Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([S:12][CH3:13])=[N:7][C:6]=2[N:5]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][CH:19]=2)[C:4](=[O:28])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:37])C=1.[OH-:40].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([S:12]([CH3:13])(=[O:37])=[O:40])=[N:7][C:6]=2[N:5]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH:17]=[CH:18][CH:19]=2)[C:4](=[O:28])[CH:3]=1
Reactant: CSc1ncc2c(C)cc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2cccc(NC(=O)OC(C)(C)C)c2)c2nc(S(C)(=O)=O)ncc12
Reaction time: 1.5 h
Yield: 95 %

Procedure:
At RT, tert-butyl (3-(5-methyl-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (54) (440 mg, 1.10 mmol) in DCM (10 mL) was treated with MCPBA (75 wt. %, 681 mg, 2.76 mmol) and stirred for 90 min. The reaction mixture was diluted with DCM (25 mL), treated with ice and 1 N NaOH (30 mL). The DCM layer was separated and the aqueous layer was extracted with an additional amount of DCM (2×20 mL), dried over Na2SO4 and concentrated to furnish tert-butyl (3-(5-methyl-2-(methylsulfonyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (451 mg, 1.05 mmol, 95% yield) as an off-white foam. The crude material was used without purification. m/z (ESI, +ve ion) 453.0 (M+Na)+. 1H NMR (400 MHz, CDCl3) δ ppm 9.11 (1H, s), 7.60 (1H, br. s.), 7.45 (1H, t, J=8.0 Hz), 7.23 (1H, dt, J=8.2, 1.0 Hz), 6.91 (1H, ddd, J=7.9, 1.9, 0.8 Hz), 6.80 (1H, d, J=1.4 Hz), 6.60 (1H, s), 3.04 (3H, s), 2.60 (3H, d, J=1.2 Hz), 1.49 (9H, s).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]1[O:10][C:9](/[CH:15]=[CH:16]/[CH:17]2[CH2:19][CH2:18]2)([C:11]([F:14])([F:13])[F:12])[C:8]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:7]=2[N:6](CC2C=CC(OC)=CC=2)[C:5]1=[O:34].O>C(#N)C>[Br:1][CH2:2][CH2:3][C@@H:4]1[O:10][C@:9](/[CH:15]=[CH:16]/[CH:17]2[CH2:18][CH2:19]2)([C:11]([F:13])([F:14])[F:12])[C:8]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:7]=2[NH:6][C:5]1=[O:34]
Reactant: COc1ccc(CN2C(=O)C(CCBr)OC(/C=C/C3CC3)(C(F)(F)F)c3cc(Cl)ccc32)cc1
Solvent: O
Solvent: CC#N
Product: O=C1Nc2ccc(Cl)cc2[C@@](/C=C/C2CC2)(C(F)(F)F)O[C@H]1CCBr
Reaction time: 0.33 h

Procedure:
To a room temperature solution of 750 mg of trans-3-(2bromoethyl)-7-chloro-5-cyclopropylethenyl-1,5-dihydro-l-(4-methoxybenzyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one in 35 mL of acetonitrile was added 18 mL of water and 3.78 g of ceric ammonium nitrate. After 20 min, the reaction mixture was partitioned between water and ether, and the organic layer was washed with aqueous bicarbonate and brine, dried and evaporated. This produced two diastereomeric products which were separated by column chromatography over silica gel (elution with 10-25% ethyl acetate in hexanes). The first diastereomer eluted (162 mg) was the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([N:24]1[CH2:28][C@H:27]2[C@H:29]([NH2:32])[CH2:30][CH2:31][C@H:26]2[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:33](N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)C1C=CC=CC=1>>[CH2:17]([N:24]1[CH2:28][C@H:27]2[C@H:29]([NH:32][C:14](=[O:16])[C@H:9]([N:8]([CH3:33])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:30][CH2:31][C@H:26]2[CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Product: CC(C)C[C@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)N(C)C(=O)OC(C)(C)C

