Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][N:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[CH3:22][O:23][C:24]1(B(O)O)[N:29]=[CH:28][CH:27]=[CH:26][NH:25]1.C([O-])([O-])=O.[Na+].[Na+].O>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.COCCOC.CCO>[CH3:22][O:23][C:24]1[N:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][N:21]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])=[CH:26][N:25]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccnc(Br)c1
Reactant: COC1(B(O)O)N=CC=CN1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: COc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)ccn2)cn1

Procedure:
2-Bromo-N-(4-(trifluoromethoxy)phenyl)isonicotinamide (Stage 69.1, 70 mg, 0.194 mmol), 2-methoxypyrimidine boronic acid (45 mg, 0.291 mmol), Pd(PPh3)2Cl2 (5.44 mg, 7.75 μmol), Na2CO3 (71.9 mg, 0.678 mmol), water (194 μL), EtOH (129 μL) and DME (969 μL) were added to a vial, which was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 20 min. The RM was stirred with Si-Thiol (53.8 mg, 0.078 mmol) for 30 min. The resin was filtered off and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Biotage Silica gel column, 4 g, DCM/MeOH+1% NH4OH from 1.5% to 20% MeOH+1% NH4OH) to yield the title compound as an off-white solid. UPLC-MS (Condition 1) tR 2.58 min, m/z=391[M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 4.01 (s, 3H) 7.42 (d, J=8.56 Hz, 2H) 7.84 (dd, J=5.01, 1.35 Hz, 1H) 7.90 (m, J=9.30 Hz, 2H) 8.46 (s, 1H) 8.89 (d, J=5.14 Hz, 1H) 9.34 (s, 2H) 10.71 (s, 1H).
Reaction SMILES: C(OC([N:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:11]=1)[NH2:9])=O)(C)(C)C.[ClH:22]>CO.O1CCOCC1>[ClH:22].[ClH:22].[ClH:22].[N:16]1([C:12]2[CH:11]=[C:10]([NH:8][NH2:9])[CH:15]=[CH:14][CH:13]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N(N)c1cccc(N2CCOCC2)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NNc1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of N-(3-morpholin-4-yl-phenyl)-hydrazinecarboxylic acid tert-butyl ester (468 mg, 1.60 mmol) in methanol (20 mL) was added a solution of 4 N HCl in dioxane (10 mL). The mixture was stirred at room temperature overnight, then concentrated to give (3-morpholin-4-yl-phenyl)-hydrazine 3 HCl salt (484 mg, 100%) as a yellow solid. MS (ES+): m/z=194.1; 1H NMR (CD3OD, 500 MHz): δ 3.60-3.71 (m, 4H), 4.06-4.15 (m, 4H), 7.06 (d, 1H), 7.26-7.35 (m, 2H), 7.50-7.58 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[S:18][C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[N:21]=3)[CH:13]=2)[N:8]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:7]=1[CH3:33])C.CO.[OH-].[Na+]>O1CCCC1>[S:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[CH2:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:7]([CH3:33])=[C:6]2[CH2:5][C:4]([OH:34])=[O:3]
Reactant: CCOC(=O)Cc1c(C)n(Cc2ccccc2)c2ccc(OCc3nc4ccccc4s3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CC(=O)O)c2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccccc1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A solution containing the compound of Example 50, (2.5 g, 5.31 mmol), methanol (200 mL), tetrahydrofuran (200 mL) and 1N sodium hydroxide (9.5 mL) is refluxed for 3 hours. Upon cooling, the mixture is concentrated under reduced pressure, diluted with water (200 mL) and acidified with 2 N HCl. After stirring for 30 minutes, the product is filtered and recrystallized from acetonitrile to give the title compound as a white solid in 85% yield, m.p. 186°-188° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=O)=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[CH:40]1([NH2:45])[CH2:44][CH2:43][CH2:42][CH2:41]1>O1CCCC1>[CH:40]1([NH:45][C:18](=[O:20])[C@@H:17]2[CH2:21][CH2:22][CH2:23][N:16]2[C:14](=[O:15])[C@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: NC1CCCC1
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NC1CCCC1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 71 %

