Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1)=O.[CH3:24][C@H:25]([NH2:34])[C@H:26]([OH:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:33][C@H:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@@H:25]([NH:34][CH2:1][C:3]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1)[CH3:24]
Reactant: O=Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)O)c1
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](NCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)O)c1)[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[3-(2-Formyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid (0.12 g, 0.37 mmol), (1R,2S)-(−)-norephedrine (0.056 g, 0.37 mmol), and sodium triacetoxyborohydride (0.12 g, 0.56 mmol) were combined in CH2Cl2(10 mL), and the reaction was stirred at room temperature for 2 hours. The mixture was worked-up to give the title compound. M+H=460.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[CH:21]=[CH:20][S:19][C:18]=3[C:22]([O:24]C)=[O:23])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].CO>O1CCCC1>[N:4]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[CH:21]=[CH:20][S:19][C:18]=3[C:22]([OH:24])=[O:23])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(N2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1sccc1NS(=O)(=O)c1ccc(N2CCOCC2)cc1
Temperature: 40 °C
Yield: 18 %

Procedure:
To a solution of 85 (306 mg; 0.8 mmol) in tetrahydrofuran (2.7 mL) were added aqueous sodium hydroxide (5.3 mL; 2N) and methanol (5.3 mL) sequentially. The reaction mixture was heated at 40° C. for 17 hours, allowed to cool to room temperature, and then extracted with aqueous sodium hydroxide (20 mL; 2N). The aqueous layer was washed with diethyl ether (30 mL×2), acidified with aqueous hydrochloric acid (40 mL; 6N), and extracted with dichloromethane (40 mL). The organic layer was washed with aqueous saturated sodium chloride (20 mL), dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting pale yellow solid was recrystallized from hot 80% ethyl acetate in hexane, to yield the title compound as a white solid (53 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:63][CH2:64][C:65]([CH3:69])([CH3:68])[CH2:66][OH:67]>C(#N)C.C(OCC)(=O)C.O>[OH:67][CH2:66][C:65]([CH3:69])([CH3:68])[CH2:64][NH:63][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[CH:19]=1)=[O:23]
Reactant: CC(C)(CN)CO
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NCC(C)(C)CO)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
2-(6-Fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (80 mg, 0.18 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (87 mg, 0.27 mmol) and N,N-diisopropylethylamine (0.16 ml, 0.91 mmol) were dissolved in acetonitrile (1.8 ml). 3-Amino-2,2-dimethylpropan-1-ol (22 mg, 0.22 mmol) was added and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added, the layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give 85 mg (89%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-hydroxy-2,2-dimethyl-propyl)-amide. (M+Na)+=549.
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]([CH3:7])=[O:6])=O.[F:8][C@@H:9]1[C@@H](CO)[O:12][C@@H:11]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10]1>N1C=CC=CC=1>[C:5]([O:4][CH2:2][C@H:1]1[O:12][C@@H:11]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10][C@@H:9]1[F:8])(=[O:6])[CH3:7]
Reactant: Cc1cn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
56 mMol acetanhydride is added at 0° C. to a solution of 50 mMol 3'-deoxy-3'-fluorothymidine in 50 ml pyridine. The reaction solution stands overnight at room temperature and is subsequently poured into ice water. The aqueous phase is decanted. The oily product is purified in a chromatographic column on silica gel with chloroform eluent. The fractions obtained from the product are isolated as a solid material which is recrystallized from ethanol. M.P.97°-98° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH2:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Br)cc2)CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1ccc(C2=CCCC2)cc1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
To a solution of 2.62 g of 1-(4-bromo-phenyl)-cyclopentanol (10.9 mmol) in 50 ml toluene were added 124 mg of toluene-4-sulfonic acid (1 mmol) and the mixture was heated to reflux for 4 h. After the reaction mixture was allowed to cool to RT it was washed with sat. NaHCO3-solution and brine, dried (MgSO4), filtered and concentrated in vacuo to give 2.12 g of 1-bromo-4-cyclopent-1-enyl-benzene (88%) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[Br:15]Br>>[Br:15][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([S:11](=[O:13])(=[O:14])[NH2:12])[CH:4]=1)=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1ccc(F)c(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cc(C(=O)CBr)ccc1F

