Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[O:9]1[CH2:14][CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:9]1[CH2:10][CH:11]=[C:12]([C:2]2[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)[CH2:13][CH2:14]1
Reactant: Nc1ccc(I)cn1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
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: CN(C)C=O
Product: Nc1ccc(C2=CCOCC2)cn1
Temperature: 120 °C
Yield: 110.7 %

Procedure:
0.220 g of 5-iodopyridin-2-amine (1.0 mmol), 0.315 g of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.50 mmol), 0.116 g of tetrakis(triphenylphosphine)palladium(0) (0.100 mmol) and 2.25 ml of a 2M sodium carbonate solution (4.50 mmol) were dissolved/suspended in 8.6 ml of DMF in a microwave vessel, flushed with vacuum/argon, and subsequently heated in the microwave for 20 min at 120° C. HPLC/MSD indicated almost complete formation of the desired product. The solvent was evaporated under reduced pressure, 2M HCl was added to the residue and the mixture extracted three times with DCM. To the acidic water phase 2M NaOH was added up to pH 9 and the mixture was extracted three times with ethyl acetate. The combined ethyl acetate solutions were washed once with brine, dried over sodium sulfate and the solvent removed under reduced pressure. 195 mg of the desired product were obtained as yellow powder (yield: quant.). The quite pure raw material (about 90%) was used without further purification in the next step.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][C:5]=1[Cl:14].Cl>CO>[NH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[Cl:14]
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(C(=O)O)cc1Cl
Temperature: 45 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
1 N NaOH (11 mL; 11 mmol) was added to a solution of methyl 4-amino-3-chlorobenzoate (2 g; 10.8 mmol) in MeOH (20 mL) at 45° C. The reaction mixture was stirred for 5 h at 45° C. and overnight at room temperature. More 1N NaOH was added (5 mL; 5 mmol) and the reaction was stirred at 45° C. for 2 h. After concentration of solvent was added 1N HCl (16 ml). The solid precipitate was filtered and dried to give 4-amino-3-chlorobenzoic acid, C, as a with solid (1,75 g; 10.2 mmol). Yield 94.6%.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([F:21])=[CH:8][CH:9]=2)[N:4]=1.O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([F:21])=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:2][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][NH:28]2
Reactant: O=c1c2ccc(F)cc2nc(CCl)n1-c1ccccc1Cl
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2ccc(F)cc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 52.6 %

Procedure:
Prepared according to Procedure C using Intermediate 2c (200 mg, 0.619 mmol), 6-mercaptopurine monohydrate (116 mg, 0.681 mmol), K2CO3 (95 mg, 0.687 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 143 mg of a white crystalline solid (53%), mp 151.4-154.2° C. (discolors). 1H NMR (DMSO-d6) δ: 13.55 (br s, 1H); 8.48 (s, 1H); 8.44 (s, 1H); 8.23 (dd, J=6.3, 8.7 Hz, 1H); 7.77 (dd, J=1.7, 7.4 Hz, 1H); 7.64 (d, J=7.4 Hz, 1H); 7.57 (d, J=9.8 Hz, 1H); 7.45-7.52 (m, 3H); 4.48 (s, 2H). 13C NMR (DMSO-d6) ppm: 169.0 (d, J=253 Hz), 162.6, 159.3, 157.0, 154.0, 152.2, 151.7 (d, J=13 Hz), 146.1, 136.5, 134.7, 134.2, 134.0, 133.0, 132.6 (d, J=11 Hz), 131.3, 120.2, 118.9 (d, J=24 Hz), 115.3 (d, J=22 Hz), 34.6. MS (ES): m/z 439.0 (M+). Anal. calcd. for C20H12ClFN6OS.0.4C2H6O.0.4H2O(0.15KCl: C, 52.52; H, 3.22; Cl, 8.57; N, 17.67. Found: C, 52.25; H, 3.11; Cl, 8.20; N, 17.69.
Reaction SMILES: CO.[NH3:3].Cl[C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[CH:15][NH:16]3)[CH:6]=1>O1CCCC1>[NH2:3][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[CH:15][NH:16]3)[CH:6]=1
Reactant: Clc1cc(Nc2cccc3[nH]ccc23)ncn1
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(Nc2cccc3[nH]ccc23)ncn1
Temperature: 130 °C
Yield: 82 %