Procedure:
6.4 g (0.02 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline were dissolved in 100 ml of dry tetrahydrofuran and the solution was cooled to -10° C. 2.54 ml of N-ethylmorpholine and 2.62 ml of isobutyl chloroformate were added and the mixture was stirred at -10° C. for 20 minutes. 1.98 ml of cyclopentylamine were then added and the mixture was stirred at 0° C. for 1 hour and then at room temperature overnight. The mixture was then evaporated and the product which crystallised on the addition of water was extracted into ethyl acetate. The organic layer was washed neutral, dried over sodium sulphate and evaporated, the product crystallising on the addition of ether. There were obtained 4.8 g (71%) of N-benzyloxycarbonyl-L-alanyl-L-proline cyclopentylamide of melting point 118°-119° C.; [α]D20 =-93.5° (c=1.0228% in methanol).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:9][C:10]([N:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]([CH3:23])[C:15](=[O:24])[C:14]2[CH:25]=[N:26][CH:27]=[N:28][C:13]1=2)=[O:11].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH3:23][N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:12]([C:10](=[O:11])[CH2:9][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[C:13]2[N:28]=[CH:27][N:26]=[CH:25][C:14]=2[C:15]1=[O:24]
Reactant: CN1C(=O)c2cncnc2N(C(=O)CCl)c2ccccc21
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CN1CCN(CC(=O)N2c3ccccc3N(C)C(=O)c3cncnc32)CC1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
2.6 g (0.0266 mol) of N-methylpiperazine are added dropwise at 50° C., in the course of 15 minutes, to a suspension of 4.0 g (0.0133 mol) of 11-chloroacetyl-6-methyl-5,6-dihydropyrimido[4,5-b][1,5]benzodiazepin-5-one in 30 ml of absolute benzene, and the mixture is stirred for a further 1.5 hours at 70° C. After cooling, the mixture is poured into 100 ml of saturated sodium bicarbonate solution and is extracted once with 50 ml of ethyl acetate and twice with 100 ml, each time, of chloroform. After drying, the organic phase is concentrated in vacuo, and the liquid residue is induced to crystallize by means of ether. It is purified by filtering through neutral silica gel (elution with chloroform) and evaporating the filtrate; yield: 2.7 g, m.p. 183° to 185° C.
Reaction SMILES: B(O)O.Br[C:5]1[N:10]=[C:9]([CH:11]=[O:12])[C:8]([F:13])=[CH:7][CH:6]=1.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O>>[F:13][C:8]1[C:9]([CH:11]=[O:12])=[N:10][C:5]([C:15]2[O:14][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:7]=1
Reactant: OB(O)c1ccco1
Reactant: O=Cc1nc(Br)ccc1F
Agent: OBO
Product: O=Cc1nc(-c2ccco2)ccc1F

Procedure:
3-fluoro-6-(furan-2-yl)picolinaldehyde was prepared using the general boronic acid coupling procedure with 6-bromo-3-fluoropicolinaldehyde and furan-2-ylboronic acid (41 mg, 94 mg theoretical, 43.6%). LC-MS m/z 192 (M+1).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].I[C:32]1[CH:33]=[CH:34][C:35]([NH:38][C:39](=[O:41])[CH3:40])=[N:36][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:32]4[CH:37]=[N:36][C:35]([NH:38][C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:2])[CH3:3]
Reactant: CC(=O)Nc1ccc(I)cn1
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3O2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(-c2ccc3c(c2)CC(C2CCN(C(=O)OC(C)C)CC2)O3)cn1
Temperature: 90 °C

Procedure:
To a mixture of 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid isopropyl ester (41.5 mg) and N-(5-iodo-pyridin-2-yl)-acetamide (39.3 mg) in N,N-dimethylformamide (2 mL) a 2 M aqueous Na2CO3 solution (0.125 mL) is added. The mixture is sparged with argon for 10 min and PdCl2[1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (8 mg) is added. The resulting mixture is stirred over night at 90° C. After cooling to room temperature, the mixture is filtered over basic alumina and eluted with N,N-dimethyl-formamide/MeOH (9:1; 2 mL). The solvent is evaporated and the residue is purified by preparative HPLC (eluent water (+0.1% NH3)/MeOH) to yield the desired product. HPLC (method 13): tR=0.25 min; Mass spectrum (ESI+): m/z=424 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([OH:24])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=3)[C:9]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.C(OC1C=C(C=[C:43]([N+:46]([O-])=O)C=1O)C=O)C.NC(N)=O.Cl>CCO>[CH2:26]([O:25][C:17]1[CH:16]=[C:15]([CH:10]2[C:9]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:43]#[N:46])=[C:8]([C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)[NH:13][C:12](=[O:14])[NH:11]2)[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]=1[OH:24])[CH3:27]
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: CCOc1cc(C2NC(=O)NC(c3ccc(Br)cc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Agent: Cl
Agent: NC(N)=O
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2C#N)cc([N+](=O)[O-])c1O
Yield: 29 %

