Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: c1cn[nH]c1
Product: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-nitro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-nitro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([N:22](CCO)[CH2:23][CH2:24][NH:25][C:26](=O)OC(C)(C)C)[CH:16]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[O:36]1CCOC[CH2:37]1>Cl>[ClH:21].[ClH:21].[C:1]12([CH2:11][NH:12][C:13](=[O:14])[C:15]3[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([NH:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:37][OH:36])[CH:16]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)NCCN(CCO)c1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Agent: Cl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCNCCO)ncc1Cl
Reaction time: 0.5 h

Procedure:
tert-Butyl 2-[(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)(2-hydroxyethyl)amino]ethylcarbamate (Example 13(i)) (0.013 g) was dissolved in anhydrous hydrogen chloride in 1,4-dioxane (4M, 2 ml) and the resulting mixture was allowed to stand at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to afford the titled product (0.020 g).
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[C:3]=1[O:15][CH2:16][O:17][CH3:18].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH3:12][C:11]1[C:2]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:3]([O:15][CH2:16][O:17][CH3:18])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:13][CH3:14])=[CH:6][CH:5]=2
Reactant: OB(O)c1ccccc1
Reactant: COCOc1c(Br)c(C)cc2cc(OC)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COCOc1c(-c2ccccc2)c(C)cc2cc(OC)ccc12
Temperature: 160 °C
Reaction time: 0.42 h
Yield: 182.6 %

Procedure:
2-Bromo-3-methyl-6-(methyloxy)-1-{[(methyloxy)methyl]oxy}naphthalene (14) (2.32 g, 7.46 mmol), phenylboronic acid (1.83 g, 15.0 mmol, 2.0 eq), tetrakistriphenylphosphine palladium (0) (0.869 g, 0.752 mmol, 10 mol %), 2 M sodium carbonate (65 mL), and ethylene glycol dimethyl ether (65 mL) were combined in a glass pressure bottle. The bottle was sealed with a screw cap and the reaction mixture was heated at 160° C. with stirring for 25 min. The reaction mixture was allowed to cool at RT. The reaction mixture was transferred to a separatory funnel and extracted with Et2O. The organic phase was separated, dried over MgSO4, filtered, and the filtrate was concentrated to give 4.96 g of the crude product. The crude product was combined with an additional 4.43 g of crude product (from a second Suzuki coupling reaction) and purified the crude product by chromatography over SiO2 with hexanes:CH2Cl2 (2:3) to give 4.2 g (91%) of the title compound (15) as a yellow oil. 1H NMR (400 MHz; DMSO-d6): δ 2.13 (s, 3H), 2.98 (s, 3H), 3.86 (s, 3H), 4.64 (s, 2H), 7.13 (dd, J=2.4 Hz, 9.1 Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 7.29 (d, J=7.0 Hz, 2H), 7.36 (t, J=7.5 Hz, 1H), 7.45 (t, J=7.5 Hz, 2H), 7.51 (s, 1H), 7.94 (d, J=9.1 Hz, 1H).
Reaction SMILES: ClCCl.O=C1CCC(=O)N1[O:11][C:12]([O:14][CH2:15][C:16]([CH3:22])([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=O.OCC(C)(C)C(OC)=O.[C:32]1([C@H:42]([N:44]([CH2:52][C@@H:53]2[C@@H:57]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[CH2:56][NH:55][CH2:54]2)[C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH3:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>C(N(CC)CC)C>[C:47]([O:46][C:45]([N:44]([CH2:52][C@@H:53]1[C@@H:57]([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH2:56][N:55]([C:12]([O:14][CH2:15][C:16]([CH3:22])([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[O:11])[CH2:54]1)[C@@H:42]([C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1)[CH3:43])=[O:51])([CH3:49])([CH3:50])[CH3:48]
Reactant: COC(=O)C(C)(C)COC(=O)ON1C(=O)CCC1=O
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: COC(=O)C(C)(C)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)COC(=O)N1C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)[C@@H](c2ccccc2)C1
Temperature: 25 °C

