Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[H-].[Na+].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][S:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:28])=[O:27])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)c4ccccc4)cc23)CC1
Yield: 70.8 %

Procedure:
To a solution of 3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (4.75 g, 20.6 mmol) in dimethylformamide (25 mL), stirring at 0° C. under nitrogen, was added sodium hydride in one portion (0.83 g of a 60% dispersion in oil, 20.6 mmol). The green solution turned brown; after stirring for 30 minutes at 0° C. benzenesulfonyl chloride (2.63 mL, 20.6 mmol) was added in one portion, then the reaction mixture was allowed to stir until the reaction was complete. The solution was poured into water (125 mL), then extracted with ethyl acetate (4×125 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to a residue which was further purified on silica gel. Elution with a 9:1 mixture of dichloromethane and 2 N ammonia in methanol provided 5.40 g (70%) of benzenesulfonic acid 3-(1-methylpiperidin-4-yl)-1H-indol-5-yl ester as a tan solid: mp=189-194° C.; 1H NMR (400 MHz, dmso-d6): 10.97 (br s, 1H), 7.85-7.72 (m, 3H), 7.65-7.54 (mm, 2H), 7.24 (d, 1H, J=8.8 Hz), 7.11 (d, 1H, J=2.0 Hz), 6.88 (d, 1H, J=1.2 Hz), 6.69 (dd, 1H, J=8.8, 1.6 Hz), 2.77 (br d, 2H, J=11.2 Hz), 2.52-2.40 (m, 1H), 2.16 (s, 3H), 1.91 (br t, 2H, J=11.2 Hz), 1.67 (br d, 2H, J=12.0 Hz), 1.58-1.44 (m, 2H); MS(ES+): m/e 371.0 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][C@@H:14]3[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]3)[CH:8]=[N:7][C:6]=2[N:5]([CH3:21])[C:4](=[O:22])[C:3]=1[F:23].[F:24][C:25]1[CH:31]=[C:30]([I:32])[CH:29]=[CH:28][C:26]=1[NH2:27].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:19][C:16]1([CH3:20])[O:15][C@H:14]([CH2:13][N:9]2[C:10](=[O:12])[C:11]3[C:2]([NH:27][C:26]4[CH:28]=[CH:29][C:30]([I:32])=[CH:31][C:25]=4[F:24])=[C:3]([F:23])[C:4](=[O:22])[N:5]([CH3:21])[C:6]=3[N:7]=[CH:8]2)[CH2:18][O:17]1
Reactant: Nc1ccc(I)cc1F
Reactant: Cn1c(=O)c(F)c(Cl)c2c(=O)n(C[C@@H]3COC(C)(C)O3)cnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1c(=O)c(F)c(Nc2ccc(I)cc2F)c2c(=O)n(C[C@@H]3COC(C)(C)O3)cnc21
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Combine (R)-5-chloro-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (0.050 g, 0.15 mmol) and 2-fluoro-4-iodoaniline (0.052 g, 0.22 mmol) in de-gassed dioxane (2.0 mL). Add palladium acetate (1.6 mg) and Xantphos (8.5 mg) and sodium t-butoxide (35 mg). Heat to 85° C. After 2 hours, dilute with ethyl acetate, wash with aqueous hydrochloric acid and then brine, dry over sodium sulfate, and concentrate in vacuo to give a residue. Purify the residue with flash chromatography eluting with ethyl acetate/hexane to give the title compound.
Reaction SMILES: Br[C:2]1[S:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.B([O-])([O-])O[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OC(C)C)(C)C.C(OCC)(=O)C>C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C(O)C>[C:19]1([C:2]2[S:16][C:5]3[O:6][C:7]4[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=4[NH:9][C:10](=[O:11])[C:4]=3[CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [O-]B([O-])Oc1ccccc1
Reactant: O=C1Nc2ccccc2Oc2sc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C1Nc2ccccc2Oc2sc(-c3ccccc3)cc21
Temperature: 25 °C
Yield: 83.8 %

Procedure:
2-Bromothieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.0 g) was dissolved in 2M sodium carbonate (8 ml)-toluene (8 ml)-ethanol (8 ml) and phenyl borate (620 mg) and tetrakistriphenylphosphine palladium (390 mg) were added. The mixture was stirred under reflux with heating for 80 minutes. The reaction system was cooled to room temperature and diisopropyl ether and ethyl acetate were added. The precipitated crystals were collected by filtration and the obtained crystals were washed with ethyl acetate and water to give 2-phenylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (830 mg).
Reaction SMILES: [C:1]1(=O)[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1([NH2:16])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1[NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:16]=1
Reactant: Nc1ccccc1N
Reactant: O=C1CCCCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: NCCCCCc1nc2ccccc2[nH]1