Procedure:
tert-Butyl(R)-1-((3aS,4R,6aR)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-ylamino)-4-methyl-1-oxopentan-2-yl(methyl)carbamate was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-D-leucine for N-(tert-butoxycarbonyl)-L-leucine and (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Example 16 Steps A-E for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.27 (d, J=5.9 Hz, 1H), 7.45-7.40 (m, 2H), 7.38-7.32 (m, 2H), 7.27 (dd, J=10.3, 4.3 Hz, 1H), 4.45-4.33 (m, 1H), 3.59 (d, J=13.1 Hz, 1H), 3.44 (d, J=13.2 Hz, 1H), 3.07 (d, J=23.2 Hz, 3H), 2.86-2.80 (m, 1H), 2.54-2.37 (m, 3H), 2.32 (d, J=8.6 Hz, 1H), 2.27-2.18 (m, 1H), 2.13-1.98 (m, 1H), 1.94-1.86 (m, 1H), 1.88-1.71 (m, 3H), 1.57 (td, J=13.4, 6.6 Hz, 2H), 1.48 (d, J=8.9 Hz, 9H), 1.40-1.31 (m, 1H), 0.86 (dd, J=19.8, 6.5 Hz, 6H); MS (ESI+) m/z 444 (M+H)+.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].[F:9][C:10]1([F:28])[O:14][C:13]2[CH:15]=[CH:16][C:17]([C:19](=C)[C:20](=O)[CH2:21][C:22](OC)=O)=[CH:18][C:12]=2[O:11]1>CO>[F:28][C:10]1([F:9])[O:14][C:13]2[CH:15]=[CH:16][C:17]([CH:19]3[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH3:8])[NH:1][C:21]([CH3:22])=[C:20]3[C:4]([O:6][CH3:7])=[O:5])=[CH:18][C:12]=2[O:11]1
Reactant: COC(=O)/C=C(/C)N
Reactant: C=C(C(=O)CC(=O)OC)c1ccc2c(c1)OC(F)(F)O2
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccc2c(c1)OC(F)(F)O2

Procedure:
20 mmol of methyl β-aminocrotonate and 20 mmol of crude methyl (2,2-difluoro-1,3-benzodioxol-5-yl)-methylene-acetoacetate are heated under reflux in 30 ml of methanol for 12 hours, the methanol is evaporated off and the residue is chromatographed on silica gel with chloroform. The evaporated product fraction is taken up in a little methylene chloride and the mixture is foamed to a glass by rapid evacuation.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]O)[CH2:2][CH3:3].S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][Cl:15])[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1CO
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCOc1ccccc1CCl
Yield: 104.6 %