Procedure:
12.5 g of 4'-fluoro-3'-sulfamoylacetophenone were reacted as described in Example 12 with 9.2 g of bromine to give the 2-bromo-4'-fluoro-3'-sulfamoylacetophenone, melting point: 125° C.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[ClH:10].Cl.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]([NH2:28])=[NH:27])=[NH:24])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>C(O)C>[ClH:10].[NH2:24][C:23]1[N:22]([C:19]2[CH:20]=[CH:21][C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:17][CH:18]=2)[CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:27]=[C:26]([NH2:28])[N:25]=1
Reactant: CC(C)(C)c1ccc(NC(=N)NC(=N)N)cc1
Reactant: CCCCCCCC=O
Agent: Cl
Solvent: CCO
Product: CCCCCCCC1N=C(N)N=C(N)N1c1ccc(C(C)(C)C)cc1

Procedure:
100 ml of ethanol, 4.3 g (33.1 mmol) of 1-octanal and 0.9 ml of concentrated hydrochloric acid were added to 6.0 g (22.2 mmol) of N1-(4-tert-butylphenyl)-biguanide hydrochloride, and the mixture was refluxed for 20 hours. The solvent was concentrated under reduced pressure, and the residue was cooled. The resulting precipitated colorless crystals were collected by filtration, and recrystallized from 80% aqueous ethanol to obtain 4.2 g of colorless crystals having a melting point of 239 to 241° C.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([C:17]([O:19]C)=[O:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]2)[CH2:3][CH2:2]1.[OH-].[K+]>CO.O>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][C:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)([C:17]([OH:19])=[O:18])[CH2:6]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)C1(CC2CC2)CCN(C(=O)OC(C)(C)C)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CC2CC2)(C(=O)O)C1
Yield: 104 %