Procedure:
A mixture of caprolactam (56.5 g; 0.5 mole) and o-phenylene diamine (54 g; 0.5 mole) was heated with p-toluene sulfonic acid (4.3 g; 0.025 mole) at 200°-225° for 7 hrs. under nitrogen. A quantitative yield of 2-(5-aminopentyl) benzimidazole was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:16][CH:15]=3)[CH:8]=2)=[C:4]([F:30])[CH:3]=1.FC1C=C(N[C:55](=[O:67])[CH2:56][C:57]([NH:59][C:60]2[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=2)=[O:58])C=CC=1OC1C=CN=C(NCCN2CCOCC2)C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.COC1C=CC(CNC2N=C(OC3C=CC(N)=CC=3F)C=CN=2)=CC=1>CN(C=O)C>[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:9]2[N:10]=[CH:11][N:12]=[C:7]([O:6][C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:55](=[O:67])[CH2:56][C:57]([NH:59][C:60]4[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=4)=[O:58])=[CH:3][C:4]=3[F:30])[CH:8]=2)=[CH:19][CH:18]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1
Reactant: O=C(CC(=O)Nc1ccc(Oc2ccnc(NCCN3CCOCC3)c2)c(F)c1)Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: COc1ccc(CNc2nccc(Oc3ccc(N)cc3F)n2)cc1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1)Nc1ccc(F)cc1
Yield: 87.5 %

Procedure:
The title compound was prepared from a mixture 6-(4-amino-2-fluorophenoxy)-N-(4-(benzyloxy)phenyl)pyrimidin-4-amine (45 mg, 0.11 mmol), 3-(4-fluorophenylamino)-3-oxopropanoic acid (Compound B of Example 1, 24 mg, 0.12 mmol), TBTU (48 mg, 0.15 mmol), DIPEA (0.26 mL, 0.15 mmol), and DMF (1 mL) using a similar procedure described for the preparation of Compound C of Example 1. The crude product was triturated with isopropyl ether to give the title compound (56 mg, 88%) as a pink solid. 1H NMR (DMSO-d6) δ 10.47 (s, 1H), 10.27 (s, 1H), 9.45 (s, 1H), 8.25 (s, 1H), 7.77 (dd, 1H, J=12.7, 2.0 Hz), 7.65-7.62 (m, 2H), 7.46 (d, 4H, J=7.3 Hz), 7.40 (dd, 2H, J=7.6, 7.3 Hz), 7.37-7.29 (m, 3H), 7.17 (dd, 2H, J=9.0, 8.3 Hz), 7.00 (d, 2H, J=9.0 Hz) 6.09 (s, 1H), 5.09 (s, 2H) 3.49 (s, 2H); MS(ESI+) m/z 582.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].ClCCl.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:10])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(N)c(S(N)(=O)=O)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 0 °C
Yield: 68 %

Procedure:
A mixture of 2,5-diamino-benzenesulfonamide (0.288 g, 0.0015 mol, 1 eq.), dichloromethane (5 mL), and pyridine (5 mL) was stirred at 0° C. Methanesulfonyl chloride (119 μL, 0.0015 mol, 1 eq.) was added dropwise over 3 minutes. The reaction mixture was warmed to 25° and stirred for 18 hours. The reaction mixture was evaporated under reduced pressure and the residue was chromatographed on silica gel using a step gradient of 0-4% methanol in dichloromethane to yield 2-amino-5-[(methylsulfonyl)amino]benzenesulfonamide (68% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.87 (s, 3 H) 3.39 (s, 1 H) 5.80 (s, 1 H) 6.78 (d, J=8.82 Hz, 1 H) 7.13 (dd, J=8.64, 2.39 Hz, 1 H) 7.29 (s, 2 H) 7.45 (d, J=2.57 Hz, 1 H) 9.21 (m, 1 H). MS (ESI m/z=266 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([OH:16])=[O:15])([O-:3])=[O:2].CO.[CH3:19][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1>[CH3:19][O:15][C:14](=[O:16])[CH2:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 95 %