Procedure:
A 2 ml dichloromethane solution of methyl 3-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}oxy)-2,2-dimethylpropionate prepared from 136 mg of methyl 3-hydroxy-2,2-dimethylpropionate in the same manner as in Reference Example 46 was added to 5 ml dichloromethane solution of 235 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate and 0.21 ml of triethylamine. After 12Hours of stirring at room temperature, the reaction solution was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (hexane-ethyl acetate) to obtain 227 mg of 3-methoxy-2,2-dimethyl-3-oxopropyl (3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidine-1-carboxylate as a colorless amorphous substance.
Reaction SMILES: [C@@H:1]12[O:8][C@@H:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:10]=[C:11]([NH:15][C:16]3[C:17]4[N:25]=[CH:24][S:23][C:18]=4[N:19]=[C:20](Cl)[N:21]=3)[CH:12]=[CH:13][CH:14]=1)[CH2:2]2.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=2)[C:37]([O:39][CH3:40])=[O:38])O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[C@@H:1]12[O:8][C@@H:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:10]=[C:11]([NH:15][C:16]3[C:17]4[N:25]=[CH:24][S:23][C:18]=4[N:19]=[C:20]([C:34]4[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=4)[C:37]([O:39][CH3:40])=[O:38])[N:21]=3)[CH:12]=[CH:13][CH:14]=1)[CH2:2]2
Reactant: Clc1nc(Nc2cccc(N3C[C@H]4CC[C@@H](C3)O4)c2)c2ncsc2n1
Reactant: COC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)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: O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2nc(Nc3cccc(N4C[C@H]5CC[C@@H](C4)O5)c3)c3ncsc3n2)c1
Temperature: 100 °C
Yield: 78.2 %

Procedure:
The mixture of N-(3-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl)-5-chlorothiazolo[5,4-d]pyrimidin-7-amine (0.095 g, 0.254 mmol), methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.073 g, 0.28 mmol), Pd (PPh3)4 (0.015 g, 0.013 mmol) and Na2CO3 (0.081 g, 0.762 mmol) in dioxane (20 mL) and H2O (5 mL) was heated to 100° C. for 16 h under N2 atmosphere. Then it was concentrated to dryness. The residue was purified by column chromatography (silica gel, 200˜300 mesh, eluting with ethyl acetate:petroleum ether=1:2) to afford methyl 3-(7-(3-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (0.094 g, 78%) as a yellow solid. LC-MS: 474 [M+H]+, tR=1.84 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]Cl)=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1.[C-:11]#[N:12].[Na+]>C(O)C>[Cl:1][C:2]1[C:7]([CH2:8][C:11]#[N:12])=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: [C-]#N
Reactant: ClCc1ccc(Cl)nc1Cl
Agent: [Na+]
Solvent: CCO
Product: N#CCc1ccc(Cl)nc1Cl

Procedure:
2 g of 2,6-dichloro-3-chloromethyl-pyridine in 8 ml of ethanol at ambient temperature was treated with 0.57 g of NaCN. The resulting brown suspension was refluxed for 2 h. Ethanol was removed by evaporation under reduced pressure and the residue was taken-up in water and ethyl acetate. The aqueous layer was washed twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulphate, filtered and concentrated. 2.05 g of crude 2,6-dichloro-pyridin-3-yl)-acetonitrile was obtained as brown solid which was used in the next step without further purification. 1H-NMR (CDCl3): 7.86 ppm (d, 1H), 7.38 ppm (d, 1H), 3.84 ppm (s, 2H).
Reaction SMILES: [CH:1]([CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)=O.OC1C=CC(C(OC)=O)=CC=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1.[BH3-]C#N.[Na+]>CO.CC(O)=O>[CH:26]1([NH:29][CH2:1][CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][CH:14]=2)[CH2:28][CH2:27]1
Reactant: COC(=O)c1ccc(OCC=O)cc1
Reactant: NC1CC1
Agent: COC(=O)c1ccc(O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(OCCNC2CC2)cc1
Reaction time: 8 h
Yield: 49 %

