Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:24])=[C:7]([C:15]([C:17]2[CH:18]=[N:19][N:20]([CH3:23])[C:21]=2[OH:22])=[O:16])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])=[O:4].C(N(CC)CC)C.[CH3:32][CH2:33][S:34][C:35](Cl)=[O:36]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:24])=[C:7]([C:15]([C:17]2[CH:18]=[N:19][N:20]([CH3:23])[C:21]=2[O:22][C:35]([S:34][CH2:33][CH3:32])=[O:36])=[O:16])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])=[O:4]
Reactant: COC(=O)c1c(S(C)(=O)=O)ccc(C(=O)c2cnn(C)c2O)c1C
Reactant: CCSC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCSC(=O)Oc1c(C(=O)c2ccc(S(C)(=O)=O)c(C(=O)OC)c2C)cnn1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.1 %

Procedure:
5-Hydroxy-1-methylpyrazol-4-yl 3-(methoxycarbonyl)-2-methyl-4-(methylsulfonyl)phenyl ketone (290 mg, 0.82 mmol) was dissolved in dry tetrahydrofuran (15 mL), and triethylamine (166 mg, 1.64 mmol) was added thereto. A solution (4 mL) of 96% S-ethyl chlorothiolformate (107 mg) dissolved in dry tetrahydrofuran was added thereto little by little under cooling with ice water. The reaction mixture was stirred for 90 minutes while the reaction temperature was allowed to warm to room temperature. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:4) to obtain the desired product as an amorphous solid (202 mg, 0.46 mmol) (yield: 56%).
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[Br:20]Br.Cl>C(OCC)C>[Br:20][C:10]1[N:11]([CH3:14])[CH:12]=[CH:13][C:9]=1[S:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])(=[O:8])=[O:7]
Reactant: BrBr
Reactant: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1Br
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 58.7 %

Procedure:
To a solution of 8.85 g (41 mmol) of N-(1,1-dimethylethyl)-1-methyl-1H-pyrrole-3-sulfonamide in 200 mL diethyl ether under a nitrogen atmosphere cooled to -78° C. was added dropwise, at such a rate as to keep the temperature below -65° C., 36.0 mL (85 mmol) 2.41M n-butyllithium in hexanes. The reaction was stirred at -78° C. for ca. 15 minutes. To the reaction mixture was added 2.2 mL (41 mmol) of bromine dropwise. The light orange reaction mixture was allowed to warm to room temperature and stir for ca. 2 hours. The reaction mixture darkened as it stirred at room temperature. The reaction mixture was cooled to 0° C. and acidified with 1N HCl. The ether phase was separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue was chromatographed on silica (25% ethyl acetate/80% hexanes) affording 7.11 g of the title compound as an orange oil. 1H NMR (CDCl3, 200 MHz.) δ: 6.73(d,1H), 6.62(d,1H), 3.63(s,3H), 1.24(s,9H).
Reaction SMILES: [CH2:1]([C@H:8]([NH:19][C:20](=[O:43])[O:21][NH:22][C:23](=[O:42])[C@@H:24]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1)=[O:31])[CH2:25][C:26]([NH2:28])=[O:27])[C@H:9]([OH:18])[CH2:10][NH:11][O:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:63]1[C:71]2[C:66](=[CH:67][CH:68]=[C:69]([S:72](Cl)(=[O:74])=[O:73])[CH:70]=2)[CH:65]=[N:64]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:1]([C@H:8]([NH:19][C:20](=[O:43])[O:21][NH:22][C:23](=[O:42])[C@@H:24]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1)=[O:31])[CH2:25][C:26]([NH2:28])=[O:27])[C@H:9]([OH:18])[CH2:10][N:11]([O:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1)[S:72]([C:69]1[CH:70]=[C:71]2[C:66]([CH:65]=[N:64][NH:63]2)=[CH:67][CH:68]=1)(=[O:74])=[O:73])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2c1
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)NOC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNOC1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)NOC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCC1)S(=O)(=O)c1ccc2cn[nH]c2c1
Reaction time: 24 h