Procedure:
A mixture of 2-(2-oxo-2-phenylethyl)benzonitrile (Intermediate 33) (100 mg, 0.45 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (87 mg, 0.41 mmol), urea (81 mg, 1.36 mmol), and concentrated HCl solution (0.03 mL, 0.41 mmol) in EtOH (5 mL) was refluxed overnight. The mixture was concentrated, and purified by preparative HPLC to give Compound 70 (54.26 mg, yield 29%) as a yellow solid. 1H NMR (DMSO-d6 300 MHz): δ 10.24 (s, 1H), 8.91 (s, 1H), 7.61 (s, 1H), 7.51-7.44 (m, 2H), 7.31 (s, 1H), 7.24-7.16 (m, 4H), 7.13-7.08 (m, 3H), 5.37 (s, 1H), 3.99-3.93 (m, 2H), 1.31 (t, J=6.8 Hz, 3H); MS (ESI): m/z 456.8 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[N:22][C:17]=1[NH:15][CH:9]1[C:10]2[NH:11][C:12]3[C:4](=[CH:3][CH:2]=[CH:14][CH:13]=3)[C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: Clc1ncccn1
Product: c1cnc(NC2CCCc3c2[nH]c2ccccc32)nc1

Procedure:
N-Pyrimidin-2-yl-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine (150 mg, 0.81 mmol) and 2-chloropyrimidine (184 mg, 1.62 mmol) in a similar manner as described in Example 22 to give 16 mg (8%) of a yellow solid. 1H-NMR (DMSO-d6): δ 10.63 (s, 1H), 8.32 (d, 2H), 7.43 (d, 1H), 7.36 (d, 1H), 7.25 (d, 1H), 7.01-6.97 (m, 1H), 6.93-6.89 (m, 1H), 6.60 (t, 1H), 5.32-5.28 (m, 1H), 2.68-2.57 (m, 2H), 2.041.97 (m, 2H), 1.87-1.75 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[C:10]4[CH:23]=[CH:22][S:21][C:11]=4[C:12](=[O:20])[NH:13][C:14]=3[CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[CH:5]=[CH:4][C:3]=1[CH:24]([CH3:34])[CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C1C(=O)N([Br:42])C(=O)C1>>[Br:42][C:15]1[C:14]2[NH:13][C:12](=[O:20])[C:11]3[S:21][CH:22]=[CH:23][C:10]=3[C:9]=2[C:8]([C:6]2[CH:5]=[CH:4][C:3]([CH:24]([CH3:34])[CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[C:2]([F:1])[CH:7]=2)=[C:17]([O:18][CH3:19])[CH:16]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CNC(=O)OC(C)(C)C)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Product: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CNC(=O)OC(C)(C)C)c(F)c1
Yield: 49.9 %