Procedure:
A 7N methanol solution of ammonia (50 ml) and tetrahydrofuran (20 ml) were added to 6-chloro-4-(1H-4-indolylamino)pyrimidine (599 mg, 2.5 mmol) and the reaction mixture was heated in a sealed tube at 130° C. for 137 hours. The solvent was distilled off under reduced pressure; the residue was purified by silica gel column chromatography (eluent; ethyl acetate:tetrahydrofuran=1:1); diethyl ether was added to the residue to crystallize; the crystals were filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (454 mg, 2.0 mmol, 82%) as pale brown crystals.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:4].Cl.[N:30]1[N:31]([CH2:35][C:36](O)=[O:37])[N:32]=[CH:33][CH:34]=1>>[N:30]1[N:31]([CH2:35][C:36]([NH:1][C@@H:2]([CH2:20][O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:3]([NH:5][C:6]2[CH:7]=[CH:8][C:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)=[O:4])=[O:37])[N:32]=[CH:33][CH:34]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)Cn1nccn1
Agent: Cl
Product: O=C(Cn1nccn1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1

Procedure:
Proceeding as in Example 1, but substituting (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide and 2-(2H-1,2,3-triazol-2-yl)acetic acid hydrochloride, gave Compound 138, (S)-2-(2-(2H-1,2,3-triazol-2-yl)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide. 1H-NMR (400 MHz, CDCl3): σ 8.33 (s, 1H), 7.75 (s, 1H), 7.52 (s, 1H), 7.38-7.21 (m, 7H), 7.04-7.00 (m, 2H), 6.96-6.89 (m, 4H), 5.29-5.20 (m, 2H), 4.71-4.61 (m, 3H), 4.53 (d, 1H), 4.03 (dd, 1H), 3.53 (t, 1H). MS (EI) for C26H24FN5O4. found 489.9 (MH+).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:18])[N:5]([C:7]2[CH:12]=[N:11][N:10]([CH2:13][CH2:14][O:15][CH3:16])[C:9](=[O:17])[CH:8]=2)[CH:6]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[CH:27])[CH:21]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([C:26]#[C:27][C:2]2[N:3]=[C:4]([CH3:18])[N:5]([C:7]3[CH:12]=[N:11][N:10]([CH2:13][CH2:14][O:15][CH3:16])[C:9](=[O:17])[CH:8]=3)[CH:6]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: C#Cc1cccc(Cl)c1
Reactant: COCCn1ncc(-n2cc(I)nc2C)cc1=O
Product: COCCn1ncc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)cc1=O

Procedure:
The title compound, yellow crystalline solid, MS: m/e=369.2, 370.9 (M+H+), was prepared in accordance with the general method of example 21a from 5-(4-Iodo-2-methyl-imidazol-1-yl)-2-(2-methoxy-ethyl)-2H-pyridazin-3-one and 1-chloro-3-ethynyl-benzene.
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[C:4]([C:7]2[N:8]=[C:9]([O:17][CH2:18][C@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3C(OC(C)(C)C)=O)[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[NH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:20]1[CH2:21][CH2:22][CH2:23][C@@H:19]1[CH2:18][O:17][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:7]([C:4]2[NH:3][C:2](=[O:1])[NH:6][N:5]=2)[N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1nc(-c2n[nH]c(=O)[nH]2)cc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]nc(-c2cc3ccccc3c(OC[C@H]3CCCN3)n2)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 1.5 %