Procedure:
A 250 ml three-necked conical flask equipped with a nitrogen inlet and a stirrer was purged with nitrogen, and was added with 2,4-dinitrophenylacetic acid (2.26 g, 0.01 mole), methanol (20 ml) and toluene (83 ml). Stirring was conducted at room temperature until 2,4-dinitrophenylacetic acid was dissolved. Trimethylsilyldiazomethane (8.3 ml) was then added, and reaction was conducted for 3 hours at room temperature. Solvent was removed by distilling under a reduced pressure and by drying at 70° C. to obtain 2,4-dinitrophenylacetic acid methyl ester (2.28 g, yield: 95%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C@H:6]2[CH2:11][CH2:10][C@:9]3([OH:26])[C@H:12]4[C@H:22]([CH2:23][CH2:24][C@:7]23[CH3:8])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([OH:25])[CH2:18][CH2:19]2)[CH2:14][CH2:13]4)=[CH:2]1.CN(C)C=O.N1C=CN=C1.[Si:37](Cl)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]>O>[Si:37]([O:25][C@H:17]1[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@H:15]([CH2:14][CH2:13][C@@H:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:7]2([CH3:8])[C@:9]3([OH:26])[CH2:10][CH2:11][C@@H:6]2[C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)[CH2:16]1)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccoc4)CC[C@]32O)C1
Yield: 113.7 %

Procedure:
To a solution of 10 g of 17β-(3-furyl)-5β-androstane-3β,14β-diol (II-a: Ref. comp.) (Minato H. and Nagasaki T., J. Chem. Soc.(C), 1966, 377)in 80 ml of dimethylformamide, 18 g of imidazole and 20.0 g of t-butyldimethylsilyl chloride were added at 0° C. After 12 hrs the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure and 15 g of crude 3β-tert-butyldimethylsilyloxy-17β-(3-furyl)-5β-androstan-14β-ol were obtained. A suspension of this protected alcohol and 1.3 g of KH in 75 ml of tetrahydrofuran was heated at 70° C. for an hr; then 2.7 g of methyl iodide were added. After 30' the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give 12 g of 3β-tert-butyldimethylsilyloxy-14β-methoxy-17β-(3-furyl)-5β-androstane as a white amorphous solid.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].CN(C=O)C.[Br:17][CH2:18][C:19](Br)=[O:20].[Br-]>O1CCOCC1>[Br:17][CH2:18][C:19]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])=[O:20]
Reactant: O=C(Br)CBr
Reactant: COC(=O)c1ccccc1N
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1NC(=O)CBr
Temperature: -5 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
A solution of methyl anthranilate (10.0 g, 66 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to -5° C. using an ice-bath. Bromoacetyl bromide (13.32 g, 5.8 mL, 66 mmol) was added dropwise, keeping the internal temperature between -5° to 0° C. over a 1/2 h period. After the addition of the bromide was completed, the solution was warmed to rt, stirred overnight and then the resulting solution was slowly poured into 500 mL of ice-water, causing a white solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 16.4 g (91%) of the title compound as a white solid, mp 86°-87° C.: 1H NMR (DMSO-d6) δ11.07 (s, 1H), 8.24 (dd, J=8.4, J=1.2, 1H), 7.94 (dd, J=8.0, J=1.6, 1H), 7.64 (dt, J=8.8, J=1.6, 1H), 7.24 (dt, J=8.4, J=1.2, 1H), 4.23 (s, 2H), 3.87 (s, 3H); 13C NMR (DMSO-d6) δ167.26, 165.02, 138-82, 133.97, 130.62, 123.91, 121.13, 118-09, 52.46, 30.34; MS (EI, m/z) 271 (M+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>O.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:6][N:7]=1
Reactant: OCCO
Reactant: O=Cc1ccc(Br)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc(C2OCCO2)cn1
Yield: 96.6 %

Procedure:
To a toluene (100 mL) solution of 6-bromo-pyridine-3-carbaldehyde (5.0 g, 27 mmol) described in Manufacturing Example 154-1-1 were added ethylene glycol (3.0 mL, 54 mmol) and p-toluenesulfonic acid monohydrate (512 mg, 2.7 mmol), which was refluxed for 3 hours and 40 minutes under nitrogen atmosphere. Sodium hydrogencarbonate and water were added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate=1:1) to obtain the title compound (6.0 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:15]=O.C[O-].[Na+].[BH4-].[Na+]>CO>[CH3:15][NH:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][P:7](=[O:12])([O:8][CH3:9])[O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: COP(=O)(Cc1ccc(N)cc1)OC
Reactant: C=O
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNc1ccc(CP(=O)(OC)OC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 12.7 %