Procedure:
Following General Procedure I, tert-butyl 2-(2-fluoro-4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (500 mg, 1.0 mmol) was reacted with NBS (220 mg, 1.2 mmol) to afford the desired product (280 mg, 48%) as a brown oil. ESI MS m/z 561 [C26H26BrFN2O4S+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]2[S:11][C:12]3[CH2:19][CH2:18][CH2:17][C:16]4[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:15]=4[C:13]=3[N:14]=2)[CH2:5][CH2:4]1.N1C=CC=CC=1.C(N(C(C)C)CC)(C)C.Cl[C:41]([O:43][CH2:44][CH2:45][Cl:46])=[O:42]>O>[Cl:46][CH2:45][CH2:44][O:43][C:41](=[O:42])[NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[S:11][C:12]3[CH2:19][CH2:18][CH2:17][C:16]4[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:15]=4[C:13]=3[N:14]=2)[CH2:5][CH2:4]1
Reactant: NC[C@H]1CC[C@H](Nc2nc3c(s2)CCCc2ccc(F)cc2-3)CC1
Reactant: O=C(Cl)OCCCl
Solvent: c1ccncc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCC(Nc2nc3c(s2)CCCc2ccc(F)cc2-3)CC1)OCCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of trans-N2-[4-(aminomethyl)cyclohexyl]-9-fluoro-5,6-dihydro-4H-benzo-[6,7]cyclohepta[d][1,3]thiazol-2-amine (5.00 g, 11.95 mmol), 20 ml anhydrous pyridine, and 8 ml diisopropylethylamine was stirred under N2. Then 2-chloroethyl chloroformate (1.40 ml, 13.6 mmol) was added dropwise to the stirring solution. The solution was stirred at room temperature for 2 hours and then poured into 250 ml water and extracted with 250 ml EtOAc. The extract was separated and evaporated to yield 100% (5.40 g) of the desired product as a highly viscous golden oil: 1H-NMR (CDCl3) δ 1.13 (3H, m), 1.43 (1H, m), 1.82 (2H, m), 2.06 (2H, m), 2.22 (2H, m), 2.81 (4H, m), 3.06 (2H, t, J=6.4 Hz), 3.25 (1H, m), 3.70 (3H, m), 4.31 (2H, t, J=5.7 Hz), 4.89 (2H, m), 6.82 (1H, t, J=2.8 Hz), 7.04 (1H, m), 7.70 (1H, dd, J=2.7, 10.8 Hz); 452 (ESMS, MH+).
Reaction SMILES: [OH-].[Na+].[CH3:3][Sn:4](Cl)(Cl)[CH3:5].C[Sn](Cl)(Cl)Cl.[CH2:13]([CH:21]([SH:25])[C:22]([O-:24])=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19]>O>[CH2:13]([CH:21]([SH:25])[C:22]([O-:24])=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20].[CH2:13]([CH:21]([SH:25])[C:22]([O-:24])=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20].[CH3:3][Sn+2:4][CH3:5]
Reactant: C[Sn](C)(Cl)Cl
Agent: CC(C)CCCCCC(S)C(=O)[O-]
Agent: C[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: C[Sn+2]C

Procedure:
A suitable reaction vessel was charged with 14.48 grams (0.362 mole) of sodium hydroxide dissolved in 80 ml water. A solution of 28.77 grams (0.131 mole) of dimethyltin dichloride and 7.92 grams (0.033 mole) of monomethyltin trichloride was added at a rate sufficient to maintain the exothermic reaction mixture at or below 75° C. Then, 75.1 grams (0.362 mole) isooctylthioglycolate was added and reacted. After separating off the aqueous phase, the oily product phase was vacuum stripped and filtered to yield 100 grams of a 75% dimethyltin bis(isooctylthioglycolate)/25% monomethyltin tris(isooctylthioglycolate) mixture.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[Li]CCCC.[CH:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1)=[O:19].[Li]>C1COCC1>[OH:19][CH:18]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1)[C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=1
Reactant: Cc1cc(Br)c2ccccc2n1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)c2cc(C)nc3ccccc23)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
4-Bromo-2-methylquinoline, 209a (1.0 g, 4.5 mmol) was dissolved in 10 mL of anhydrous THF and the resulting solution was cooled down to −78° C. A solution of n-BuLi (3.0 mL, 1.6M, 4.8 mmol) was added slowly and the resulting solution was maintained at −78° C. for 5 min. Meanwhile, in another flask methyl 4-formylbenzoate (0.9 g, 5.4 mmol) was dissolved in 20 mL of anhydrous THF and the resulting solution was cooled to −78° C. before the lithium reagent made above was cannulated. The whole mixture was stirred for 30 min before quenched with MeOH. The solution was then diluted with ethyl acetate and washed with H2O and brine. After dried over MgSO4, the organic solution was filtered and concentrated. The residue was purified on silica gel to provide methyl 4-[hydroxy(2-methyl-4-quinolinyl)methyl]benzoate (0.9 g, 65%). MS (AP+): 308 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:25]5[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([C:37]#[N:38])[CH:3]=1.[CH3:39]/[C:40](/B(O)O)=[CH:41]/[CH3:42].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[C:37]([C:4]1[CH:3]=[C:2](/[C:40](/[CH3:39])=[CH:41]\[CH3:42])[C:10]2[O:9][C:8]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:20][CH2:21][N:22]([C:25]5[N:30]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:28]=[CH:27][N:26]=5)[CH2:23][CH2:24]4)=[O:16])=[CH:35][CH:36]=3)=[N:7][C:6]=2[CH:5]=1)#[N:38]
Reactant: C/C=C(/C)B(O)O
Reactant: N#Cc1cc(Br)c2oc(-c3ccc(C(=O)NCC4CCN(c5nccc(C(F)(F)F)n5)CC4)cc3)nc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C/C=C(/C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(c5nccc(C(F)(F)F)n5)CC4)cc3)oc12

