Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19](Br)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C[O:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:37]=[C:33]4[N:32]=[C:31]([OH:30])[CH:36]=[CH:35][N:34]4[C:19]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: COc1ccnc(N)n1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(O)ccn4c3-c3ccccc3)cc2)CCC1
Temperature: 90 °C

Procedure:
A mixture of crude {1-[4-(2-bromo-2-phenyl-acetyl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester [Int-1-A] (1.26 g) and 4-methoxypyrimidin-2-ylamine (0.67 g) in DMF (21 mL) was heated overnight at 90° C. (bath temperature). On cooling the mixture was partitioned between EtOAc and water and the organic phase washed with brine, dried and concentrated to give a mixture of the title compound and Int-2-0. Purification was achieved by preparative HPLC to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH2:20][C@@H:21]([OH:23])[CH3:22])[C:8]2[N:9]=[C:10](S(C)(=O)=O)[N:11]=[CH:12][C:7]=2[CH:6]=1.[NH2:29][C@H:30]([CH3:33])[CH2:31][OH:32]>O1CCCC1>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH2:20][C@@H:21]([OH:23])[CH3:22])[C:8]2[N:9]=[C:10]([NH:29][C@H:30]([CH3:33])[CH2:31][OH:32])[N:11]=[CH:12][C:7]=2[CH:6]=1
Reactant: C[C@H](O)Cn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(S(C)(=O)=O)nc21
Reactant: C[C@@H](N)CO
Solvent: C1CCOC1
Product: C[C@H](O)Cn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(N[C@H](C)CO)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a tetrahydrofuran (5 mL) solution of 6-(2,4-difluorophenoxy)-8-((S)-2-hydroxypropyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (400 mg, 1 mmol) was added (R)-2-amino-1-propanol (0.38 mL, 5 mmol) and stirred overnight at room temperature. Concentrated under vacuum and chromatographed on silica gel eluding with 2% methanol in dichloromethane and converted to the hydrochloride salt to give 370 mg 6-(2,4-difluoro-phenoxy)-2-((R)-2-hydroxy-1-methyl-ethylamino)-8-((S)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one (mass spec. M+1=407, MP=174.9-178.1° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:44][CH2:45][CH:46]([OH:58])[CH2:47][N:48]1[CH2:57][CH2:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:49]1>C(Cl)Cl>[CH2:49]1[C:50]2[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:56][CH2:57][N:48]1[CH2:47][CH:46]([OH:58])[CH2:45][NH:44][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: O=C(O)c1ccccc1-c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1ccccc1-c1ccccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.5 %