Procedure:
The title compound was prepared according to general procedure B described in connection with Scheme 2. 1-t-Butyl 3-methyl 3-(cyclopropylmethyl)pyrrolidine-1,3-dicarboxylate (1.00 g, 3.5 mmol.) was dissolved in 2 mL MeOH and a solution KOH (0.59 g, 10.6 mmol.) in 2 mL H2O was added. The reaction mixture was microwaved at 130° C. for 30 min. The methanol was evaporated and 10 mL of 10% KHSO4 solution was added to the residue. The acid was extracted with EtOAc (2×20 mL). The combined organic fractions were dried over Na2SO4; evaporation of solvent gave 0.98 g of the desired product as orange oil which crystallized on standing (quantitative yield). 1H NMR (400 MHz, CDCl3): δ 3.81-3.93 (m, 1H), 3.36-3.44 (m, 2H), 2.28 (d, 1H), 2.33-2.46 (m, 1H), 1.83-1.91 (m, 1H), 1.60-1.70 (m, 2H), 1.45 (s, 9H), 0.62-0.75 (m, 1H), 0.42-0.50 (m, 2H), 0.05-0.12 (m, 2H); MS (ESI) m/z: Calculated for C14H23NO4: 269.2. found: 292 (M+Na)+.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[Br:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[CH:20][CH:19]=[C:18]([C:29]([OH:31])=O)[CH:17]=2.[CH3:32][N:33]([CH3:38])[S:34]([NH2:37])(=[O:36])=[O:35].C1CCN2C(=NCCC2)CC1>C1COCC1.CCOC(C)=O>[Br:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[CH:20][CH:19]=[C:18]([C:29]([NH:37][S:34]([N:33]([CH3:38])[CH3:32])(=[O:36])=[O:35])=[O:31])[CH:17]=2
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: CN(C)S(N)(=O)=O
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
Carbonyl diimidazole (6.0 g, 37 mmol) was added to a solution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (10 g, 31 mmol) in THF (30 mL) and the reaction was stirred at 50° C. for 2 h (a white precipitate had formed). The reaction was cooled to rt and treated with N,N-dimethylsulfamide (4.6 g, 37 mmol). Then DBU (6.7 mL) in THF (20 mL) was added dropwise and the reaction was stirred at rt overnight. The solution was diluted with EtOAc (300 mL) and washed with H2O (150 mL), 1N aqueous HCl (2×100 mL) and brine (100 mL). The combined aqueous layers were extracted with EtOAc (200 mL) and the organic layer was washed with 1N aqueous HCl (150 mL) and brine (50 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to an oil. The oil was diluted with Et2O and concentrated to a semi-solid which was triturated with Et2O to yield 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-indole-6-carboxamide (6.1 g, 14 mmol, 46%) as a light yellow solid. The organic washes where concentrated and purified by silica gel chromatography (20-35% EtOAc/hexanes) to yield additional 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-indole-6-carboxamide (2.5 g, 6 mmol, 19%). 1HNMR (500 MHz, CD3OD) δ 7.90 (d, J=1.8 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.56 (dd, J=1.8, 8.5 Hz, 1H), 3.01 (s, 6H), 2.93-2.86 (m, 1H), 2.04-1.76 (m, 7H), 1.54-1.37 (m, 3H). LCMS: m/e 426 (M−H)−, ret time 1.55 min, column A, 2 minute gradient.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:14](N1C=CN=C1)([N:16]1C=CN=C1)=[S:15].N>ClCCl.CO>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:11][C:14]([NH2:16])=[S:15])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CCCCCOc1ccc(N)cc1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CCCCCOc1ccc(NC(N)=S)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Pentyloxyaniline (370 ml, 2 mmol) in dichloromethane (3 ml) is added to a solution of 1,1′-thiocarbonyldiimidazole (537 mg, 3 mmol) in dichloromethane (5 ml) at room temperature and the mixture is stirred at room temperature for 30 minutes. 2 N Ammonia in methanol (30 ml) is added to the solution, and the solution is stirred for additional 1 hour at room temperature. The solvent is removed, and the product extracted with ethylacetate and H2O. The crude product is recrystallized from dichloromethane and hexane to afford the thiourea as a white solid. 1H NMR (300 Hz, CDCl3) δ 7.92 (s, 1H, NH), 7.15 (d, J=8.4 Hz, 2H, Aryl H), 6.92 (d, J=8.4 Hz, 2H, Aryl H), 6.0 (br s, 2H, NH2), 3.95 (t, J=6.6 Hz, 2H, CH2), 1.79 (m, 2H, CH2), 1.44-1.38 (m, 4H, (CH2)2), 0.94 (t, J=7.2 Hz, 3H, CH3). MS (APCI) m/z 239 [M+H]±.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[N:15][C:16]([Cl:33])=[C:17]([NH:19][S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH:30]([F:32])[F:31])[CH:24]=4)(=[O:22])=[O:21])[CH:18]=3)=[N:9][N:8]2[C:34]=1[C:35]1[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH:36]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>>[Cl:33][C:16]1[N:15]=[CH:14][C:13]([C:10]2[CH:11]=[CH:12][C:7]3[N:8]([C:34]([C:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH:36]=4)=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[N:6]=3)[N:9]=2)=[CH:18][C:17]=1[NH:19][S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH:30]([F:31])[F:32])[CH:24]=1)(=[O:21])=[O:22]
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4cccc(OC(F)F)c4)c3)nn2c1C1=CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4cccc(OC(F)F)c4)c3)nn2c1C1=CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A sealable vial was charged with tert-butyl 4-(2-acetamido-6-(6-chloro-5-(3-(difluoromethoxy)phenylsulfonamido)pyridin-3-yl)imidazo[1,2-b]pyridazin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (104.0 mg, 151 μmol) and neat trifluoroacetic acid (1.16 mL, 15.1 mmol). The solution was stirred at rt for 1 h. The solution was then concentrated to give N-(6-(6-chloro-5-(3-(difluoromethoxy)phenylsulfonamido)pyridin-3-yl)-3-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide, which was of sufficient purity for further use. Methanol (2.0 mL) was added to the crude residue followed by an aqueous solution of sodium hydroxide (6 N, 502 μl, 3014 μmol). The solution was heated at 50° for 18 h. The solution was concentrated, then taken up in minimal MeOH/DMSO and purified by preparative HPLC (Gilson GX-218, Middletown, Wis.: 5-90% (0.1% TFA in CH3CN) in H2O over 15 min, Phenomenex, Zorbax 00F-4435-UO 150×30 mm, 5 micron) to afford the title compound, N-(5-(2-amino-3-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl)-2-chloropyridin-3-yl)-3-(difluoromethoxy)benzenesulfonamide (8.6 mg, 8.6% yield) as a yellow solid. LCMS (ESI positive ionization) m/z: 548.1 (M+1); 1H NMR (400 MHz, MeOH) δ ppm 3.12-3.23 (m, 2H); 3.59 (t, J=5.97 Hz, 2H); 3.97-4.08 (m, 2H); 6.35-6.48 (m, 1H); 6.84 (t, J=73.02 Hz, 1H); 7.40-7.46 (m, 1H); 7.49-7.66 (m, 3H); 7.87-7.94 (m, 1H); 7.97-8.04 (m, 1H); 8.79 (dd, J=15.55, 2.25 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]CC2C=CC(OC)=CC=2)=[CH:12][C:11]=1[CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28].C1(OC)C=CC=CC=1.[OH-].[Na+]>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:11]=1[CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: COc1ccc(CSc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COc1ccc(F)c(-c2ccc(S)cc2CC(C)(C)C)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a solution of (2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)(4-methoxybenzyl)sulfane (1.68 g) in trifluoroacetic acid (6.6 mL) was added anisole (2.15 mL) at room temperature, and the mixture was stirred at 90° C. for 8 hr. The reaction mixture was cooled to 0° C., neutralized with 8N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (918 mg) as a pale-yellow oil.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[N-:6]([C:9]#[N:10])[C:7]#[N:8].[Na+].CS(C)=O>CC(O)CC>[NH2:8][C:7]([NH:6][C:9]#[N:10])=[C:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#C[N-]C#N
Reactant: N#CCC#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCC(C)O
Product: N#CNC(N)=C(C#N)C#N
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 94.7 %