Procedure:
A mixture of 4-(7-bromo-5-cyano-1,3-benzoxazol-2-yl)-N-({1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methyl)benzamide (30 mg, 0.051 mmol), [(1E)-1-methylprop-1-en-1-yl]boronic acid (18 mg, 0.18 mmol), potassium carbonate (3M solution in water) (150 μl), and 1,1′-bis(di-t-butylphosphino)-ferrocene palladium chloride (2 mg, 0.0031 mmol) in tetrahydrofuran (5 ml) was heated at reflux overnight. The mixture was diluted with ethyl acetate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to afford the title compound. Mass spectrum (ESI) 561.2 (M+1).
Reaction SMILES: [CH:1]1([S:7](Cl)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:11]>>[CH:1]1([S:7]([NH2:11])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: N
Product: NS(=O)(=O)C1CCCCC1
Yield: 60 %

Procedure:
According to Reference Example 9-19, by use of cyclohexanesulfonyl chloride (300 mg, 1.6 mmol) and a 25% aqueous ammonia solution (2 mL), the mixture was stirred and reacted at room temperature for 18 hours. Then, purification by silica gel column chromatography (chloroform/methanol=1/0 to 20/1) was performed to give cyclohexanesulfonamide (Compound FW) (161 mg, yield: 60%).
Reaction SMILES: N12CCN(CC1)CC2.[CH3:9][N:10]([CH3:14])[C:11](Cl)=[S:12].[Cl:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:26])[C:17]=1[OH:27]>CN(C)C=O>[Cl:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:26])[C:17]=1[O:27][C:11]([N:10]([CH3:14])[CH3:9])=[S:12]
Reactant: COC(=O)c1ccc(Cl)c(O)c1C
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)c(OC(=S)N(C)C)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under an atmosphere of nitrogen, 12.3 g (109.7 mmol) of 1,4-diazabicyclo[2.2.2]octane and then 13.6 g (109.7 mmol) of dimethylaminothiocarbonyl chloride were added to 11.0 g (54.8 mmol) of methyl 4-chloro-3-hydroxy-2-methylbenzoate in 200 ml of N,N-dimethylformamide. The mixture was stirred at room temperature (RT) for 16 h and, for work-up, poured on ice-water. The product precipitated out and was removed by filtration. The residue was washed with 1M HCl. This gave 14.7 g of clean product.
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:22])[CH2:5][N:6]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7]1(=[O:21])=[O:20])=[CH:18][CH:17]=[CH:16][CH:15]=3.C(O)(C)(C)C.Cl>CO>[CH3:2][O:3][C:4]([C:5]1[NH:6][S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:22]
Reactant: COC(=O)CN1C(=O)c2ccc3ccccc3c2S1(=O)=O
Agent: Cl
Agent: [Na]
Solvent: CC(C)(C)O
Solvent: CO
Product: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Temperature: 60 °C