Procedure:
To a stirred solution of 4:1 mixture of methyl 4-formylmethyloxybenzoate and methyl 4-hydroxybenzoate (1.00 g) and cyclopropylamine (425 ml, 6.18 mmol) in MeOH—AcOH (10:1, 11 ml) was added NaBH3CN (681 mg, 10.3 mmol). After stirring overnight, the mixture was quenched by addition of sat. NaHCO3 (50 ml) and extracted with CHCl3 (2×200 ml). The combined extracts were dried over MgSO4 and evaporated. The residue was chromatographed on silica gel with CHCl3—MeOH (20:1) to give methyl 4-(2-cyclopropylaminoethoxy)benzoate (595 mg, 49%) as a colorless oil. 1H-NMR (CDCl3) δ0.37-0.49 (m, 4 H), 1.91 (m, 1 H), 2.18-2.23 (m, 1 H), 3.11 (t, J=5.2 Hz, 2 H), 3.88 (s, 3 H), 4.12 (t, J=5.2 Hz, 2 H), 6.92 (, J=8.88 Hz, 2 H), 7.98 (d, J=8.8 Hz, 2 H).
Reaction SMILES: [ClH:1].[C:2]1([N:8]2[CH2:13][CH2:12][N:11](CCCCN3C(=O)C4C=CC=C5C=4C(=CC=C5)C3=O)[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]1[C:49](=[O:50])[C:48]2[CH:51]=[CH:52][CH:53]=[C:46]3[C:47]=2[C:42](=[CH:43][CH:44]=[CH:45]3)[C:41]1=[O:54].BrCCCCN1C(=O)C2C=CC=C3C=2C(=CC=C3)C1=O>>[C:2]1([N:8]2[CH2:13][CH2:12][N:11]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]3[C:49](=[O:50])[C:48]4[CH:51]=[CH:52][CH:53]=[C:46]5[C:47]=4[C:42](=[CH:43][CH:44]=[CH:45]5)[C:41]3=[O:54])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:1]
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCN(c2ccccc2)CC1
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCBr
Agent: Cl
Agent: O=C1c2cccc3cccc(c23)C(=O)N1CCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCN1CCN(c2ccccc2)CC1

Procedure:
Following the procedure of part (b) of example 34 but substituting 2-(6-bromohexyl)-1H-benz[de]isoquinoline-1,3(2H)-dione for the 2-(4-bromobutyl)-1H-benz[de]isoquinoline-1,3-(2H)-dione, one obtains 2-[6-(4-phenyl-1-piperazinyl)hexyl]-1H-benz[de]isoquinoline-1,3(2H)-dione, )-dione, hydrochloride.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([NH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[NH:21][C:20]([C:23]([O:25]CC)=[O:24])=[CH:19]2)(=[O:12])=[O:11])=[O:4].CO.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([NH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[NH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19]2)(=[O:12])=[O:11])([OH:4])=[O:2]
Reactant: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3ccsc3C(=O)OC)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2cccc(NS(=O)(=O)c3ccsc3C(=O)O)c2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.5 %

Procedure:
To a mixed solution of ethyl 7-({[2-(methoxycarbonyl)-3-thienyl]sulfonyl}amino)-1H-indole-2-carboxylate (0.35 g) in tetrahydrofuran (10 mL)-methanol (10 mL) was added aqueous solution (5 mL) of 85% potassium hydroxide (350 mg), and the mixture was stirred at room temperature for 18 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (193 mg, yield 62%) as pale-yellow crystals. melting point 272-275° C. (decomposition).
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=O.[CH3:17][S:18]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[N:25]([C:24]3[CH:23]=[CH:22][C:21]([S:18]([CH3:17])(=[O:20])=[O:19])=[CH:27][CH:26]=3)[CH:2]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: O=C(CCC1OCCO1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-n2cccc2-c2ccc(F)cc2)cc1
Yield: 49.1 %

Procedure:
A mixture of the ketone (Step 2) (448 mg, 2 mmol), 4-(methylsulfonyl)aniline (380 mg, 2.2 mmol) and p-toluenesulfonic acid (30 mg) in toluene (40 ml) was heated to reflux for 18 hours. The reaction was cooled, filtered and concentrated. The crude solid (750 mg) was purified by chromatography (silica gel, hexane/ethyl acetate, 1/1) to give 2-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-pyrrole (310 mg, 55%) as a white solid: mp (DSC) 201° C. Anal Calc'd. for C17H14NSFO2 ·0.2 H2O: C, 64.01; H, 4.55; N, 4.39; S, 10.05. Found: C, 64.18; H, 4.33; N, 4.32; S, 10.36.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[Cl:16][C:17]1[CH:33]=[CH:32][C:20]([O:21][C:22]2[N:27]=[CH:26][C:25]([CH:28]([NH2:30])[CH3:29])=[CH:24][C:23]=2[CH3:31])=[CH:19][CH:18]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:30]([CH:28]([C:25]3[CH:26]=[N:27][C:22]([O:21][C:20]4[CH:19]=[CH:18][C:17]([Cl:16])=[CH:33][CH:32]=4)=[C:23]([CH3:31])[CH:24]=3)[CH3:29])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)cnc1Oc1ccc(Cl)cc1
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1Oc1ccc(Cl)cc1
Yield: 83 %