Procedure:
To a 250 ml flask is charged 6.6 gm (0.1 mole) of malononitrile, 8.9 gm (0.1 mole) of sodium dicyanamide and 40 ml of dimethyl sulfoxide. The stirred mixture is heated to 140° C. and held for 1.5 hours; then cooled to about room temperature. Then 150 ml 2-butanol is added and the stirred mixture is cooled in an ice bath. The solids are filtered, washed with 2-butanol and dried. There is obtained 12.6 gm of 1-amino-1-cyanamido-2,2-dicyanoethylene, sodium salt, 72.3% pure or a 58.8% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([C@H:9]([C:11](=[O:26])[NH:12][C@H:13]1[CH2:19][S:18][C:17]2[C:20]([NH2:24])=[CH:21][CH:22]=[CH:23][C:16]=2[NH:15][C:14]1=[O:25])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:1]([O:5][C:6](=[O:27])[N:7]([C@H:9]([C:11](=[O:26])[NH:12][C@H:13]1[CH2:19][S:18][C:17]2[C:20]([NH2:24])=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=[CH:38][CH:37]=2)[C:14]1=[O:25])[CH3:10])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: BrCc1cccc2ccccc12
Reactant: C[C@@H](C(=O)N[C@H]1CSc2c(N)cccc2NC1=O)N(C)C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N[C@H]1CSc2c(N)cccc2N(Cc2cccc3ccccc23)C1=O)N(C)C(=O)OC(C)(C)C
Reaction time: 36 h
Yield: 83.8 %

Procedure:
To a solution of (S)-1-((R)-9-amino-4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]thiazepin-3-ylcarbamoyl)-ethyl-methyl-carbamic acid tert-butyl ester (1.5 g, 3.9 mmol) in DMF (25 mL) was added K2CO3 (2.6 g, 19.0 mmol) and 1-bromomethyl-naphthalene (631 mg, 2.9 mmol) in DMF (10 mL) was added dropwise. After 36 h, the mixture was diluted with sat. aq. citric acid and extracted with EtOAc. The combined extracts were washed with H2O, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (1.3 g, 81%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[N+]=[N-])=[CH:3][CH:2]=1.[CH2:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:13]([CH:12]1[CH2:11][N:7]1[C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C=CCCCCCCCC
Reactant: Cc1ccc(N=[N+]=[N-])cc1
Product: CCCCCCCCC1CN1c1ccc(C)cc1