Procedure:
To a solution of 2-(pyridin-2-yl)benzoic acid (150 mg, 0.75 mmol) in DCM (6 mL) was added EDCI (215 mg, 1.1 mmol), HOBt (148 mg, 1.1 mmol), Et3N (228 mg, 2.25 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (185 mg, 0.9 mmol). The mixture was stirred at 25° C. for 16 h. The reaction solution was washed with water and extracted with DCM. The organic layer was then concentrated, and the residue was purified by prep-HPLC to give the title compound (80 mg, Yield 27.5%). 1H NMR (CD3OD, 400 MHz): δ 8.60-8.53 (m, 1H), 7.89-7.81 (m, 1H), 7.63-7.51 (m, 4H), 7.48-7.43 (m, 1H), 7.39-7.32 (m, 1H), 7.12-7.05 (m, 3H), 7.05-6.98 (m, 1H), 4.05-3.93 (m, 1H), 3.73-3.63 (s, 2H), 3.46-3.37 (m, 1H), 3.31-3.23 (m, 1H), 2.92-2.75 (m, 4H), 2.56 (s, 2H). LCMS (m/z): 388.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(Cl)(=O)C([Cl:20])=O>ClCCl.CN(C)C=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([Cl:20])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(C(=O)Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 50 mL round bottom flask, dissolved 4-(4-methylpiperazin-1-yl)benzoic acid (1.00 g, 4.50 mmol) in dichloromethane (5.0 mL). Added oxalyl chloride (1.2 mL, 9.1 mmol) and N,N-dimethylformamide (2 drops). Stirred at RT for 2 hours. Concentrated and isolated 4-(4-methylpiperazin-1-yl)benzoyl chloride as an off-white solid. LC/MS of methyl ester (quenched with methanol) revealed an MS (M+H)+ of 235; Calc'd 234.29 for C13H18N2O2 (methyl ester).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[N+](=[C:25]([C:30]([O:32][CH3:33])=[O:31])[C:26]([O:28][CH3:29])=[O:27])=[N-]>C(Cl)Cl.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[F:20][C:17]([F:19])([F:18])[CH2:16][N:15]([C:12]1[CH:11]=[CH:10][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:21])([F:22])[F:1])=[CH:14][CH:13]=1)[CH:25]([C:30]([O:32][CH3:33])=[O:31])[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC
Reactant: OC(c1ccc(NCC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)F
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: COC(=O)C(C(=O)OC)N(CC(F)(F)F)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
The product from step 1 (500 mg, 1.47 mmol), dimethyl diazomalonate (220 mg, 1.4 mmol, prepared via Synthetic Comm., 17 (14), 1709-16 (1987)), and rhodium acetate (65 mg, 0.015 mmol) were combined and dissolved in CH2Cl2 (12 mL). The resulting mixture was heated at reflux over 1.5 h, cooled to room temperature, and concentrated in vacuo. Purification by flash chromatography (4:1 hexanes/EtOAc) afforded the title compound as a colorless oil (626 mg, 95%). MS (ES+) m/z 472 (MH+).
Reaction SMILES: Cl[CH2:2][CH:3]=[C:4]([CH3:7])[CH:5]=[CH2:6].[CH3:8][CH2:9][C:10](=[O:13])[CH2:11][CH3:12].[OH-].[K+]>CCCCC>[CH3:8][CH:9]([CH2:6][CH:5]=[C:4]([CH3:7])[CH:3]=[CH2:2])[C:10](=[O:13])[CH2:11][CH3:12]
Reactant: CCC(=O)CC
Reactant: C=CC(C)=CCCl
Agent: [K+]
Agent: [OH-]
Solvent: CCCCC
Product: C=CC(C)=CCC(C)C(=O)CC
Yield: 61.7 %

Procedure:
According to the procedure described in Example 1, from 58 g of 1-chloro-3-methyl-2,4-pentadiene and 43 g of pentan-3-one (diethyl ketone) in the presence of 50 g of powdered potassium hydroxide in 200 ml of dry pentane there are obtained 51 g of crude 4,7-dimethyl-6,8-nonadien-3-one which are subjected to a fractional distillation.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH3:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH2:17][S:18][CH3:19])[NH2:15].[CH3:21][N:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:35][C:34](=[O:36])[C:33]3([CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[N:32]=2)=[CH:27][CH:26]=1)[CH3:23]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH2:17][S:18][CH3:19])[NH:15][C:34]([C:33]1([NH:32][C:31]([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][N:22]([CH3:23])[CH3:21])=[CH:26][CH:27]=2)=[O:35])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:36]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: CN(C)Cc1ccc(C2=NC3(CCCCC3)C(=O)O2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](CCSC)NC(=O)C1(NC(=O)c2ccc(CN(C)C)cc2)CCCCC1
Reaction time: 8 h
Yield: 59.1 %