Procedure:
Dimethyl 4-aminobenzylphosphonate (21.5 g) and then paraformaldehyde (80%, 5.3 g) were added at room temperature to a solution of sodium methoxide in methanol (prepared from 27 g of sodium and 250 ml of methanol). After this mixture was stirred at room temperature for 15 hours, sodium borohydride (3.8 g) was added, and the mixture was heated for 1.5 hours while refluxing. The reaction mixture was concentrated under reduced pressure and then the residue was treated with 1NKOH (500 ml) and extracted with chloroform. The chloroform layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-chloroform-methanol (25:25:1, v/v) to yield dimethyl 4-methylaminobenzylphosphonate (2.9 g, 13%) as an oily substance. NMR(δ ppm in CDCl3): 2.55(1H,broad s), 2.82(3H,s), 3.07(2H,d,J=21 Hz), 3.63(3H,s), 3.69(3H,s), 6.57(2H,dd,J=9&1 Hz), 7.11(2H,dd,J =9&3 Hz)
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[O:11])=[CH:2]1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+].O>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:12]1([S:18]([N:1]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[C:3]([CH:10]=[O:11])=[CH:2]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=Cc1c[nH]c2ncccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=Cc1cn(S(=O)(=O)c2ccccc2)c2ncccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1H-Pyrrolo[2,3-b]pyridine-3-carbaldehyde (200 mg, 1.368 mmol) was dissolved in DCM (8 mL). Then tetra-n-butylammonium hydrogen sulfate (48.4 mg, 0.137 mmol), benzensulfonyl chloride (0.176 mL, 1.37 mmol) and NaOH 50% (0.263 mL, 3.3 mmol) were added. The RM was stirred at rt for 1 h. Water was added and it was extracted with DCM twice. The combined organic layers was washed with brine and dried over Na2SO4, filtered and evaporated to afford the title compound as a light yellow solid (tR 2.0 min (conditions 1), MH+=287).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[C:8]([CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:10][CH2:11][CH3:12])=[O:9]>C(#N)C>[CH2:11]([O:10][C:8](=[O:9])[CH:13]=[C:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[CH3:12]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCOCC1
Solvent: CC#N
Product: CCOC(=O)C=C1CCOCC1
Temperature: 70 °C
Yield: 63.5 %

Procedure:
To a solution of tetrahydro-pyran-4-one (25 g, 0.25 mol) in acetonitrile (250 mL) was added (carbethoxymethylene)triphenylphosphorane (96 g, 0.28 mol) at room temperature. The resulting mixture was heated at 70° C. for 16 h. The reaction mixture concentrated in vacuo. Purification by flash column chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 30% ethyl acetate/hexanes) afforded (tetrahydro-pyran-4-ylidene)-acetic acid ethyl ester (27 g, 63%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[C:4]([S:17][CH3:18])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCOCC1.O>[CH3:18][S:17][C:4]1[N:3]=[C:2]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1
Reactant: OB(O)c1ccccc1
Reactant: CSc1nc(Cl)c(C=O)c(Nc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CSc1nc(Nc2ccccc2)c(C=O)c(-c2ccccc2)n1
Yield: 69.8 %

Procedure:
To a solution of 4-chloro-2-methylsulfanyl-6-phenylamino-pyrimidine-5-carbaldehyde (300 mg, 1.07 mmol) in dioxane (21 mL) and H2O (7 mL) was added anhyd K2CO3 (443 mg, 3.21 mmol, 3 eq) followed by phenylboronic acid (196 mg, 1.6 mmol, 1.5 eq). The reaction mixture was degassed and tetrakis(triphenylphophine)palladium (61 mg, 0.053 mmol, 0.05 eq) was added. The reaction mixture was then heated under reflux for 24 h and cooled 23°, the layers were separated, EtOAc (50 mL), followed by H2O (10 mL), was added, the organic layer was separated, washed with satd aq NaCl, dried (MgSO4) and filtered. The yellow solution was then evaporated. Product was purified by column chromatography or by crystallization from 10 mL of isopropanol:H2O (2:1) to give 240 mg (70% yield) of pure 2-methylsulfanyl-4-phenyl-6-phenylamino-pyrimidine-5-carbaldehyde. 1H-NMR δ 2.60 (s, 3H), 7.22 (m, 1H), 7.35-7.81 (m, 9H), 9.89 (s, 1H), 11.31 (br s, 1H), LC MS (m/e)=322 (MH+).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[F:17].CN([CH:21]=[O:22])C.O>C1COCC1>[Br:9][C:10]1[C:11]([F:17])=[C:12]([C:13]([Cl:16])=[CH:14][CH:15]=1)[CH:21]=[O:22]
Reactant: Fc1cc(Cl)ccc1Br
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1c(Cl)ccc(Br)c1F
Reaction time: 0.17 h
Yield: 47.9 %