Procedure:
0.1% catalyst loading: p-Tolyl azide (0.240 g, 1.81 mmol), 1-decene (7.410 g, 52.8 mmol), and [(Me,EtTCPh)Fe(NCCH3)2](PF6)2 (0.0025 g, 0.0018 mmol) were used in the General Catalytic Reaction described above yielding 0.312 g, 70.4%. 1% catalyst loading: p-Tolyl azide (0.103 g, 0.773 mmol), 1-decene (2.223 g, 15.8 mmol), and [(Me,EtTCPh)Fe(NCCH3)2](PF6)2 (0.0107 g, 0.0077 mmol) were used in the General Catalytic Reaction described above yielding 0.156 g, 82.1%. 1H NMR (CDCl3, 499.74 MHz): δ 7.03 (d, J=7.5 Hz, 2H), 6.89 (d, J=7.0 Hz, 2H), 2.28 (s, 3H), 2.03 (m, 3H), 1.59 (m, 4H), 1.40 (m, 2H), 1.31 (m, 8H), 0.91 (t, J=6.0 Hz, 3H). 13C NMR (CDCl3, 125.66 MHz): δ 152.77, 131.45, 129.51, 120.65, 40.33, 34.17, 33.41, 32.02, 29.74, 29.69, 29.42, 27.85, 22.80, 20.78, 14.24. GC/MS (m/z): 245.2. DART HR MS (m/z): [M+H]+246.2211 (found). C17H28N, 246.2222 (calcd).
Reaction SMILES: C(OC([N:6]1[CH2:25][CH2:24][C:10]2[C:11]3[CH:12]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=O)C>C(O)(=O)C.Br>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH:12]2[C:11]3[C:10]4[CH2:24][CH2:25][NH:6][CH2:7][CH2:8][C:9]=4[CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13]2)[CH:19]=1
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(c1cccnc1)CC3
Agent: Br
Solvent: CC(=O)O
Product: c1cncc(C2CCc3ccc4c(c32)CCNCC4)c1
Temperature: 60 °C

Procedure:
Into a glass vial, the product from step (c) in 2.5 ml acetic acid and 2.5 ml HBr (33% in acetic acid) was added. The stirred reaction mixture was heated at 60° C. for 6 hours. The reaction mixture was cooled and the volatiles were evaporated in vacuo. The residue was dissolved in water (25 ml) and washed with diethyl ether (3×). The aqueous layer was basified with 2M NaOH to pH 10 and extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the title compound as a colorless oil (35 mg). 1H NMR (300 MHz, CDCl3) δ 8.43-8.38 (m, 2H); 7.22-7.12 (m, 2H); 7.08-7.00 (m, 2H); 4.49 (dd, J=8.7 Hz, 2.7 Hz, 1H); 3.10-2.82 (m, 6H); 2.73-2.45 (m, 5H); 2.04-1.93 (m, 2H); MS: ESI (positive): 265 (M+1).
Reaction SMILES: S([NH:11][N:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(C1C=CC(C)=CC=1)(=O)=O.C[O-].[Na+]>CO>[C:14]1([CH:13]=[N+:12]=[N-:11])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)NN=Cc2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=Cc1ccccc1
Reaction time: 2 h

Procedure:
In an oven-dried round bottom flask was placed benzaldehyde tosylhydrazone (1.15 g, 4.2 mmol), followed by 4.3 mL of a 1.0 M solution of sodium methoxide in methanol (2.3 g Na metal dissolved in absolute methanol and diluted to 100 mL). The mixture was swirled until all the contents dissolved. Most of the solvent was removed via rotary evaporation and the last traces of solvent by evacuation of the flask under high vacuum for 2 hours. The solid obtained was subjected to a Kugelrohr distillation at 215° C. and 200 millitorr for 1 hour. At 68-70° C., the title compound, as a red oil, was collected in a receiver flask in a quantitative yield.
Reaction SMILES: Br[C:2]1[C:3]([NH:25][CH3:26])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])=[CH:11][C:10]=2[O:23][CH3:24])=[N:6][CH:7]=1.[CH2:27]([Sn](CCCC)(CCCC)C#CC)[CH2:28][CH2:29]C>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>[CH3:24][O:23][C:10]1[CH:11]=[C:12]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[CH:13]=[CH:14][C:9]=1[NH:8][C:5]1[N:4]=[C:3]([NH:25][CH3:26])[C:2]([C:27]#[C:28][CH3:29])=[CH:7][N:6]=1
Reactant: CNc1nc(Nc2ccc(C(=O)N3CCOCC3)cc2OC)ncc1Br
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC#Cc1cnc(Nc2ccc(C(=O)N3CCOCC3)cc2OC)nc1NC
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of (4-(5-bromo-4-(methylamino)pyrimidin-2-ylamino)-3-methoxyphenyl)(morpholino)methanone (140 mg, 0.233 mmol), Pd(PPh3)4 (50 mg, 0.04 mmol) and tributyl(prop-1-ynyl)stannane (0.20 mL, 0.66 mmol) in toluene (5 mL) was stirred in a sealed tube at 110° C. for 1 hour. The reaction mixture was filtered and concentrated. Purification of the crude product was achieved by reverse phase HPLC (9 mg, 10%). Additional compounds made using the above procedure are shown in Table 4 above.