Procedure:
(2S)-4-Amino-4-oxo-2-[(2-quinolinylcarbonyl)-amino]butanamido N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)-amino]-2-hydroxypropylcarbamate (Step 1, Example 51), (44 mg, 0.0825 mmol), 1-trityl-1H-indazole-6-sulfonyl chloride (38 mg, 0.0825 mmol), and anhydrous diisopropylethylamine (0.05 mL, 0.280 mmol) were combined in anhydrous tetrahydrofuran (3 mL) in a 25 mL round bottomed flask under nitrogen. The reaction was stirred for 24 hours and concentrated in vacuo. Ethyl acetate (30 mL) and water (10 mL) were added and the layers were separated. The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The compound was deprotected as described in Example 57 and purified by preparative silica gel TLC using 90:10 chloroform:methanol as an eluent to provide the desired product as a white film (9 mg, 0.013 mmol, 15%). 1HNMR (d6-DMSO) δ: 8.84 (d, J=8.5 Hz, 1H), 8.61 (d, J=8.5 Hz, 1H), 8.31-6.95 (m, 13H), 5.24 (d, J=6.6 Hz, 1H), 4.81-4.72 (m, 2H), 3.97 (bs, 1H), 3.68 (bs, 1H), 3.40-1.20 (m, 15H). MS(ES): 714 (M+1), 712 (M−1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][C:11]([F:36])([F:35])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[CH:29]=[N:28][C:27]([O:30][CH2:31][C:32]#[CH:33])=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:17][C:16]=2[F:34])([CH3:14])[N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[O:9][CH2:10][C:11]([F:35])([F:36])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[CH:29]=[N:28][C:27]([O:30][CH2:31][C:32]#[CH:33])=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:17][C:16]=2[F:34])([CH3:14])[N:13]=1
Reactant: C#CCOc1cnc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(NC(=O)OC(C)(C)C)OCC3(F)F)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CCOc1cnc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OCC3(F)F)c2)cn1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
((R)-5,5-Difluoro-4-{2-fluoro-5-[(5-prop-2-ynyloxy-pyrazine-2-carbonyl)-amino]-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl)-carbamic acid tert-butyl ester (350 mg, 674 μmol) was combined with DCM (5.2 ml) to give a light yellow solution. The solution was cooled to 0° C. and TFA (768 mg, 519 μl, 6.74 mmol) was added. After stirring 30 min at 0° C. the ice bath was removed and the reaction was allowed to warm up and was stirred at RT for 6 h. The pH of the reaction mixture was adjusted to 8 by dropwise addition of sat. aq. NaHCO3 and the product was extracted with DCM. The organic layers were dried over Na2SO4 and concentrated under vacuum. A colorless foam was obtained that was purified by flash chromatography (SiO2, 10 g, 0 to 80% EtOAc in heptane). Colorless foam (230 mg, 81%). MS (ISP): m/z=420.1 [M+H]+.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([C:11](NC(C)(C)C)=[O:12])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:18][CH2:19][C@H:20]3[NH:26][C:24](=[O:25])[CH2:23][CH2:22][C@:21]3([CH3:27])[C@H:5]1[CH2:4][CH2:3]2.Cl.C[OH:30]>>[CH3:1][C@@:2]12[C@@H:10]([C:11]([OH:30])=[O:12])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:18][CH2:19][C@H:20]3[NH:26][C:24](=[O:25])[CH2:23][CH2:22][C@:21]3([CH3:27])[C@H:5]1[CH2:4][CH2:3]2
Reactant: CO
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Product: C[C@]12CCC(=O)N[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)O)CC[C@@H]12
Reaction time: 10 h

