=[N:3][C:4]([CH3:24])=[N:5][C:6]=3[CH2:7][N:8]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]=2[CH:16]=1
Reactant: CS
Reactant: Cc1nc(Cl)c2c(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc(C)nc2c1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In one portion 1.0 g (2.8 mmol) of 1,9-dichloro-3-methyl-7-phenyl-5H-pyrimido[4,5-d][2]benzazepine was added to a solution of 150 mg (3.1 mmol) of 50% mineral oil dispersion of sodium hydride and an excess of methyl mercaptan (>3.1 mmol) in 25 mL of dimethylformamide. The mixture was stirred at room temperature for 30 min and diluted with water. The resulting precipitate was collected by filtration to give a yellow solid. Recrystallization from a mixture of ether and methylene chloride gave pale yellow prisms, mp 181°-183°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([C:19]#[C:20][CH2:21]O)=[CH:13][CH:12]=3)=[O:5])[CH3:2].S(Cl)([Cl:25])=O>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([C:19]#[C:20][CH2:21][Cl:25])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(C#CCO)cc12
Reactant: O=S(Cl)Cl
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(C#CCCl)cc12

Procedure:
78 mg of 6-(3-hydroxy-1-propinyl)-beta-carboline-3-carboxylic-acid-ethylester in 2 ml of thionyl chloride is stirred for 3 h at room temperature. After evaporating till dry, the mixture is heated in ethanol and evacuated. By recrystallization from acetic-acid/cyclohexane, 40 mg of 6-(3-chloro-1-propinyl)-beta-carboline-3-carboxylic-acid-ethylester is obtained.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[C:8]([C:25]#[N:26])=[N:7]1.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][C@@H:45]1[CH2:50][OH:51])=[O:43])([CH3:40])([CH3:39])[CH3:38]>>[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][N:47]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:27]=[CH:28][C:29]([C:31]([F:33])([F:34])[F:32])=[CH:30][C:3]=3[C:2]([F:1])([F:35])[F:36])[N:7]=[C:8]4[C:25]#[N:26])[C:17](=[O:24])[N:18]=2)[CH2:46][C@@H:45]1[CH2:50][OH:51])=[O:43])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CO
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(c2)c(C#N)nn3Cc2ccc(C(F)(F)F)cc2C(F)(F)F)S1
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(c3)c(C#N)nn4Cc3ccc(C(F)(F)F)cc3C(F)(F)F)S2)C[C@@H]1CO

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-cyano-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-5-(2-ethylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-1H-indazole-3-carbonitrile and 2-(R)-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH2:11](C([Sn])=C(CCCC)CCCC)[CH2:12]CC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:11]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1)=[CH2:12]
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=Cc1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.8 %