Procedure:
Add a 2M LDA in THF (22 mL, 44 mmol) to 1-bromo-4-chloro-2-fluorobenzene (9.2 g, 44 mmol) in THF (100 mL) at −78° C. Stir for 10 minutes. Add DMF (10 mL, 132 mmol) and warm up to room temperature. Add the reaction mixture to ice and water. Extract the mixture with ethyl acetate (100 mL). Wash the organic layer with aqueous LiCl (20 mL, 10%), dry with magnesium sulfate, filter and evaporate solvent under reduced pressure to obtain 5 g (48%) of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[O:8][N:7]=[C:6]([CH3:9])[C:5]=1[Cl:10].C[O:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[S:20](Cl)(=[O:22])=[O:21])=[O:14]>O1CCCC1>[Cl:10][C:5]1[C:6]([CH3:9])=[N:7][O:8][C:4]=1[NH:3][S:20]([C:19]1[CH:18]=[CH:17][S:16][C:15]=1[C:13]([OH:14])=[O:12])(=[O:21])=[O:22]
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: Cc1noc(N)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2ccsc2C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.8 %

Procedure:
At about 0° C., sodium hydride (60% dispersion in mineral oil, 458 mg, 19 mmol) was added to a solution of 5-amino-4-chloro-3-methylisoxazole (1.1 g, 8.3 mmol) in anhydrous tetrahydrofuran (30 mL). The resulting mixture was stirred for about 10 minutes and 2-(methoxycarbonyl)thiophene-3-sulfonyl chloride (1.95 g, 8.11 mmol) was slowly added. Under continuous stirring, the mixture was maintained at ambient temperature for about 4 hours. The mixture was then diluted with hexanes (30 mL) and the resulting precipitate was filtered and washed with hexanes. The precipitate was then dissolved in 1 N sodium hydroxide and stirred at ambient temperature for about 1 hour. After acidifying to pH ˜2 with 2 N hydrochloric acid, the resulting precipitate was filtered, washed with water, and dried in vacuo to give the desired product 3-[(4-chloro-3-methyl-5-isoxazolyl)sulfamoyl]-2-thiophenecarboxylic acid (1.2 g, 45%) as a yellow powder. 1H NMR (300 MHz, CD3OD) δ 7.82 (d, J=5.4 Hz, 1H), 7.53 (d, J=5.4 Hz, 1H), 2.24 (s, 3H); LC-MS: m/z=323 (MH)+.
Reaction SMILES: [CH:1]([N:4]([CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[NH2:22][NH:23][C:24]([NH2:26])=[O:25].C(O)C.[OH-].[Na+]>O>[CH:1]([N:4]([CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)/[C:10](=[N:22]\[NH:23][C:24]([NH2:26])=[O:25])/[C:8]1=[O:9])([CH3:3])[CH3:2]
Reactant: NNC(N)=O
Reactant: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)N(CCN1C(=O)/C(=N/NC(N)=O)c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
A suspension of 10.00 g of 1-(2-diisopropylaminoethyl)isatin and 4.88 g of semicarbazide hydrochloride in 350 ml of a mixture of ethanol and water (2.5:1) was stirred for 2 hours at room temperature. The suspension was warmed to make a solution, and then 44.0 ml of a 1N-aqueous sodium hydroxide solution was added dropwise to the solution. The precipitates were collected by filtration and washed with water to obtain 10.56 g of (E)-1-(2-diisopropylaminoethyl)isatin 3-semicarbazone. The chemical properties of this product were identical with those of the product obtained by Examle 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[CH:9]=[CH:8]2.[Br:14]Br>CO>[Br:14][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([CH3:13])=[N:11]2
Reactant: BrBr
Reactant: COc1cccc2ccc(C)nc12
Solvent: CO
Product: COc1ccc(Br)c2ccc(C)nc12
Temperature: 45 °C

Procedure:
A solution of 8-methoxy-2-methylquinoline (1.0 g) in methanol (30 ml) was treated at room temperature with bromine (0.31 ml). The mixture was heated at 45° C. for 2 hours and the reaction quenched with 5% aqueous sodium metabisulphite (50 ml). The solution was basified with 25% aqueous sodium hydroxide to pH13 and the product extracted with ethyl acetate (2×100 ml). The extracts were combined, dried over magnesium sulphate, filtered and the filtrate evaporated in vacuo. The residue was dissolved in ethyl acetate and passed through a silica pad. The solution was evaporated in vacuo to yield the desired product as an off-white solid (0.43 g).