Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].O1C[CH2:9][CH2:8][CH2:7]1.[C:11](=[S:13])=[S:12].C(Cl)C=C>O>[CH2:7]([S:13][C:11](=[S:12])[N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH:8]=[CH2:9]
Reactant: S=C=S
Reactant: C1CCOC1
Reactant: CCNCC
Solvent: C=CCCl
Solvent: O
Product: C=CCSC(=S)N(CC)CC

Procedure:
9.7 Grams of diethylamine was added to 50 ml of tetrahydrofuran, and while maintaining the mixture at a temperature of 0°-5° C. and under agitation, 5.0 gr of carbon disulfide was added dropwise to the mixture over the period of 30 minutes. Thereafter, the temperature of the mixture was allowed to rise up to a room temperature, followed by dropwise addition of 4.6 gr of allyl chloride over the period of 30 minutes. The reaction mixture was poured into water and the separated organic substance was extracted twice with 30 ml of toluene, washed with diluted hydrochloric acid and further washed with water. After removal of toluene by distillation, there was obtained 8.3 gr of the desired product.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[NH4+]>>[C:13]1([NH:12][C:2]2[C:3]3[CH:11]=[CH:10][CH:9]=[N:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1ncnc2ncccc12
Reactant: Nc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Product: c1ccc(Nc2ncnc3ncccc23)cc1
Yield: 26.7 %

Procedure:
4-Chloropyrido [2,3-d]pyrimidine (0.15 g, 0.91 mmol) was carefully added to a solution of aniline (0.15 g, 1.61 mmol) on water (1.5 mL). The solution was heated for 0.5 hour on a steam bath, cooled, and then basified with conc. ammonium hydroxide. The crude precipitate was collected by filtration and recrystallized from 95% ethanol to give the title product as yellow crystals (0.054 g, 27%). MP 258° C.; LC-MS: 223 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[I-].ClC1[CH:29]=[CH:28][CH:27]=[CH:26][N+]=1C.C(O)CCC>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[C:11]([CH2:13][C:14]([O:16][CH2:26][CH2:27][CH2:28][CH3:29])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: C[n+]1ccccc1Cl
Reactant: O=C(O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccsc1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CCCCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccsc1
Yield: 69.6 %

Procedure:
0.55 g of 2-[2-(4-chlorophenyl)-5-(3-thienyl)-4-oxazolyl]acetic acid, 0.44 g of 2-chloro-1-methyl-pyridinium iodide, 0.13 ml of n-butanol and 0.2 g of triethylamine are treated in the same manner as described in Example 20. 0.45 g of n-butyl 2-[2-(4-chlorophenyl)-5-(3-thienyl)-4-oxazolyl]acetate is thereby obtained.
Reaction SMILES: N1CCCC(COC2C=C([O:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])(=[O:19])=[O:18])C=C(C)C=2)C1.C(N(CC)C(C)C)(C)C.NN=CS(O)(=O)=O>CN(C=O)C>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[S:17]([OH:19])(=[O:18])=[O:16]
Reactant: Cc1cc(OCC2CCCNC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: NN=CS(=O)(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
A solution of 2-chlorobenzenesulfonic acid 3-[(piperidin-3-yl)methoxy]-5-methylphenyl ester (396 mg, 1.0 mmol), as prepared in the preceding step, in DMF (10 mL) containing N,N-diisopropylethylamine (0.5 mL) and aminoiminomethanesulfonic acid (248 mg, 2.0 mmol) was stirred at room temperature overnight. The DMF was removed in vacuo and the residue was purified by flash column chromatography (90:10 methylene chloride:methanol saturated with NH3) to give the title compound as a white foam (159 mg, 36%). 1H-NMR (300 MHz, CDCl3) δ 1.45-1.92 (m, 4H), 2.11 (m, 1H), 2.23 (s, 3H), 3.07 (m, 2H), 3.81 (d, 2H), 3.92 (m, 2H), 6.50 (s, 2H), 6.61 (s, 1H), 7.24 (bs, 3H), 7.40 (m, 1H), 7.63 (m, 2H), 7.95 (dd, 1H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C20H24N3 O4SCl: 438.1 (M+H), 460.1 (M+Na), Found: 438.5, 460.5.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].[Na]>C(OCCO)C>[Cl:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(O)ccc2N1
Reactant: ClCCCBr
Agent: [Na]
Solvent: CCOCCO
Product: O=C1COc2cc(OCCCCl)ccc2N1
Yield: 65 %