Procedure:
0.90 mol of methanol-free sodium methylate was prepared by dissolving 20.7 gm (0.90 gm-atom) of sodium in 350 ml of absolute methanol, subsequently distilling off the alcohol, and repeated azeotropic distillation with xylene. After addition of 9.15 gm (0.30 mol) of 3-oxo-naphth[2,1-d]isothiazoline-2-acetic acid methyl ester-1,1-dioxide, 250 ml of anhydrous tert.butanol were added. The reaction mixture was slowly heated to 60° C, kept at 60°-65° C for 11/4 hours, and subsequently refluxed for 1 hour. The mixture was allowed to cool, was then decomposed with ice and adjusted to a pH-value of 3-4 with concentrated hydrochloric acid. The solid product which formed was suction-filtered off, washed with water and dried, yielding 72.0 gm (78% of theroy) of 4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1 -dioxide, m.p. 218°-220° C (after recrystallizing twice from ethylene chloride).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](=[O:29])[N:24]([CH3:30])[CH:23]=2)[C:9]2[N:10]([CH:18]3[CH2:20][CH2:19]3)[CH:11]=[CH:12][C:13]=2[C:14]([O:16]C)=[O:15])=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](=[O:29])[N:24]([CH3:30])[CH:23]=2)[C:9]2[N:10]([CH:18]3[CH2:19][CH2:20]3)[CH:11]=[CH:12][C:13]=2[C:14]([OH:16])=[O:15])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccn(C2CC2)c1C(Nc1cc(C)c(=O)n(C)c1)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(NC(c2ccc(Cl)cc2)c2c(C(=O)O)ccn2C2CC2)cn(C)c1=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
A mixture of methyl 2-((4-chlorophenyl)((1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)amino)methyl)-1-cyclopropyl-1H-pyrrole-3-carboxylate (Step 240.4) (2.2 g, 5.17 mmol) and 2M NaOH (20.7 mL, 41.3 mmol) in THF (20 mL) and MeOH (20 mL) was stirred at 70° C. for 2 hr and concentrated. The aqueous residue was acidified with 2N HCl to pH 5, and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated to afford the title compound (2 g, 89% yield) as a red foam. tR: 0.94 min (LC-MS 6); ESI-MS: 412.2 [M+H]+ (LC-MS 6).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH:16]=[C:15]([C:17]([OH:19])=O)[C:14]2[N:13]=[C:12]3[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:11]3=[CH:10][C:9]=2[C:8]1=[O:25])=[O:5])[CH3:2].[CH:26]1[N:30]=[CH:29][N:28]([C:31](N2C=NC=C2)=O)[CH:27]=1>C(#N)C>[CH3:29][N:28]([CH3:31])[CH2:27][CH2:26][NH:30][C:17]([C:15]1[C:14]2[N:13]=[C:12]3[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:11]3=[CH:10][C:9]=2[C:8](=[O:25])[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:16]=1)=[O:19]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)Cn1cc(C(=O)O)c2nc3c(C)cccc3cc2c1=O
Solvent: CC#N
Product: CCOC(=O)Cn1cc(C(=O)NCCN(C)C)c2nc3c(C)cccc3cc2c1=O
Yield: 79 %

Procedure:
From acid 18i with a reflux time of 48 h and a recharge with an equal amount of CDI after 24 h, and obtained as a yellow solid (79%), mp 214-215° C. (from acetonitrile). 1H NMR (CDCl3): δ 1.28 (t, J=7.2 Hz, 3H, CO2CH2CH3), 2.29 [s, 6H, N(CH3)2], 2.62 (t, J=6.4 Hz, 2H, CH2CH2NMe2), 2.87 (s, 3H, ArCH3), 3.72 (q, J=5.9 Hz, CH2CH2NMe2), 4.25 (q, J=7.1 Hz, CO2CH2CH3), 4.78 (s, 2H, CH2CO2Et), 7.51 (t, J=7.6 Hz, 1H, H-8), 7.74 (d, J=6.9 Hz, 1H, H-7), 7.87 (d, J=8.2 Hz, 1H, H-9), 8.53 (s, 1H, H-3), 9.28 (s, 1H, H-10), 10.96 (br t, J=4.8 Hz, 1H, CONH). 13C NMR (CDCl3): δ 13.7 (CO2CH2CH3), 18.1 (ArCH3), 37.3 (CH2CH2NMe2), 45.1 [N(CH3)2], 50.1 (CH2CO2Et), 58.4 (CH2CH2NMe2), 61.6 (CO2CH2CH3), 109.8 (C-4), 118.7 (C-10a), 125.5 (C-9a), 126.4 (CH, C-8), 126.9 (CH, C-9), 132.6 (CH, C-7), 135.6 (C-6), 139.6 (CH, C-10), 142.7 (CH, C-3), 147.8 (C-5a), 148.4 (C-4a), 162.0 (C-1), 163.9 (CONH), 166.9 (CO2Et).