Procedure:
A suspension of 100 g (0.26 mol) of dihydrofinasteride, 480 g of 20% HCl solution (2.63 mol) and 120 g of methanol are heated to reflux and boiled intensively for 8-12 hours. The reactant goes into solution on heating; after 8 hours, there is a suspension which can be readily filtered. The filtercake is washed three times intensively with 100 g each time of water, suction-dried for approx. 15 minutes and subsequently dried overnight. Yield: 60 g.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[O:27]1[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:32]([CH:29]3[CH2:30][CH2:31][O:27][CH2:28]3)=[O:33])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)C1CCOC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)C1CCOC1

Procedure:
The title compound, light yellow solid (79 mg, 75%), MS (ISP) m/z=425.2 [(M+H)+], mp 183° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and (RS)-tetrahydro-furan-3-carboxylic acid.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][NH2:12])[CH2:3][CH2:2]1.F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][NH:12][C:19]2[CH:20]=[N:21][CH:22]=[CH:14][C:15]=2[C:16]([OH:18])=[O:17])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccncc1F
Reactant: NCC1CCOc2ccccc21
Product: O=C(O)c1ccncc1NCC1CCOc2ccccc21
Yield: 13 %

Procedure:
The title compound was prepared in 13% yield from 1-(3,4-dihydro-2H-chromen-4-yl)methanamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 53. 1H NMR (400 MHz, DMSO-d6): δ 8.33 (s, 1H), 7.78 (d, 1H, J=5.0 Hz), 7.74 (br s, 1H), 7.50 (d, 1H, J=5.0 Hz), 7.23 (d, 1H, J=7.4 Hz), 7.04 (t, 1H, J=7.1 Hz), 6.78 (t, 1H, J=7.3 Hz), 6.69 (d, 1H, J=8.0 Hz), 4.06-4.17 (m, 2H), 3.59-3.65 (m, 1H), 3.41-3.47 (m, 1H), 3.04-3.09 (m, 1H), 1.79-1.96 (m, 2H). [M+H] calc'd for C16H16N2O3, 285. found 285.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]([Si](C)(C)C)([F:22])[F:21]>CN(C)C=O>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]([OH:8])[C:20]([F:22])([F:21])[F:19])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(c1ccc(C(F)(F)F)cc1)C(F)(F)F
Yield: 57.1 %

Procedure:
According to Reference Example 8-2, by use of 4-(trifluoromethyl)benzaldehyde (100 μL, 0.732 mmol), potassium carbonate (20.2 mg, 0.146 mmol), (trifluoromethyl)trimethylsilane (162 μL, 1.10 mmol) and N,N-dimethylformamide (2.0 mL), the mixture was stirred and reacted at room temperature for 1 hour. Then, purification by silica gel column chromatography (chloroform/methanol=9/1) was performed to give 1-(trifluoromethyl)-4-(2,2,2-trifluoro-1-hydroxyethyl)-benzene (Compound CF) (102 mg, yield: 57%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH:16]1[C:25]2[C:20](=[C:21]3[CH:33]=[CH:32][CH:31]=[CH:30][C:22]3=[C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]3=2)[CH:19]=[C:18](O)[N:17]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:18]1[N:17]=[CH:16][C:25]2[C:20]([CH:19]=1)=[C:21]1[CH:33]=[CH:32][CH:31]=[CH:30][C:22]1=[C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=21)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1cc2c3ccccc3c3ccccc3c2cn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Oc1cc2c3ccccc3c3ccccc3c2cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoromethanesulfonic anhydride (5.2 g, 19 mmol) was added to a mixture of dibenzo[f,h]isoquinolin-3-ol (0.91 g, 3.7 mmol), pyridine (1.2 g, 15 mmol) and dichloromethane 100 mL under nitrogen at 0° C. and stirred overnight at room temperature. The reaction was quenched with saturated NaHCO3. The organic layer was washed with water and dried on Na2SO4. The residue was purified by flash chromatography on silica (hexane:ethyl acetate) to give (1.1 g, 79%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].Cl[C:19]1[S:20][C:21]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=2[N:23]=1.Cl.O1CCOCC1>CCO>[CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:19]3[S:20][C:21]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=4[N:23]=3)=[CH:15][CH:16]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc(N)cc2)no1
Reactant: Fc1ccc2nc(Cl)sc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)no1
Temperature: 60 °C
Yield: 57.2 %