Procedure:
7-Hydroxy-2H-1,4-benzoxazin-3(4H)-one was treated with 3-bromo-1-chloro-propane and sodium metal in ethyleneglycol monoethyl ether to give the desired product in 65% yield, mp 95° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Br:32])[C:24]=1[C:25]([OH:27])=[O:26].C(N(C(C)C)C(C)C)C>CC(O)C>[Br:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:23]([NH:22][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:6]=3[N:7]=[C:2]([Cl:1])[N:3]=2)[C:24]=1[C:25]([OH:27])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: Nc1cccc(Br)c1C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(Br)c4C(=O)O)nc(Cl)nc32)cc1
Temperature: 90 °C
Yield: 49.2 %

Procedure:
A suspension of 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (2 g, 5.84 mmols), 2-amino-6-bromobenzoic acid (2.53 g, 11.69 mmols), and N-ethyl-N-(1-methylethyl)-2-propanamine (7.55 g, 58.4 mmols) in 2-propanol (150 ml) was heated at 90° C. for 5 days. The solvent was removed, residue redissolved in DCM (150 ml), washed with 1M HCl(100 ml), organic layer separated, adsorbed onto silica gel, and purified by silica gel chromatography (DCM to 10% MeOH/DCM). The crude product was then recrystallized from ethyl acetate/hexanes to obtain 2-bromo-6-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzoic acid (1.5 g, 49%). ESIMS (M+H)+=521.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@@H:3]([C:14]([OH:16])=[O:15])[NH:2]1.[OH-].[Na+].C(O)C.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1.[C:31](=[S:33])=[S:32]>>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][S:33][C:31]([N:2]2[C@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH2:1]2)=[S:32])=[CH:25][CH:24]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=C(O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1ccc(Cl)cc1
Yield: 69 %

Procedure:
In the same manner as described in Example 16, (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (1.08 g), 2N NaOH (5 ml), 50% ethanol (15 ml), carbon disulfide (0.3 ml) and 4-chlorobenzyl chloride (1.13 g) are reacted and treated. The product is crystallized from n-hexane to give the title compound (1.44 g, 69%), m.p. 139°-141° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]=[O:10])=[C:7]([CH3:11])[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=1.[CH2:21]([O:28][C:29]1[C:30]([C:36]([O:38][CH3:39])=[O:37])=[N:31][C:32](Br)=[CH:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].CCCCCC>COCCOC.O.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>[CH2:21]([O:28][C:29]1[C:30]([C:36]([O:38][CH3:39])=[O:37])=[N:31][C:32]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([CH:9]=[O:10])[C:7]=2[CH3:11])=[CH:33][CH:34]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1nc(Br)ccc1OCc1ccccc1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1C=O
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: CCCCCC
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1nc(-c2ccc(OC)c(C=O)c2C)ccc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 111.5 %

Procedure:
A suspension of the 6-methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde produced in Example 4-1 (1.91 g, 6.92 mmol), methyl 3-(benzyloxy)-6-bromopyridine-2-carboxylate (PCT Int. Appl., 2010080478, 15 Jul. 2010) (2.23 g, 6.92 mmol), sodium carbonate (2.20 g, 20.8 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.40 g, 0.35 mmol) in 1,2-dimethoxyethane (38 ml) and water (17 ml) was prepared at room temperature, and the suspension thus prepared was then stirred at 90° C. for 3 hours. After air-cooling, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer thus obtained was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (ethyl acetate:hexane=2:3, v/v) to obtain the title compound (3.02 g, yield: 112%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[Cl:34])[N:30]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:29]=[C:28]2[NH:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47].C(OCC)(=O)C>O.O1CCOCC1.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:34][C:33]1[CH:32]=[C:31]2[C:27]([C:28]([NH:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47])=[N:29][N:30]2[CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:40])[CH3:41])=[CH:26][C:25]=1[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(Br)cc12
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
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: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccc(OCc4ccccc4)cc3)cc12
Yield: 95.4 %