Procedure:
The title compound is prepared in 83% yield (270 mg, off white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (400 mg, 1.4 mmol, Step-1 of Intermediate-1) and 1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (260 mg, 0.87 mmol, Amine-43, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([SH:14])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([CH2:30][CH2:31]I)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].O>CN(C)C=O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([CH2:30][CH2:31][S:14][C:8]2[CH:7]=[C:6]3[C:11]([CH2:12][CH2:13][N:4]([C:1](=[O:3])[CH3:2])[CH2:5]3)=[CH:10][CH:9]=2)([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)C1(CCI)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)N1CCc2ccc(S)cc2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CCSc2ccc3c(c2)CN(C(C)=O)CC3)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Crude crystals (1.26 g) of 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-thiol were dissolved in dimethylformamide (15 ml) and thereto were added 60% sodium hydride (243 mg) and 4-ethoxycarbonyl-4-(2-iodoethyl)piperidine-1-carboxylic acid tert-butyl ester (1 g), and the mixture was stirred at 70° C. for 1 hour. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:7) and dried under reduced pressure to give the title compound (535 mg).
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])(C)(C)C.Br[C:21]1[CH:22]=[C:23]([S:28]([CH2:31][CH2:32][CH2:33][OH:34])(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[CH3:27]>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:19])=[C:10]([C:17]#[C:18][C:21]2[CH:22]=[C:23]([S:28]([CH2:31][CH2:32][CH2:33][OH:34])(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=2[CH3:27])[CH:11]=1)#[N:16]
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)CCCO)cc1Br
Product: Cc1ccc(S(=O)(=O)CCCO)cc1C#Cc1cc(C#N)ccc1OCC(=O)O

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-cyano-2-ethynyl phenoxy)acetate (Intermediate 46) and 3-[(3-bromo-4-methylphenyl)sulfonyl]propan-1-ol (Intermediate 68), the title compound was obtained as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:7])=[O:8])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:2]
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(OC)cc1
Reactant: BrCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
To stirred solution of the (4-methoxy-benzenesulfonyl)-acetic acid ethyl ester (2.5 g, 10 mmol), benzyl bromide ( 1.8 gm, 10 mmol) and 18-Crown-6 (500 mg) in acetone (250 ml) was added K2CO3 (10 gms, excess) and the mixture was refluxed for 24 hours. At the end, the reaction mixture was filtered and the acetone layer was concentrated. The residue obtained was extracted with chloroform, washed well with water, dried over anhydrous MgSO4, filtered and concentrated. The product obtained was purified by silica-gel column chromatography, eluting with 30% ethyl acetate: hexane. The product, 2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester was isolated as a low melting solid. Yield: 3.0 gm 86%; Low melting solid; MS: 349 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19].Br[C:28]1[C:29]([CH3:35])=[N:30][C:31]([NH2:34])=[N:32][CH:33]=1.C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:34][C:31]1[N:30]=[C:29]([CH3:35])[C:28]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([NH:17][S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:19])=[O:20])[CH:4]=2)=[CH:33][N:32]=1
Reactant: Cc1nc(N)ncc1Br
Reactant: CC1(C)OB(c2ccc(Cl)c(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: Cc1nc(N)ncc1-c1ccc(Cl)c(NS(=O)(=O)c2ccccc2)c1

Procedure:
N-[2-Chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzenesulfonamide (Intermediate B) (50 mg, 0.13 mmol), 5-Bromo-4-methyl-pyrimidin-2-ylamine (Intermediate C) (26 mg, 0.14 mmol) and PdCl2(dppf).DCM (10 mg, 0.013 mmol) are placed in a microwave vial containing degassed DME (3 ml) and 2M Na2CO3 (1 ml). The resulting mixture is heated using microwave radiation at 100° C. for 45 minutes. The reaction mixture is diluted with DCM, MgSO4 is added and the mixture is filtered through Celite® (filter agent). The filtrate is absorbed onto silica and purification by flash chromatography on silica eluting with MeOH:DCM (1% to 2% MeOH) affords the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[OH:10])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[C:5]1([CH2:8][N:1]([CH2:9][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[OH:10])=[CH:6][CH:7]=2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: Cc1ccccc1C(O)Cc1ccc(N)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(O)Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Reaction time: 4 h
Yield: 106.2 %