Procedure:
A mixture of the compound of step 2 (3.0 g; 12.9 mmol) and 2-chloro-6-fluoro benzothiazole (2.67 g; 14.2 mmol) in EtOH (60 ml) was heated at 60° C. to get a clear solution. To the hot solution 4N HCl in dioxane (1.6 ml; 6.45 mmol) was added and the resulting reaction mixture was refluxed for 20 hours. The reaction mixture was cooled to room temperature and the solid was filtered, and washed with EtOH (2×10 ml). The solid was dried under vacuum to yield 2.83 g (57.2%) of the title compound. Mass (ES−) 382 (M−1); IR (KBr): 3410 (br), 2710 (br), 1729, 1719, 1630, 1598; 1H NMR (DMSO-d6): δ 1.36 (t, 3H), 4.41 (q, 2H), 7.20 (m, 1H), 7.67 (m, 1H), 7.78 (m, 1H), 7.81 (s, 1H), 7.87-7.99 (m, 4H), 10.92 (br, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[C:4]([C:7]2[N:8]=[C:9]([NH:17][C@H:18]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)[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][C@H:18]([NH:17][C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:16]=[C:7]([C:4]3[NH:3][C:2](=[O:1])[NH:6][N:5]=3)[N:8]=2)[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3ccccc23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]nc(-c2cc3ccccc3c(N[C@H]3CCNC3)n2)[nH]1
Reaction time: 1 h

Procedure:
To crude (S)-tert-butyl 3-((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)amino)pyrrolidine-1-carboxylate was added DCM (3 mL) and TFA (1 mL). The mixture was stirred for 1 hour and concentrated. The crude product was purified by preparative HPLC eluting with a gradient of 5-30% ACN in water (acid mode) to give the title compound (8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].[H-].[Na+].I[CH3:17]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:17])[C:10]([O:12][CH3:13])=[O:11]
Reactant: CI
Reactant: COC(=O)Cc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)c1ccc(Cl)cc1Cl
Reaction time: 3 h
Yield: 80 %

Procedure:
To a stirred mixture of 22 parts of methyl 2,4-dichlorobenzeneacetate and 135 parts of N,N-dimethylformamide are added 3.1 parts of sodium hydride dispersion 78% while nitrogen gas is introduced. The whole is stirred till foaming has ceased and cooled in an ice-bath. Then there are added dropwise 16 parts of iodomethane. Upon completion, stirring is continued for 3 hours at room temperature. The reaction mixture is poured onto water and the product is extracted with 2,2'-oxybispropane. The extract is washed with water, dried, filtered and evaporated, yielding 20 parts (80%) of methyl 2,4-dichloro-α-methylbenzeneacetate as a residue.
Reaction SMILES: [O:1]=[S:2]1(=[O:34])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]([C:12]2[CH:33]=[CH:32][C:15]([C:16]([NH:18][C@@H:19]3[CH2:27][C@:22]4([O:26][CH2:25][CH2:24][CH2:23]4)[CH2:21][C@@H:20]3[C:28](OC)=[O:29])=[O:17])=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36].Cl.[NH2:43][OH:44]>CO.C[O-].[Na+]>[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36].[O:34]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]([C:12]2[CH:33]=[CH:32][C:15]([C:16]([NH:18][C@@H:19]3[CH2:27][C@:22]4([O:26][CH2:25][CH2:24][CH2:23]4)[CH2:21][C@@H:20]3[C:28]([NH:43][OH:44])=[O:29])=[O:17])=[CH:14][CH:13]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)[C@H]1C[C@]2(CCCO2)C[C@H]1NC(=O)c1ccc(C2CCS(=O)(=O)c3ccccc32)cc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1C[C@@]2(CCCO2)C[C@@H]1C(=O)NO)c1ccc(C2CCS(=O)(=O)c3ccccc32)cc1
Reaction time: 1 h
Yield: 37 %