Procedure:
1.54 g of 4-benzyloxyphenylboronic acid, 1.32 g of sodium carbonate in 20 cm3 of water and 404 mg of tetrakis(triphenylphosphine)palladium are added to 2 g of N-[5-bromo-6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described in Example 58, in 100 cm3 of dioxane. The mixture is refluxed for 18 hours, the temperature is then allowed to return to room temperature to add 75 cm3 of ethyl acetate and 50 cm3 of water, and the reaction medium is filtered through a sinter funnel packed with Celite. The filtrate is separated by settling and the organic phase is washed successively with 100 cm3 of water and then with 75 cm3 of saturated aqueous sodium chloride solution, separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60/μm; diameter 4.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is taken up in 50 cm3 of cyclohexane, filtered off, washed with 2×25 cm3 of cyclohexane and dried under reduced pressure (90 Pa; 50° C.) to give 2.35 g of N-[6-chloro-5-[4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide in the form of white crystals melting at 130° C.
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([OH:18])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:22]=C=NC(C)C)(C)C.N1(O)C2C=CC=CC=2N=N1>CN(C=O)C>[O:1]([C:8]1[N:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([NH2:22])=[O:18])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N=C=NC(C)C
Reactant: O=C(O)C=Cc1ccc(Oc2ccccc2)nc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: NC(=O)C=Cc1ccc(Oc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
100 mg (0.415 mmol) of 3-(6-phenoxy-pyridin-3-yl)-acrylic acid was dissolved in 4 ml of DMF, and 52 mg (0.415 mmol) of N,N′-diisopropylcarbodiimide and 126 mg (0.830 mmol) of the ammonium salt of benzotriazol-1-ol were added. After 1 h a further 126 mg (0.830 mmol) of the ammonium salt of benzotriazol-1-ol were added. The reaction was stirred at room temperature for 16 h, filtered, and the product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a solid. Yield: 75 mg.
Reaction SMILES: Br[C:2]1[C:3]2[N:10]([CH2:11][CH3:12])[C:9]([C:13]3[C:14]([NH2:18])=[N:15][O:16][N:17]=3)=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH2:18][C:14]1[C:13]([C:9]2[N:10]([CH2:11][CH3:12])[C:3]3[C:2]([NH:65][C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)=[CH:7][N:6]=[CH:5][C:4]=3[N:8]=2)=[N:17][O:16][N:15]=1
Reactant: Nc1ccccc1
Reactant: CCn1c(-c2nonc2N)nc2cncc(Br)c21
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCn1c(-c2nonc2N)nc2cncc(Nc3ccccc3)c21
Temperature: 175 °C
Yield: 0 %

Procedure:
Under Ar, a solution of the product from Example 100 (24 mg, 77.6 mol) in 1,4-dioxane (0.8 ml) and toluene (1.2 ml) was treated with Tris(dibenzylidene-acetone)dipalladium (7.2 mg, 7.8 mol), racemic-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (9.7 mg, 15.6 mol), aniline (8.5 l, 93.1 mol), and sodium tert-butoxide (10.5 mg, 108.6 mol). This mixture was then heated to 175° C. by microwave for 45 min. After cooled to ambient temperture, the reaction mixture was diluted with ethyl acetate (30 ml), filtered though a celite pad and then the filtrate was concentrated in vacuo. The residue was purified with reverse phase HPLC (10% MeCN/H2O→80% MeCN/H2O), to afford the title compound, (6.3 mg, 24%); MS (ES+) m/e 322 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Mg]Cl.[O:9]1[CH2:14][CH2:13][CH2:12][O:11][CH:10]1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:22][C:23]3[CH:29]=[C:28]([C:30](N(OC)C)=[O:31])[CH:27]=[CH:26][C:24]=3[N:25]=2)=[C:17]([F:36])[CH:16]=1.[NH4+].[Cl-]>C1COCC1>[O:11]1[CH2:12][CH2:13][CH2:14][O:9][CH:10]1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:22][C:23]3[CH:29]=[C:28]([C:30]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[O:31])[CH:27]=[CH:26][C:24]=3[N:25]=2)=[C:17]([F:36])[CH:16]=1
Reactant: CON(C)C(=O)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1
Reactant: Cl[Mg]c1ccccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1)c1ccccn1
Reaction time: 0.5 h