Procedure:
To crude (R)-tert-butyl 2-(((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)oxy)methyl)pyrrolidine-1-carboxylate was added DCM (3 mL) followed by TFA (2 mL). The mixture was stirred at RT for 2 hours and the solvent was removed in vacuo. The crude product was purified by preparative HPLC eluting with a gradient of 10-25% ACN in water (acid mode) to give the title compound (10 mg, 1.5% over 3 steps). ESI-MS m/z [M+H]+ 312.4.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([C:29]([O-:31])=[O:30])=[CH:19][CH:18]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32](Cl)Cl>>[CH:6]1[C:7]2[C:15]([C:17]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:20]([C:29]([O:31][CH3:32])=[O:30])=[CH:19][CH:18]=3)=[N:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:1][C:2]=2[CH:3]=[CH:4][CH:5]=1
Reactant: O=C(Nc1ccccc1Oc1ccccc1)c1ccc(C(=O)[O-])c(-c2ccccc2)c1
Reactant: ClCCl
Product: COC(=O)c1ccc(C2=Nc3ccccc3Oc3ccccc32)cc1-c1ccccc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a stirring solution of methyl 5-(2-phenoxyphenylcarbamoyl)biphenyl-2-carboxylate 102 (0.723 g, 1.7 mmol) in DCM (3 mL) was added PPA (40 g, 1.7 mmol). The reaction was heated to slowly distill off the DCM then stirred at 110° C. for 1 h. The reaction mixture was cooled to room temperature, poured into ice water then extracted with DCM. The combined organic layers were washed with water, dried over Na2SO4, filtered and solvent evaporated to provide 103 as a yellow solid (0.537 g, 78% yield) after purification by ISCO (5 to 30% ethyl acetate in hexane).
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][NH:25]C(=O)OC(C)(C)C)[C:16]=3[Cl:33])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[ClH:34]>CO.O1CCOCC1>[ClH:33].[ClH:34].[C:1]12([CH2:11][NH:12][C:13](=[O:14])[C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][NH2:25])[C:16]=3[Cl:33])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CC(C)(C)OC(=O)NCCCNc1nccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCCCNc1nccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl 3-[(4-{[(1-adamantylmethyl)amino]carbonyl}-3-chloropyridin-2-yl)amino]propylcarbamate (0.41 g) Example 36(i)) in methanol (15 ml) was treated with a solution of HCl in 1,4-dioxane (4 ml) and the mixture was stirred at room temperature for 18 hrs. The solution was evaporated. Methanol was added and the solution was evaporated to give the title compound as a pale yellow solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[C:26]1([C:37](O)=[O:38])[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[Cl:11][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:37]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=23)=[O:38])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(Cl)c1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol (448 mg, 1.24 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (234 mg, 1.24 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (357 mg, 1.86 mmol) and 1-hydroxybenzotriazole hydrate (190 mg, 1.24 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the objective substance (444 mg, 67%).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH:15]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=2)[CH3:16])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.CC(O)=O.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH:15]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=2)[CH3:16])=[CH:6][CH:5]=1
Reactant: CC(Oc1ccc([N+](=O)[O-])c2ccccc12)c1ccnc(N)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CO
Product: CC(Oc1ccc(N)c2ccccc12)c1ccnc(N)c1
Yield: 98.6 %

Procedure:
A solution of 4-(1-(4-Nitronaphthalen-1-yloxy)ethyl)pyridin-2-amine (38) (91 mg, 0.294 mmol) in MeOH (15 mL) and AcOH (3.0 mL) was passed through a Thales H-cube (1.0 mL·min−1, 30° C., 55 mm, 10% Pt/C Cat-Cart, full hydrogen mode). The volatiles were removed under reduced pressure, leaving a purple solid, which was then subjected to SCX capture and release to give the title compound (39) (81 mg, 99%) as a purple oil: m/z 280 (M+H)+ (ES+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]3)[C:8]2=[NH:11])=[CH:4][CH:3]=1.O=[C:20]([CH3:24])[C:21](=[S:23])[NH2:22]>CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([C:8]42[NH:22][C:21](=[S:23])[C:20]([CH3:24])=[N:11]4)[CH2:12][CH2:13][C:14]([F:17])([F:18])[CH2:15][CH2:16]3)=[CH:4][CH:3]=1
Reactant: N=C1c2cc(Br)ccc2CC12CCC(F)(F)CC2
Reactant: CC(=O)C(N)=S
Solvent: CO
Product: CC1=NC2(NC1=S)c1cc(Br)ccc1CC21CCC(F)(F)CC1
Temperature: 60 °C
Yield: 72.9 %