Procedure:
A 2 liter flask was charged with 316 grams (1.9 moles, 1.0 eg.) of 2-propoxybenzyl alcohol and 15 grams of pyridine (0.0126 moles) in 750 ml of toluene. 237 grams (1.99 moles, 1.01 ec.) of thionyl chloride was slowly added dropwise, allowing the reaction mixture to reflux during the addition. The reaction was stirred 4 hours at room temperature after which the toluene and thionyl chloride were removed under reduced pressure. To the remaining oil was added water and ether and washed with saturated NaHCO3 Drying and removal of the solvent gave 367 grams (100% yield) of a red oil.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][N:43]1[C:52]2[C:47](=[CH:48][N:49]=[C:50]([CH3:53])[CH:51]=2)[CH:46]=[C:45]([C:54]2[CH:55]=[C:56]([NH:61]/[C:62](/[NH2:65])=[N:63]/O)[CH:57]=[CH:58][C:59]=2[CH3:60])[C:44]1=[O:66]>CN(C=O)C>[OH:1][CH2:2][C:3]([C:4]1[O:6][N:63]=[C:62]([NH:61][C:56]2[CH:57]=[CH:58][C:59]([CH3:60])=[C:54]([C:45]3[C:44](=[O:66])[N:43]([CH3:42])[C:52]4[C:47]([CH:46]=3)=[CH:48][N:49]=[C:50]([CH3:53])[CH:51]=4)[CH:55]=2)[N:65]=1)([CH3:8])[CH3:7]
Reactant: CC(C)(CO)C(=O)O
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(C(C)(C)CO)n3)ccc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-hydroxy-2,2-dimethylpropanoic acid (88 mg, 0.7 mmol) in DMF (5 mL) were added DIPEA (0.26 mL, 1.5 mmol) and HATU (0.21 g, 0.7 mmol). After stirring at rt for 15 min, 17 (0.25 g, 0.7 mmol) was added as a solution in DMF (2 mL). The reaction was stirred at rt until complete consumption of 17 was determined by LC/MS and then was heated at 100° C. for 2 h. Subsequently the reaction was cooled to rt, partitioned with EtOAc (30 mL) and 5% aq NaHCO3 (20 mL). The aqueous layer was extracted with fresh EtOAc (2×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and reduced to dryness. The crude material was purified by flash column chromatography on silica with DCM/4% MeOH as eluant to give 3-(5-(5-(1-hydroxy-2-methylpropan-2-yl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A35) as a clear glassy solid. 1H NMR (400 MHz, d6-DMSO) 9.86 (s, 1H), 8.81 (s, 1H), 7.93 (s, 1H), 7.43 (s, 1H), 7.37 (dd, J=8, 2 Hz, 1H), 7.28 (d, J=2 Hz, 1H), 7.21 (d, J=8 Hz, 2H), 5.10 (t, J=5.5 Hz, 1H), 3.65 (s, 3H), 3.55, (d, J=5.5 Hz, 1H) 2.61 (s, 3H), 2.07 (s, 3H), 1.31 (s, 6H). MS m/z 420.4 (M+1).
Reaction SMILES: [OH:1]C1C=CC=CC=1C(O)=O.C(OO)(C)(C)C.[CH3:17][CH:18]([C:20](=[CH:23][CH:24]=[C:25]([CH3:37])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:36])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[C:21]#[N:22])[CH3:19]>C(Cl)Cl.[Se](=O)=O>[OH:1][CH2:34][C:33]([CH3:35])=[CH:32][CH2:31][CH2:30][C:29]([CH3:36])=[CH:28][CH2:27][CH2:26][C:25]([CH3:37])=[CH:24][CH:23]=[C:20]([CH:18]([CH3:17])[CH3:19])[C:21]#[N:22]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(C)=CCCC(C)=CCCC(C)=CC=C(C#N)C(C)C
Agent: CC(C)(C)OO
Agent: O=[Se]=O
Solvent: ClCCl
Product: CC(=CCCC(C)=CCCC(C)=CC=C(C#N)C(C)C)CO
Reaction time: 0.5 h
Yield: 317.6 %

Procedure:
To a suspension of selenium dioxide (58 mg) and 2-hydroxybenzoic acid (365 mg) in methylene chloride (10.5 ml) was gradually added an aqueous solution of 80% t-butyl hydroperoxide (11.6 ml) with stirring on a water bath. After 30 minutes, 2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenenitrile (7.56 g, 26.8 mmol) was added to the mixture, which was then allowed to stand at room temperature for 30 hours. Most of the solvent was removed by evaporation in vacuo, and the residue was dissolved in ether. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and concentrated. The resultant residue was subjected to silica gel column chromatography to give the aimed 14-hydroxy-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenenitrile (2.53 g, 31%). The starting material was also recovered (3.10 g, 40%) in the column chromatography. The yield of the aimed product based on the consumed starting material was 52%.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH:10][CH3:11].[NH2:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:16]=2[N:17]=1.[C:27](N1C=CN=C1)(N1C=CN=C1)=S>C(Cl)CCl>[CH3:11][N:10]1[C:3]2[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=2[N:1]=[C:27]1[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([O:22][C:23]([F:26])([F:24])[F:25])[CH:19]=[CH:18][C:16]=2[N:17]=1
Reactant: CNc1cc(C#N)ccc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Solvent: ClCCCl
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2ccc(C#N)cc21
Yield: 78 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-6-carbonitrile (2.27 g) was prepared by following General Procedure D starting from 4-amino-3-methylamino-benzonitrile (1.1 g), 2-amino-6-(trifluoromethoxy)-benzothiazole (1.75 g), 1,1′-thiocarbonyldiimidazole (1.78 g), and EDC (1.9 g). LC/MS: m/z 391.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][NH:28][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:27]2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: COc1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(c1)CN(c1c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 70.2 %