Procedure:
2-Pyridylmagnesium chloride (3.92 mL, 2.84 mmol, solution in THF) was added to a solution of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-N-methoxy-N-methylbenzo[d]thiazole-6-carboxamide (0.52 g, 1.29 mmol) in THF (2 mL) and the reaction mixture was stirred for 30 min. Satd. NH4Cl (aq) was added and the mixture was extracted with DCM three times. The combined extracts were dried (MgSO4) and concentrated under vacuum to give (2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)benzo[d]thiazol-6-yl)(pyridine-2-yl)methanone as a yellow solid. MS (ESI) m/z: Calculated: 420.1; Observed: 421.0 (M++1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]1[S:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].N1CCNCC1>O.O1CCOCC1>[CH3:15][O:14][C:12]([C:10]1[S:11][C:7]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][N:1]2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[CH:8][CH:9]=1)=[O:13]
Reactant: COC(=O)c1ccc(C2CCCCN2)s1
Reactant: O=C(Cl)OCc1ccccc1
Agent: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C2CCCCN2C(=O)OCc2ccccc2)s1
Reaction time: 4 h

Procedure:
To a mixture of EXAMPLE 28B (0.3 g), potassium carbonate (0.36 g), dioxane (20 mL) and water (5 mL) was added benzyl chloroformate (0.23 mL), and the mixture stirred for 4 hours. Piperazine was added, and the mixture stirred for 30 minutes and partitioned between ethyl acetate and brine. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated. The concentrate was flash chromatographed on silica gel with 10-50% ethyl acetate in hexane.
Reaction SMILES: O=[C:2]1[CH2:20][CH2:19][N:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]2[CH2:3]1.[CH3:21][NH2:22].[H][H]>C(O)C.[Pd]>[CH3:21][NH:22][CH:2]1[CH2:20][CH2:19][N:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]2[CH2:3]1
Reactant: CN
Reactant: O=C1CCN2c3ccccc3Cc3ccccc3C2C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CNC1CCN2c3ccccc3Cc3ccccc3C2C1

Procedure:
1 g of 2-keto-1,2,3,4,10,14b-hexahydro-pyridino[ 1,2-a] -dibenzo[c,f]-azepine is dissolved in 100 ml of ethanol, after which 10 ml of methylamine and 200 mg of palladium (10%) on charcoal are added. Then hydrogen is passed through this mixture until no hydrogen is absorbed any longer.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].[OH-].[K+]>[OH-].[Na+]>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[Cl:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: Oc1ccccc1Cl
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc2ccc(Oc3ccccc3Cl)nc2n1
Temperature: 120 °C
Yield: 76.1 %

Procedure:
A mixture composed of 2-amino-7-chloro-1,8-naphthyridine (17.9 g), 2-chlorophenol (51.4 g) and potassium hydroxide pellets (13.2 g; 85% purity) is heated for 4 hours at 120° C. The mixture produced is poured into 4N caustic soda (100 cc), and the precipitate formed is separated by filtration and washed with water until the pH =7. After being dried at 40°C. under reduced pressure (0.067 kPa), 2-amino-7-(2-chlorophenoxy)-1.8 naphthyridine (20.6 g) is produced, m.p. 166° C.
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2[CH:3]=[CH:2]1)[CH2:7]3.ClC(Cl)(Cl)C(Cl)(Cl)Cl.C1(C#C)C=CC=CC=1>C(Cl)Cl>[CH2:1]1[CH:5]2[C@@H:6]3[CH:10]=[CH:9][C@H:8]([CH:4]2[CH:3]=[CH:2]1)[CH2:7]3
Reactant: C1=CC2C3C=CC(C3)C2C1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C#Cc1ccccc1
Product: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Reaction time: 3 h