Procedure:
To a solution of Compound XII (900 mg, 2.2 mmol) in 50 ml of ethyl acetate was added 10 percent palladium on activated carbon (100 mg). The reaction vessel was pressurized to 50 psi with hydrogen on a PARR hydrogenation apparatus. The reaction was complete after four hours, and was then filtered through celite and concentrated in vacuo yielding 476 mg of Compound XIII, 95 percent of the theoretical amount. This material was used without further purification in the next example. TLC Rf =0.05, 4:1 methylene chloride:hexanes.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][C:10]2[CH:14]=[C:13](Br)[S:12][C:11]=2[CH3:16])=[CH:7][CH:6]=1)C=C.[Na+].[I-:20].CNCCNC>O1CCOCC1.[Cu]I>[I:20][C:13]1[S:12][C:11]([CH3:16])=[C:10]([CH2:9][C:8]2[CH:17]=[CH:18][C:5]([O:4][CH3:1])=[CH:6][CH:7]=2)[CH:14]=1
Reactant: [I-]
Reactant: C=CCOc1ccc(Cc2cc(Br)sc2C)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(Cc2cc(I)sc2C)cc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To a solution of bromide 13 (906 mg, 2.80 mmol) in 1.4-dioxane (10 mL) were added NaI (841 mg, 5.61 mmol), CuI (54 mg, 0.28 mmol) and N1,N2-dimethylethane-1,2-diamine (0.06 mL, 0.56 mmol) at room temperature. The reaction mixture was evacuated and backfilled with nitrogen. The mixture was stirred 120° C. for 18 hours. The mixture was cooled to room temperature and filtered off through celite. The filtrate was extracted with EtOAc/H2O (50 mL/50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product 14 was dried under high vacuum and used without further purification (846 mg, 81%).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[C:14]([N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:13]=2)[N:3]=1.C(O)(C(F)(F)F)=O.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[CH3:31][N:26]([S:27]([CH3:30])(=[O:29])=[O:28])[C:14]1[CH:13]=[C:12]([NH:11][C:4]2[N:3]=[C:2]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[CH:10]=[CH:9][C:5]=2[C:6]([NH2:8])=[O:7])[CH:17]=[CH:16][C:15]=1[C:18]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19]
Reactant: CN(c1cc(Nc2nc(Cl)ccc2C(N)=O)ccc1C(=O)N1CCOCC1)S(C)(=O)=O
Reactant: C1COCCN1
Solvent: O=C(O)C(F)(F)F
Product: CN(c1cc(Nc2nc(N3CCOCC3)ccc2C(N)=O)ccc1C(=O)N1CCOCC1)S(C)(=O)=O
Yield: 38 %

Procedure:
A solution of 6-chloro-2-(3-(N-methylmethylsulfonamido)-4-(morpholine-4-carbonyl)phenylamino)nicotinamide (19 mg, 0.041 mmol) in morpholine (0.4 mL) in a sealed tube was stirred at 85° C. for 2 h. The morpholine was evaporated. The crude material was dissolved in 1 N aqueous HCl-MeOH (1:1, total 2 mL) and purified by reverse phase HPLC, using Shimadzu VP-ODS 20×100 mm column and eluting with 20% to 100% solvent B (10% MeOH-90% H2O-0.1% TFA) in solvent A (90% MeOH-10% H2O-0.1% TFA), to give the desired product as brown solid (11.7 mg, 38% yield) as bis-TFA salt. LCMS: (M+H)+=519.1. 1H NMR (400 MHz, methanol-d4) δ ppm 8.06 (1H, d, J=2.26 Hz), 7.90 (1H, d, J=8.78 Hz), 7.48 (1H, dd, J=8.41, 2.13 Hz), 7.26 (1H, d, J=8.53 Hz), 6.25 (1H, d, J=9.03 Hz), 3.70-3.93 (7H, m), 3.56-3.69 (7H, m), 3.41 (2H, t, J=4.64 Hz), 3.26 (3H, s), 3.06 (3H, s).