Procedure:
6′-Bromo-4,4-difluorospiro[cyclohexane-1,2′-inden]-1′(3′H)-imine (Example 27 Step 2, 418 mg, 1.33 mmol) and 2-oxopropanethioamide (Intermediate 2, 412 mg, 3.99 mmol) were dissolved in dry MeOH (6 mL) and the resulting solution was heated at 60° C. under N2(g) overnight. The reaction mixture was allowed to cool to r.t. A precipitate formed which was filtered off and dried in vacuo, yielding the title compound (387 mg, 73% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.29-1.47 (m, 2H), 1.49-1.62 (m, 2H), 1.81-2.08 (m, 4H), 2.28 (s, 3H), 3.09 (d, 1H), 3.15 (d, 1H), 7.02 (d, 1H), 7.33 (d, 1H), 7.53 (d, 1H), 12.42 (s, 1H); MS (ES+) m/z 399.0 [M+H]+.
Reaction SMILES: [CH3:1][Li].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:6][CH:5]=1>CCOCC>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12](=[O:14])[CH3:1])=[CH:8][CH:9]=1
Reactant: [Li]C
Reactant: O=C(O)CCc1ccc(Cl)cc1
Solvent: CCOCC
Product: CC(=O)CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.6 M Methyl lithium (33.9 mL, 54.17 mmol) was added over 70 min to a stirring 0° C. solution of 3-(4-chlorophenyl)-propionic acid (5.0072 g, 27.08 mmol) in dry Et2O (135 mL, 0.2 M): The ice bath was removed, and the reaction was allowed to stir at room temperature overnight. The reaction was the poured into rapidly stirring ice water containing aq. HCl. The organic layer was removed, washed with NaHCO3 and brine, then dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 98:2 to 95:5 Hexanes:EtOAc) to achieve pure 66 (2.4253 g, 49.0%): 1H (CDCl3, 400 MHz): δ 7.14 (2H, d, J=8.3 Hz), 7.03 (2H, d, J=8.3 Hz), 2.77 (2H, t, J=7.5 Hz), 2.64 (2H, t, J=7.5 Hz), 2.04 (3H, s) ppm. 13C (CDCl3, 100 MHz): δ 207.12, 139.38, 131.59, 129.55, 128.35, 44.62, 29.82, 28.78 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 29.82; CH2 carbons: 44.62, 28.78; CH carbons: 129.55, 128.35 ppm. HPLC: 10.361 min. (Note: SM has HPLC retention time of 9.409 min.)
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([CH3:7])[S:4][CH:3]=1.Cl[C:9]([O:11][CH3:12])=[O:10]>>[CH3:7][C:5]1[S:4][CH:3]=[C:2]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=1
Reactant: COC(=O)Cl
Reactant: Cc1cc(Br)cs1
Product: COC(=O)c1csc(C)c1

Procedure:
Alternatively, initial lithiation of 3-bromo-5-methylthiophene followed by capture with methyl chloroformate gives methyl 5-methylthiophene-3-carboxylate. Free-radical bromination of the methyl group followed by treatment with an alkali azide, subsequent reduction and hydrolysis provides 5-(aminomethyl)thiophene-3-carboxylic acid (VI). ##STR38##
Reaction SMILES: Cl[C:2]1[C:10]([S:11](Cl)(=[O:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)(=O)C>[NH:18]([C:2]1[C:10]([S:11](=[O:13])(=[O:12])[NH:15][C:3]2[CH:4]=[CH:5][CH:9]=[CH:10][CH:2]=2)=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c(S(=O)(=O)Cl)c1
Reactant: Nc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)c1cc([N+](=O)[O-])c(Nc2ccccc2)c(S(=O)(=O)Nc2ccccc2)c1

Procedure:
To a solution of 4-chloro-3-nitro-5-chlorosulphonyl-benzoic acid (6 g) in ethyl acetate (50 ml), aniline (7.5 g) was added, while stirring. The reaction mixture was stirred for a further 8 hours and filtered. The filtrate was evaporated, and the residue was dissolved in a mixture of aqueous sodium hydrogen carbonate and diethyl ether. The aqueous layer was separated, and the 4-anilino-3-nitro-5-phenylsulphamyl-benzoic acid was precipitated by addition of 4N hydrochloric acid. After recrystallization from aqueous ethanol (25% ethanol in water), the melting point was 249°-250° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:11][N:9]1[C:10]2[C:2]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:3][CH:4]=[CH:5][C:6]=2[C:7]2[C:15](=[O:16])[NH:14][CH2:13][CH2:12][C:8]1=2
Reactant: Cn1c2c(c3cccc(Br)c31)C(=O)NCC2
Reactant: OB(O)c1ccccc1
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: COCCOC
Product: Cn1c2c(c3cccc(-c4ccccc4)c31)C(=O)NCC2
Yield: 90.9 %