Procedure:
298 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 230 mg of 5-methoxyisoindoline, 300 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 300 mg of the target compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[CH2:31][NH2:32]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:32][CH2:31][CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][O:25]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: NCC1CCCCO1
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC3CCCCO3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (tetrahydro-2H-pyran-2-yl)methanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17-1.31 (m, 2H) 1.32-1.45 (m, 2H) 1.77-1.91 (m, 4H) 2.40-2.46 (m, 3H) 3.37-3.49 (m, 1H) 3.65-3.82 (m, 1H) 4.58 (br. s., 1H) 7.65 (dd, J=7.83, 1.52 Hz, 1H) 7.73 (s, 1H) 7.77 (d, J=7.83 Hz, 1H) 8.16 (br. s., 1H) 8.25-8.65 (m, 3H) 8.80-9.01 (m, 1H) 12.36-13.83 (m, 1H). MS m/z [M+H]+418.2.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:19]=[C:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[N:12](C(OCC(Cl)(Cl)Cl)=O)[CH:11]=3)[N:7]([C:29]([O:31][CH2:32][C:33](Cl)([Cl:35])[Cl:34])=[O:30])[CH2:6]1)=O.[NH2:37][NH2:38].[Cl-:39].[Na+]>C(Cl)(Cl)Cl>[Cl:39][C:33]([Cl:34])([Cl:35])[CH2:32][O:31][C:29]([N:7]1[C@H:8]2[C:18]([C:17]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:20]=3[C:10]([CH2:9]2)=[CH:11][NH:12]4)=[CH:19][CH:5]([C:3]([NH:37][NH2:38])=[O:2])[CH2:6]1)=[O:30]
Reactant: COC(=O)C1C=C2c3cccc4c3c(cn4C(=O)OCC(Cl)(Cl)Cl)C[C@H]2N(C(=O)OCC(Cl)(Cl)Cl)C1
Reactant: NN
Reactant: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: NNC(=O)C1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C(=O)OCC(Cl)(Cl)Cl)C1

Procedure:
490 mg of the ester (0.8 mmol) in 35 ml of chloroform is stirred together with 12 ml of hydrazine for 25 hours at room temperature. The mixture is then distributed between chloroform and saturated sodium chloride solution, the organic phase is dried with magnesium sulfate and evaporated. The crude product, amounting to 287 mg, is chromatographed on silica gel, thus isolating 193 mg of 9,10-didehydro-6-(2,2,2-trichloroethoxycarbonyl)-8-ergolinecarboxylic acid hydrazide as an oily mixture of isomers (55% of theory).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH2:8][OH:9])=[C:5]([CH3:7])[N:6]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].O>ClCCl>[Br:1][C:2]1[S:3][C:4]([CH2:8][O:9][S:18]([CH3:17])(=[O:20])=[O:19])=[C:5]([CH3:7])[N:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(Br)sc1CO
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1nc(Br)sc1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 67.2 %