Procedure:
The title compound was prepared by following general procedure 2. To a solution of 5-bromo pyridine-2-carboxylic acid (5 g, 24.75 mmol) in 50 mL of 1,4-dioxan, dichlorobis(triphenylphosphine)palladium(II) (2.08 g, 2.96 mmol) was added at RT and stirred at RT for 5 min. Tributylvinyltin (11.7 g, 36.9 mmol) was added slowly at RT and stirred at 100° C. for 3 h. The reaction mixture was monitored by TLC and LCMS. After completion of the starting material, evaporated the solvent below 40° C. and purified by column chromatography using ethyl acetate to afford the 5-vinylpyridine-2-carboxylic acid (3.5 g, 94.5%).
Reaction SMILES: C([NH2:5])(C)(C)C.C(O)C.[C:9]([OH:15])([C:11]([F:14])([F:13])[F:12])=[O:10].[OH2:16]>>[OH:16][NH-:5].[C:9]([OH:15])([C:11]([F:14])([F:13])[F:12])=[O:10]
Reactant: CC(C)(C)N
Reactant: O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: [NH-]O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of compound 25.4 (0.027 g), ethanol (1.5 mL), TFA (0.6 mL) and water (0.5 mL) was stirred at 60° C. for 18 h. The mixture was concentrated under reduced pressure, and the residue was purified by HPLC to afford compound 25.6 as a TFA salt (0.014 g, 51%). 1H NMR (CD3OD): δ 1.4 (t, J=8 Hz, 6H), 2.9 (M, 4H), 3.2 (m, 2H), 3.58 (brs, 2H), 3.65 (m, 2H), 4.25 (m, 4H), 4.42 (d, J=10 Hz, 2H), 4.85 (m, 2H), 6.75 (d, J=9 Hz, 2H), 6.9 (m, 4H), 7.0 (d, J=9 Hz, 2H), 7.4-7.6 (m, 6H), 8.1 (brs, 2H). 31P NMR (CD3OD): δ 20.8. MS: 769 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[CH2:10]([CH2:14][C:15](=O)[CH3:16])[C:11]([CH3:13])=O>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH3:16][C:15]1[N:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=2)[C:11]([CH3:13])=[CH:10][CH:14]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Cc1cc(C)nc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of 4,6-dimethyl-2-aminopyridine (7, 12.2 g, 100 mmol) in toluene (100 mL) was added acetonylacetone (12.3 mL, 105 mmol) and p-TsOH (190 mg, 1.0 mmol). The reaction mixture was heated in a Dean-Stark apparatus under reflux for 6 h. After cooling to room temperature, the mixture was concentrated with a rotary evaporator, and the resulting brown oil was purified by flash column chromatography (EtOAc/hexanes, 1:19-1:9) to give 8 (18.2 g, 91 mmol, 91%) as a pale yellow solid: 1H NMR (500 MHz, CDCl3) δ 2.13 (s, 6H), 2.40 (s, 3H), 2.56 (s, 3H), 5.88 (s, 2H), 6.85 (s, 1H), 7.00 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 13.4, 21.2, 24.4, 106.8, 119.9, 123.1, 128.6, 149.6, 151.7, 158.4; LCQ-MS (M+H+) calcd for C13H17N2 201. found 201; LC-TOF-MS (M+H+) calcd for C13H17N2 201.13917. found 201.13881.
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH3:7])[C:3](OC)=[O:4].[CH2:9]([NH2:12])[CH2:10][CH3:11]>CO>[CH2:9]([NH:12][C:3](=[O:4])[C:2]([NH2:1])([CH3:8])[CH3:7])[CH2:10][CH3:11]
Reactant: CCCN
Reactant: COC(=O)C(C)(C)N
Solvent: CO
Product: CCCNC(=O)C(C)(C)N

Procedure:
To a solution of 26.3 parts of methyl 2-amino-2-methylpropionate in methanol is added 70 parts of n-propylamine. The mixture is placed in a bomb and left at a temperature of 100° C. for one week. The solvents are then stripped off under reduced pressure. Distillation of the residual oil affords N1 -propyl-2-amino-2-methylpropionamide, boiling at 58° C. at 0.1 mm pressure.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:27]=[CH:26][C:8]2[N:9]=[C:10]([NH:12][C:13]3[N:17]([CH3:18])[C:16]4[CH:19]=[CH:20][C:21]([C:23]([OH:25])=O)=[CH:22][C:15]=4[N:14]=3)[S:11][C:7]=2[CH:6]=1)(=[O:4])=[O:3].CN.[CH3:30][N:31](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:30][NH:31][C:23]([C:21]1[CH:20]=[CH:19][C:16]2[N:17]([CH3:18])[C:13]([NH:12][C:10]3[S:11][C:7]4[CH:6]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:27]=[CH:26][C:8]=4[N:9]=3)=[N:14][C:15]=2[CH:22]=1)=[O:25]
Reactant: Cn1c(Nc2nc3ccc(S(C)(=O)=O)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(S(C)(=O)=O)cc3s1)n2C
Yield: 82.3 %

Procedure:
2-(6-Methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid methylamide (34 mg) was prepared by following General Procedure F using 2-(6-methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (40 mg), methylamine (0.2 ml, 2.0 M solution in THF), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 417; and 1H NMR (DMSO-d6, 400 MHz): δ 8.45 (m, 1H), 8.04 (br, 1H), 8.00 (m, 1H), 7.93 (s, 1H), 7.71 (t, 2H), 7.43 (d, 1H), 7.18 (t, 1H), 3.63 (s, 3H), 3H), 3.27 (s, 3H), and 2.87 (s, 3H).