Procedure:
A mixture of 6-bromo-2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one (200 mg), phenylboronic acid (131 mg), tetrakis(triphenylphosphine)palladium (0) (11 mg) and 2N sodium carbonate (5 ml) in DME (10 ml) was heated at reflux for 3 h. The cooled mixture was diluted with 2N sodium carbonate (50 ml) and extracted with dichloromethane (3 100 ml). The combined organic extracts were concentrated in vacuo and the residue was purified by FCC eluting with System A (100:8:1) to give a solid (180 mg) which was triturated with ether (20 ml) to give the title compound (160 mg), m.p. 242°-245°.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[Na].[CH:8]([OH:11])([CH3:10])[CH3:9]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:11][CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)O
Reactant: BrCCCCBr
Agent: [Na]
Product: CC(C)OCCCCBr

Procedure:
The above compound is produced in analogous manner to that described in Example 10, but using isopropanol and 1,4-dibromo butane and sodium instead of sodium hydride. B.P.: 90°-91°/34 mm Hg.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:26])[NH:24][NH2:25]>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:26])[NH:24][N:25]=[C:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: NNC(=O)Nc1ccccc1Cl
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Product: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccccc1Cl

Procedure:
ninhydrin, 4-(2-chlorophenyl)-semicarbazide hydrochloride
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:18]([OH:20])=[O:19])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=1.Cl.[CH3:22]O>>[CH3:22][O:19][C:18]([C:4]1[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=[C:2]([OH:1])[CH:3]=1)=[O:20]
Reactant: CO
Reactant: O=C(O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Agent: Cl
Product: COC(=O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Yield: 47 %

Procedure:
A solution of carboxylic acid 24 (0.35 g , 1.3 mmol) in HCl/MeOH(10 ml) was refluxed for 2 hr. The reaction was then cooled, concentrated and the product was dissolved in EtOAc, washed with sat NaHCO3, separated dried, and concentrated to give a solid. The solid was triturated with CH2Cl2, filtered to give a solid (0.15 g, 47%): Mp=236–238° C.; 1NMR (DMSO-d6) δ 9.90 (s, 1 H), 9.57 (s, 1 H), 7.73 (d, 2 H, J=8.5Hz), 7.23 (d, 1 H, J=2.1 Hz), 7.17 (d. 1 H, J=2.1 Hz),7.12 (s, 1 H), 6.88 (d, 2 H, J=8.5 Hz), 3.94 (s, 3 H); MS 283 (M−H)−
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[F:11][C:12]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:13]=1[CH2:14]Br>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:14][C:13]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:12]=2[F:11])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Fc1ccc(F)c(CBr)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1ccc(F)c(CSc2ccc(Cl)cc2)c1
Yield: 99.3 %

Procedure:
4-Chlorothiophenol (253 g, 1.75 mol) was dissolved in industrial methylated spirits (1265 mL) and 2M sodium hydroxide solution (901 mL) was added, maintaining the temperature below 20° C. A solution of 2,5-difluorobenzyl bromide (355 g, 1.72 mol) in industrial methylated spirits (250 mL) was added dropwise to the thiolate solution, maintaining the temperature below 15° C. Upon completion of the reaction, water (1000 mL) was added. The resulting slurry was aged at 5° C. and then filtered. The cake was washed sequentially with cold industrial methylated spirits: water (40:60) and then water (500 mL). Drying in vacuo at ambient temperature furnished 2-[[(4-chlorophenyl)thio]methyl]-1,4-difluorobenzene (462.3 g, 99.6%). 1H NMR (CDCl3)—as obtained for the corresponding intermediate of Method (a).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:18]=3)=[O:15])[N:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:30][OH:31].C[O-].[Na+]>CN(C=O)C>[CH3:30][O:31][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:18]=3)=[O:15])[N:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CO
Reactant: O=C(Nc1cccc(CN2CCOCC2)n1)Nc1csc(-c2ccnc(Cl)c2)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-c2nc(NC(=O)Nc3cccc(CN4CCOCC4)n3)cs2)ccn1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-[2-(2-chloropyridin-4-yl)thiazol-4-yl]-3-(6-morpholin-4-ylmethyl-pyridin-2-yl)urea (100 mg, 0.23 mmol, Example 90) and MeOH (50 mL) was added solid NaOMe (1.6 g, 29.6 mmol) and DMF (20 mL). The reaction mixture was heated to 130° C. After 2 h, the reaction mixture was cooled to RT and filtered. The filtrate was concentrated in vacuo and diluted with EtOAc and filtered to remove the solid. The filtrate was concentrated in vacuo to afford an orange oil which was purified by silica flash chromatography (5% MeOH/CH2Cl2) to afford the title compound as a white solid. MS m/z: 427.2 (M+H). Calc'd for C20H22N6O3S: 426.15.