Procedure:
Methyl (5R,7S,8R)-8-{[4-(1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl)benzoyl]amino}-1-oxaspiro[4.4]nonane-7-carboxylate from reaction 33f (0.165 mmol) was dissolved in a solution of hydroxylamine hydrochloride, methanol and sodium methoxide, (2 mL) under nitrogen atmosphere at room temperature. The reaction was stirred for 1 h, made neutral with TFA, concentrated and purified by HPLC on a C-18 column eluting with an acetonitrile:water:TFA gradient, to give the title compound (0.03 g, 37%) as a white solid. MS found: (M+H)+=485, (2M+H)+=969.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.O.[CH2:12]([NH2:16])[CH2:13][CH2:14][NH2:15]>>[S:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]([NH:15][CH2:14][CH2:13][CH2:12][NH2:16])=[N:3]1
Reactant: Clc1nsc2ccccc12
Reactant: NCCCN
Solvent: O
Product: NCCCNc1nsc2ccccc12
Temperature: 80 °C

Procedure:
3-Chlorobenzo[d]isothia-zole (300 mg, 3.0 mmol) was dissolved in propane-1,3-diamine (3 mL) and heated at 80° C. for 3 h. The reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to yield N1-(benzo[d]isothiazol-3-yl)propane-1,3-diamine as a yellow solid, (530 mg). 1H NMR (300 MHz, CDCl3): 7.8 (m, 1H), 7.7 (m, 1H), 7.5 (m, 2H), 7.3 (m, 1H), 3.7 (m, 2H), 2.9 (t, 2H), 1.9 ppm (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[ClH:13].[F:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[C:22]2[NH2:25])=[CH:17][CH:16]=1>ClCCl>[ClH:13].[F:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[C:22]2[NH:25][C:10]([N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=2)[CH3:12])=[NH:11])=[CH:17][CH:16]=1
Reactant: CCc1cccc(N(C)C#N)c1
Reactant: Nc1cccc2ccc(F)cc12
Agent: Cl
Solvent: ClCCl
Product: CCc1cccc(N(C)C(=N)Nc2cccc3ccc(F)cc23)c1
Temperature: 160 °C
Yield: 53.1 %

Procedure:
A mixture of N-(m-ethylphenyl)-N-methylcyanamide (195 mg, 1.21 mmol) and 7-fluoro-1-aminonaphthalene hydrochloride (200 mg, 1.01 mmol) was heated in a pre-heated oil bath at 160° C. for 2.5 hours and then allowed to cool to room temperature. The resulting solid was taken up in dichloromethane and washed with 5% NaOH solution. The organic layer was concentrated and the resulting residue was treated at room temperature with 0.5M methanol-HCl solution (10 ml). It was concentrated and the resulting purple glass was purified by flash chromatography on silica gel to give N-(7-fluoro-1-naphthyl)-N'-(m-ethylphenyl)-N'-methylguanidine hydrochloride (192 mg, 53%) as off-white crystals. M.p.: 187°-90° C. IR (CHCl3): 1630, 3400 cm-1. 1H NMR (CD3Cl3): δ 1.259 (t, 3H, J=7.9 Hz), 2.431 (q, 2H, J=7.9 Hz), 3.564 (s, 3H), 6.76-7.94 (m, 10H). Anal. Calcd for C20 H21N3FCl: C, 67.12; H, 5.92; N, 11.74. Found: C, 67.28; H, 6.00; N, 11.87.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[NH4+:35].[OH-]>>[NH2:35][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccco1
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccco3)c2F)n1
Temperature: 120 °C