Procedure:
To an ice-cold solution of (2-Bromo-4-methyl-thiazol-5-yl)-methanol (3.2 g, 15.6 mmol) and triethylamine (3.2 mL, 23.4 mmol) in dichloromethane (80 mL) is slowly added a solution of methanesulfonyl chloride (2.1 g, 18.7 mmol) in dichloromethane (20 mL). The mixture is kept at this temperature for 45 minutes and afterwards allowed to warm to room temperature. Water (30 mL) is added after 3 hours and the mixture is extracted with ethylacetate. The organic phase is separated and dried over MgSO4. The organic solvent is removed under reduced pressure to give 3.0 g of Methanesulfonic acid 2-bromo-4-methyl-thiazol-5-ylmethyl ester, which was used without further purification.
Reaction SMILES: S(Br)([Br:3])=O.[Br:5][C:6]1[S:7][CH:8]=[C:9]([CH:11](O)[CH3:12])[N:10]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:5][C:6]1[S:7][CH:8]=[C:9]([CH:11]([Br:3])[CH3:12])[N:10]=1
Reactant: O=S(Br)Br
Reactant: CC(O)c1csc(Br)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Br)c1csc(Br)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
To a stirred solution thionyl bromide (0.787 g, 3.78 mmol, 1.05 eq.) in 20 ml dry DCM, cooled to 5° C., was added dropwise a solution of 1-(2-bromo-1,3-thiazol-4-yl)ethanol (0.75 g, 3.60 mmol, 1 eq.) and pyridine (0.285 g, 3.60 mmol, 1 eq.) in 15 ml dry DCM. On complete addition, the cooling bath was removed, the reaction warmed to room temperature and stirred 1.5 hr. 100 ml of water and 100 ml of DCM were added and stirring allowed for 2 mins. The organic layer was separated, dried of MgSO4 and evaporated to give 2-bromo-4-(1-bromoethyl)-1,3-thiazole (0.9 g, 84% yield) as a yellow viscous oil.
Reaction SMILES: S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.COC1C=C(OC)C=CC=1C[N:27]([CH:52]1[CH2:54][CH:53]1[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:28]1[C:29]2[N:40]=[N:39][N:38]([CH:41]3[CH:45]4[O:46]C(C)(C)[O:48][CH:44]4[CH:43](O)[CH2:42]3)[C:30]=2[N:31]=[C:32]([S:34][CH2:35][CH2:36][CH3:37])[N:33]=1.[N:61]1C=CC=CC=1.O.[Cl:68]CCl>>[ClH:68].[NH2:61][CH:43]1[CH2:42][CH:41]([N:38]2[C:30]3[N:31]=[C:32]([S:34][CH2:35][CH2:36][CH3:37])[N:33]=[C:28]([NH:27][CH:52]4[CH2:54][CH:53]4[C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)[C:29]=3[N:40]=[N:39]2)[CH:45]([OH:46])[CH:44]1[OH:48]
Reactant: c1ccncc1
Reactant: ClCCl
Reactant: CCCSc1nc(N(Cc2ccc(OC)cc2OC)C2CC2c2ccccc2)c2nnn(C3CC(O)C4OC(C)(C)OC43)c2n1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(N)C(O)C3O)c2n1
Product: Cl
Reaction time: 18 h

Procedure:
Triflic anhydride (0.08 ml) was added to a solution of the product from step (h) (147 mg) and pyridine (0.08 ml) in dichloromethane (2 ml) and stirred for 18 hours. Water was added and the mixture was extracted with dichloromethane. The organic layer was dried (MgSO4), evaporated and purified (SiO2, petrol:ether 3:2 as eluent) to give the sub-title compound as a white foam (166 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>O1CCOCC1.CC(C)=O>[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:1][CH:2]2[CH2:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:11]4[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=4)[CH:8]=3)[CH2:3]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccc3c(c2)CC(NS(=O)(=O)c2ccc(F)cc2)C3)=NN1
Reaction time: 2 h

Procedure:
2.9 (12.6 mmol) of 6-(2-amino-indan-5-yl)-4,5-dihydropyridazin-3(2H)-one are dissolved in a mixture of 30 ml of dioxan and 10 ml of acetone, and 1.42 g (14 mmol) of triethylamine and 2.8 g of p-fluorobenzenesulphonyl chloride are added. After 2 hours, the mixture is evaporated, water is added to the residue, and the reaction product is filtered off with suction and recrystallised from glacial acetic acid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10](=[O:12])[NH:9][C:8]2[N:7]=[C:6]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)[CH:5]=[CH:4][C:3]1=2.Cl.[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:6]2[N:7]=[C:8]3[C:3]([CH:2]([CH3:1])[CH2:11][C:10](=[O:12])[NH:9]3)=[CH:4][CH:5]=2)[CH2:30][CH2:29]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: CC1CC(=O)Nc2nc(OCCCC=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC1CC(=O)Nc2nc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
The crude 4-(5-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde in 1,2-dichloroethane (50 mL) is treated with 1-(2,3-dichlorophenyl)piperazine monohydrochloride (1.104 g, 4.13 mmol), followed by triethylamine (0.80 mL, 5.69 mmol) and sodium triacetoxyborohydride (0.911 g, 4.30 mmol). The cloudy yellow solution is stirred at room temperature for 1 hour. The mixture is quenched with water and saturated NaHCO3 solution and extracted with CH2Cl2. The organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to a yellow oil. The oil is purified by column chromatography (5:95 methanol/ethyl acetate) to afford the title compound (1.08 g, 79% over 2 steps) as a white solid. Mp 53–54° C. 1H NMR (CDCl3, 400 MHz): δ 8.94 (br s, 1H), 7.83 (d, 1H), 7.18–7.13 (m, 2H), 6.98–6.94 (m, 1H), 6.62 (d, 1H), 6.38 (d, 1H), 4.38 (t, 2H), 3.16–3.02 (m, 4H), 2.76–2.60 (m, 4H), 2.55–2.46 (m, 2H), 1.90–1.82 (m, 2H), 1.77–1.64 (m, 2H). MS ES: m/z=462.72, 464.58.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:35])[CH3:34])[NH:28][C:27](=[O:36])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:35])[CH3:34])[NH:28][C:27](=[O:36])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Reactant: CC(=O)Nc1cc2c(cc1F)CC(=O)N2
Product: CC(=O)Nc1cc2c(cc1F)C(=Cc1[nH]c3c(c1C)C(=O)N(CCN1CCOCC1)CC3)C(=O)N2
Yield: 39.3 %