Procedure:
129 mg (1 mmol) of diisopropylethylamine was added to a suspension of 84 mg (0.42 mmol) of L-methionine methyl ester hydrochloride and 100 mg (0.35 mmol) of 2-[4-[(dimethylamino)methyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in 3 ml of toluene, and the mixture was heated under reflux overnight. After the solvent was distilled off under reduced pressure, ethyl acetate was added thereto, and the mixture was washed with saturated brine, followed by drying with sodium sulfate. After the solvent was distilled off under reduced pressure, diethyl ether was added thereto, and the mixture was stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 93 mg (59%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH3:18])[C@H:8]([CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:9][NH:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[C:1]([O:5][C:6](=[O:19])[N:7]([CH3:18])[C@H:8]([CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:9][N:10]([CH3:11])[S:28]([CH3:27])(=[O:30])=[O:29])([CH3:3])([CH3:4])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CNC[C@@H](Cc1cccs1)N(C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1cccs1)CN(C)S(C)(=O)=O
Temperature: -78 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
N-Methyl-N-((1R)-2-methylamino-1-((2-thienyl)methyl)ethyl)carbamic acid tert-butyl ester (1.72 g, 6.05 mmol) was dissolved in dichloromethane (30 ml). Triethylamine (0.84 ml, 6.05 mmol) was added. The solution was cooled to −78° C. Methanesulfonyl chloride (0.47 ml, 6.05 mmol) was added dropwise. The reaction mixture was warmed to room temperature over a period of 3.5 h. It Was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane (100 ml). It was washed with 10% aqueous sodium hydrogen sulfate solution (200 ml). The aqueous phase was extracted with dichloromethane (2×50 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (200 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (180 g), using ethyl acetate/heptane 1:1 as eluent, to give 1.94 g of N-methyl-N-((1R)-2-(N-methyl-N-(methylsulfonyl)amino)-1-((2-thienyl)methyl)ethyl)carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:37])[C:5]([CH3:36])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:32]C(=O)C)=[C:17]([CH:31]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:37])[C:5]([CH3:36])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:32])=[C:17]([CH:31]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccc(C(F)(F)F)c3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cccc(C(F)(F)F)c3)c2)=C(C)C1=O
Yield: 95.9 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-3-trifluoromethylaniline (0.100 g, 0.193 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.088 g, 0.185 mmol, 96%).
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:20])C(=O)C1.[CH3:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([C:31]2[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=2[C:33]#[N:34])[N:23]=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([C:31]2[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=2[C:33]#[N:34])[N:23]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nn(-c2ccccc2C#N)c2ccccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccccc1-n1nc(CBr)c2ccccc21
Yield: 93.3 %