Procedure:
A suspension of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-furansulfonamide (150 mg, 0.287 mmol) and NH4OH (5 mL, 128 mmol) was heated in a microwave reactor at 120° C. for 40 min. LC-MS looks good for desired product. The reaction mixture was neutralized with 5N HCl and extracted with DCM×2. The crude mixture was evaporated onto silica gel and chromatographed (10-50% 1:9 MeOH:EtOAc in DCM). The title compound was obtained as a yellow solid after trituration in MeOH (102 mg, 68% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.57 (s, 1H), 7.78-7.94 (m, 2H), 7.34 (td, J=7.4, 2.0 Hz, 1H), 7.14-7.30 (m, 2H), 7.03 (d, J=3.5 Hz, 1H), 6.44-6.61 (m, 3H), 5.64 (d, J=5.3 Hz, 1H), 3.67 (t, J=4.7 Hz, 4H), 3.41 (t, J=4.6 Hz, 4H). MS (ESI): 502.2 [M−H]−.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[N:15]=[C:14]([S:16][CH3:17])[CH:13]=[C:12]([Sn](CCCC)(CCCC)CCCC)[N:11]=1>C1(C)C=CC=CC=1.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>[Cl:8][C:7]1[C:2]([C:12]2[CH:13]=[C:14]([S:16][CH3:17])[N:15]=[C:10]([CH3:9])[N:11]=2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(SC)nc(C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CSc1cc(-c2nccnc2Cl)nc(C)n1
Temperature: 110 °C
Reaction time: 48 h
Yield: 20.8 %

Procedure:
A mixture of 2,3-dichloropyrazine (0.034 mL, 0.228 mmol, Aldrich, St. Louis, Mo.), 2-methyl-4-(methylthio)-6-(tributylstannyl)pyrimidine (98 mg, 0.228 mmol) and tetrakis(triphenylphosphine)palladium (26.4 mg, 0.023 mmol, Strem Chemicals, Inc., Newburyport, Mass.) in toluene (2 mL) was stirred at 110° C. for 48 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 20% EtOAc/CH2Cl2 to give 4-(3-chloropyrazin-2-yl)-2-methyl-6-(methylthio)pyrimidine (12 mg, 21% yield). 1H NMR (300 MHz, CDCl3) δ 8.63 (d, J=2.05 Hz, 1H); 8.47 (d, J=2.19 Hz, 1H); 7.44 (s, 1H); 2.77 (s, 3H); 2.56 (s, 3H). m/z (ESI, +ve ion) 253 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH:5]([C:12]1[C:21](=[O:22])[O:20][C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]=1[OH:23])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:3].C(=O)([O-])[O-].[K+:28].[K+].O>CC(O)C>[CH3:1][C:2]([CH2:4][CH:5]([C:12]1[C:21](=[O:22])[O:20][C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]=1[O-:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[K+:28]
Reactant: CC(=O)CC(c1ccccc1)c1c(O)c2ccccc2oc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CC(=O)CC(c1ccccc1)c1c([O-])c2ccccc2oc1=O

Procedure:
Warfarin potassium salt is prepared by refluxing the pure warfarin acid with an equivalent amount or an excess of potassium carbonate in 2-propanol. The 2-propanol may be anhydrous or may contain about 0.5% to about 10% water, preferably about 1% to about 3% water. The molar ratio of potassium carbonate to warfarin acid is between about 0.9 and about 2, and is preferably between about 1.0 and about 1.3. The reaction may be conducted at a temperature ranging from room temperature to the boiling point of the solvent for a time of from about 1 hour to about 5 hours. Preferably, the reaction is conducted at reflux temperature and the preferred reaction time is from about 2 hours to about 3 hours. The unreacted carbonate is removed by filtration. The warfarin potassium is precipitated and isolated as a pure crystalline solid by filtration and drying.