Procedure:
The title compound was prepared under the same conditions as described in Example 15 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-acetamide as starting materials to give N-{5-fluoro-3-[3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-acetamide (35 mg, 39.3%) as a light brown solid.
Reaction SMILES: C(N1CCN(C2C=CC([B:16]([OH:18])[OH:17])=CC=2)CC1)(C)C.Br[C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][C@H:30]([CH3:32])[NH:29][C@H:28]([CH3:33])[CH2:27]2)=[CH:22][CH:21]=1>>[CH3:33][C@H:28]1[NH:29][C@@H:30]([CH3:32])[CH2:31][N:26]([C:23]2[CH:24]=[CH:25][C:20]([B:16]([OH:18])[OH:17])=[CH:21][CH:22]=2)[CH2:27]1
Reactant: CC(C)N1CCN(c2ccc(B(O)O)cc2)CC1
Reactant: C[C@@H]1CN(c2ccc(Br)cc2)C[C@H](C)N1
Product: C[C@@H]1CN(c2ccc(B(O)O)cc2)C[C@H](C)N1

Procedure:
The title compound was synthesized according to the synthesis of 4-(4-isopropylpiperazin-1-yl)phenylboronic acid, except substituting 1-(4-bromophenyl)-cis-3,5-dimethylpiperazine (300 mg, 1.11 mmol). The reaction was quenched with sat. NH4Cl solution, extracted with EtOAc, dried over MgSO4, filtered, and concentrated to dryness. The title compound was isolated by silica gel chromatography (MeOH/CH2Cl2, 6:94 to 1:4) as a yellow solid (59 mg, 23%). 1H NMR (400 MHz, MeOD) δ 7.59 (d, J=6.2 Hz, 2H), 6.91 (d, J=8.2 Hz, 2H), 3.67-3.63 (m, 2H), 3.09-3.01 (m, 2H), 2.32 (t, J=11.6 Hz, 2H), 1.18 (d, J=6.4 Hz, 6H); MS ESI 235.1 [M+H]+, calcd for [C12H19BN2O2+H]+ 235.15.
Reaction SMILES: CC(C)=O.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([SH:14])=[N:11][C:10]=2[CH:15]=1.[Br:16][CH:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](O)=[O:19].C(OC(=O)C)(=O)C>C(O)(=O)C>[Br-:16].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]3[S:14][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:18]([OH:19])[N+:11]=3[C:10]=2[CH:15]=1
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: Sc1nc2cc(Cl)ccc2s1
Solvent: CC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Oc1c(-c2ccccc2)sc2sc3ccc(Cl)cc3[n+]12
Product: [Br-]
Yield: 80 %

Procedure:
A 1 l. acetone solution of 10.25 g. (0.05 moles) 5-chloro-2-mercaptobenzothiazole and 10.75 g. (0.05 moles) α-bromophenylacetic acid containing 100 ml. glacial acetic acid and 30 ml. acetic anhydride is heated in an open flask until the volume reaches 300 ml. The precipitated solid, weighing 16 g. (80% yield) is collected and recrystallized from glacial acetic acid. The product melts at 225°-228° C.