Procedure:
AIBN (141 mg, 0.857 mmol) and NBS (839 mg, 4.72 mmol) were added to a suspension of 2-(3-methyl-1H-indazol-1-yl)benzonitrile (1 g, 4.29 mmol) in CCl4 (20 mL) and the mixture heated to reflux for 2 h. The mixture was concentrated and the residue purified by silica gel chromatography to give the title compound (1.25 g, 93%) as an off white solid.
Reaction SMILES: O[C:2]1[C:7]2=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[CH:10][N:6]2[N:5]=[C:4]([C:17]2[CH:18]=[C:19]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:20]=[N:21][CH:22]=2)[N:3]=1.CN([P+](O[N:38]1N=[N:45][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N1C=CC=CC=1CN>C1COCC1>[C:11]1([C:8]2[CH:9]=[CH:10][N:6]3[C:7]=2[C:2]([NH:38][CH2:39][C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][N:45]=2)=[N:3][C:4]([C:17]2[CH:18]=[C:19]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:20]=[N:21][CH:22]=2)=[N:5]3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NS(=O)(=O)c1cncc(-c2nc(O)c3c(-c4ccccc4)ccn3n2)c1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
5-(4-Hydroxy-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (0.150 g, 0.408 mmol) was dissolved in THF (10 mL) and BOP reagent (0.271 g, 0.612 mmol) and DIPEA (0.214 mL, 1.23 mmol) were added. The reaction mixture was stirred at room temperature for 30 min. Pyridin-2-ylmethanamine (0.0660 g, 0.612 mmol) in THF (3 mL) was added to the reaction mixture and the resulting mixture was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The aqueous layer was extracted with ethyl acetate (25×2 mL). The organic layer was dried (with anhydrous sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by CombiFlash (REDISEP®, silica gel, 40 g, 3% methanol in CH2Cl2) to afford 5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (0.0400 g, 21.4%). LCMS Condition B-38: retention time 1.99 min, [M+1]=458.2. HPLC Condition B-32: retention time 7.75 min, Purity 98.90%. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.94 (d, J=4.4 Hz, 2H), 6.85 (d, J=2.8 Hz, 1H), 7.29 (dd, J=5.2 Hz, J=6.8 Hz, 1H), 7.42 (t, J=4.6 Hz, 1H), 7.46-7.50 (m, 2H), 7.52-7.56 (m, 2H), 7.60 (dd, J=2.0 Hz, J=6.8 Hz, 2H), 7.75 (s, 2H), 7.79 (dt, J=1.6 Hz, J=7.6 Hz, 1H), 7.96 (d, J=2.8 Hz, 1H), 8.39 (dd, J=0.8 Hz, J=1.6 Hz, 1H), 8.94 (t, J=2.0 Hz, 1H), 9.07 (d, J=2.4 Hz, 1H), 9.58 (d, J=2.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:45]([N+:49]1[N:53]=[C:52]([CH3:54])[S:51][C:50]=1[CH3:55])[CH2:46][CH2:47][CH3:48]>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:6])/[CH:55]=[C:50]1\[S:51][C:52]([CH3:54])=[N:53][N:49]\1[CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: O=C(O)c1ccccc1Br
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2-bromobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.88 (t, 3 H) 1.26-1.37 (m, 2 H) 1.67-1.76 (m, 2 H) 2.47 (s, 3 H) 4.15 (t, 2 H) 6.16 (s, 1 H) 7.26-7.36 (m, 1 H) 7.39-7.51 (m, 2 H) 7.59-7.68 (m, 1 H); MS (ESI) m/z 353 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([S:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:8]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:7][C:5]=2[N:6]=1.[C:26](Cl)(=[O:28])[CH3:27].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:26]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([S:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:8]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:7][C:5]=2[N:6]=1)(=[O:28])[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc3sc(N)nc3cc2C(C)(C)C)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1nc2cc(C(C)(C)C)c(SS(=O)(=O)c3ccc(C)cc3)cc2s1

Procedure:
The title compound was prepared as described in Example BB-15 using toluene-4-thiosulfonic acid S-(2-amino-5-tert-butyl-benzothiazol-6-yl)ester (prepared in Example BB-1; 1.75 g, 4.47 mmol), acetyl chloride (4 mL), pyridine (5 mL), DMAP (0.3 g) and CH2Cl2 (20 mL). The crude product was purified by flash silica gel chromatography (20%-70% EtOAc in hexanes as eluents). MS(APCI): 435 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[CH:13][C:14]3[S:19][CH2:18][C:17](=[O:20])[NH:16][C:15]=3[CH:21]=2)[CH2:6]1.[CH2:22]([N:25]1C(=O)O[C:28](=[O:29])[C:27]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:26]12)[CH2:23][CH3:24]>>[O:10]=[C:8]1[N:7]([C:11]2[CH:12]=[CH:13][C:14]3[S:19][CH2:18][C:17](=[O:20])[NH:16][C:15]=3[CH:21]=2)[CH2:6][C@@H:5]([CH2:4][CH2:3][CH2:2][NH:1][C:28](=[O:29])[C:27]2[CH:33]=[CH:34][CH:35]=[CH:36][C:26]=2[NH:25][CH2:22][CH2:23][CH3:24])[O:9]1
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Reactant: CCCn1c(=O)oc(=O)c2ccccc21
Product: CCCNc1ccccc1C(=O)NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Yield: 67 %

Procedure:
Starting from 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and N-propylisatoic anhydride and using Procedure A, the title compound was obtained as a beige solid (77 mg; 67% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH:15]([C:16]([O:18]CC)=[O:17])[C:14]2([CH3:22])[CH3:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C@H:13]2[C@H:15]([C:16]([OH:18])=[O:17])[C:14]2([CH3:22])[CH3:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10]
Reactant: CCOC(=O)C1C(c2ccc(OC(F)(F)F)c(Br)c2)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)[C@@H](C(=O)O)[C@@H]1c1ccc(OC(F)(F)F)c(Br)c1

Procedure:
16 g (0.042 mol) of ethyl 3-(3-bromo-4-trifluoromethoxyphenyl)-2,2-dimethyl-cyclopropanecarboxylate were dissolved in 50 ml of ethanol, a solution of 3.4 g (0.085 mol) of sodium hydroxide in 50 ml of water was then added, and the mixture was heated under reflux for 4 hours, while stirring. The ethanol was then distilled off in the vacuum from a water jet, the residue was taken up in 300 ml of water, and the solution was extracted once with 300 ml of methylene chloride. The aqueous phase was separated off, acidified with concentrated hydrochloric acid and then extracted twice with 300 ml of methylene chloride. The organic phase was then separated off and dried over magnesium sulphate, and the solvent was distilled off in the vacuum from a water jet. The last residues of solvent were removed by incipient distillation for a short time, at a bath temperature of 50° C./2 mm Hg. 9.8 g (66.3% of theory) of (±)cis/trans-3-(3-bromo-4-trifluoromethoxyphenyl)- 2,2-dimethyl-cyclopropanecarboxylic acid were then obtained as a yellow viscous oil. The structure was confirmed by the 1H-NMR spectrum.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[CH3:23][C:24]([CH3:28])([CH3:27])[C:25]#[CH:26]>CN(C)C=O.C(NCC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:23][C:24]([CH3:28])([CH3:27])[C:25]#[C:26][C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1
Reactant: C#CC(C)(C)C
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CC(C)(C)C#Cc1cc(S(=O)(=O)c2ccc(N)cc2)cc(N2CCCC2)n1
Yield: 65.2 %

Procedure:
A mixture of 382 mg (1 mmole) 4-(2-bromo-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine, 91 mg (1.1 mmole) 3,3-dimethyl-1-butyne, 38 mg copper(I)-iodide and 35 mg bis(triphenylphosphine)-palladium(II)-chloride is refluxed for 1 hour in 5 ml dimethylformamide and 5 ml diethylamine. The solvents are removed and the residue is diluted with dichloromethane. The dichloromethane solution is washed twice with water, dried over magnesiumsulfate and concentrated in vacuo. Recrystallisation of the residue from ethanol yields 250 mg (65%) pure 4-[2-(3,3-dimethyl-but-1-ynyl)-6-pyrrolidine-1-yl-pyridine-4-sulfonyl]-phenylamine als a light brown solid mp.: 242-244° C.
Reaction SMILES: BrC1C=C(C(Cl)=O)C=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[F:33].[Br:34][C:35]1[CH:36]=[C:37]([C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:38]=[CH:39][CH:40]=1>C1(C)C=CC=CC=1.C(O)C>[Br:34][C:35]1[CH:36]=[C:37]([C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:38]=[CH:39][CH:40]=1.[Br:34][C:35]1[CH:36]=[C:37]([CH:38]=[CH:39][CH:40]=1)[C:41]([NH:43][C:44]([NH:30][C:29]1[CH:31]=[CH:32][C:26]([O:25][C:16]2[C:15]3[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=3)[N:19]=[CH:18][CH:17]=2)=[C:27]([F:33])[CH:28]=1)=[S:45])=[O:42]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1cccc(Br)c1
Agent: O=C(N=C=S)c1cccc(Br)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(Br)c4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
3-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-bromo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (79 mg, yield 90%).