Procedure:
A 10.0 gram (75.6 mmol) amount of dicyclopentadiene was added to a 100 ml round-bottom flask. A 5.0 milligram (7.2 μmol) amount of RuClH(H2)(PCy3)2, ten equivalents of hexachloroethane, and ten equivalents of phenylacetylene were added via the addition of a 0.5 mls stock solution containing 2.5 mls of CH2Cl2, 25 mg RuClH(H2)(PCy3)2, 86 mg of hexachloroethane and 36 mg of phenylacetylene. The ring opening polymerization of dicyclopentadiene was observed slowly by a gradual thickening of the solution to a rubbery viscous material after three hours. After 24 hours, it had become a soft rubbery material.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:13]([CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[CH3:18][N:19]([CH3:23])[C:20](Cl)=[S:21]>CN(C)C=O>[CH3:18][N:19]([C:20](=[S:21])[O:3][C:4]1[C:13]([CH2:14][C:15]([CH3:17])=[CH2:16])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH3:23]
Reactant: COC(=O)c1cccc(C=C(C)C)c1O
Reactant: CN(C)C(=S)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)Cc1cccc(C(=O)OC)c1OC(=S)N(C)C
Yield: 60.1 %

Procedure:
To 1 liter of dry dimethylformamide were added 16 g of 60% sodium hydride in oil. After stirring under a nitrogen atmosphere, 81.7 g of 2-hydroxy-3-(2-methylpropenyl)benzoic acid, methyl ester, as a solution in dimethylformamide, were added in dropwise fashion. After stirring at room temperature, a solution 49.6 g of dimethylthiocarbamoyl chloride in dimethylformamide was added over a one hour period. The reaction mixture was stirred at room temperature overnight, then poured onto ice and extracted with diethyl ether and ethyl acetate. The combined organic extracts were washed successively with a 10% sodium hydroxide solution and water, dried over sodium sulfate, and concentrated in vacuo. The residue was vacuum distilled, and the fraction distilling at 162°-168° C. and 0.6 torr provided 69.9 g of the desired subtitle intermediate. NMR, MS.
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[C:3]1[S:4][C:5](C(Cl)(Cl)Cl)=[N:6][N:7]=1.S(=O)(=O)(O)O>>[Cl:1][C:2]([Cl:13])([Cl:12])[C:3]1[S:4][CH:5]=[N:6][N:7]=1
Reactant: ClC(Cl)(Cl)c1nnc(C(Cl)(Cl)Cl)s1
Agent: O=S(=O)(O)O
Product: ClC(Cl)(Cl)c1nncs1
Yield: 83 %

Procedure:
6.4 parts by weight of 2,5-bis-trichloromethyl-1,3,4-thiadiazole is heated in 30 parts by volume of 91% sulfuric acid for 6 minutes at 175° to 185° C. The reaction mixture is subsequently poured carefully on to ice and the precipitated solid is filtered off. The reaction product is washed with water and treated with 20 parts by volume of methanol, and the minor amounts of undissolved starting material are filtered off. Concentration of the methanolic solution gives 3.4 parts (83% of theory) of 2-trichloromethyl-1,3,4-thiadiazole having a melting point of 58° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([NH2:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:20])=CC=1>O1CCOCC1>[OH:1][C:2]1[C:3]([C:8]([NH2:10])=[S:20])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1ncccc1O
Solvent: C1COCCO1
Product: NC(=S)c1ncccc1O
Yield: 71.6 %

Procedure:
A suspension of 3-hydroxypicolinamide (1 g) and Lawesson's reagent (2 g) in dry dioxane (75 ml) was allowed to react under Argon atmosphere at 95° C. for 4 hours. Then, insoluble solids in the reaction mixture was filtered off with suction and the filtrate was concentrated. The residue was dissolved in methylene chloride and purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1). The second yellow fraction was concentrated. the residual solids were recrystallized from CHCl3 -n-hexane to give yellow crystals of 3-hydroxythiopicolinamide (546 mg, 46%), m.p. 150°-151° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH:10]([N:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[C:18](O)=[O:19])([CH3:12])[CH3:11].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:18]([C@@H:14]2[CH2:15][CH2:16][CH2:17][N:13]2[CH:10]([CH3:12])[CH3:11])=[O:19])[NH2:9])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: CC(C)N1CCC[C@H]1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1CCC[C@H]1C(=O)N(N)c1ccc(F)cn1
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (200 mg, 1.57 mmol) in DMF (15.0 mL) was added (S)-1-isopropyl-pyrrolidine-2-carboxylic acid (Chem. Commun. 2006, 14, 1482, which is incorporated herein by reference in its entirety; 247 mg, 1.57 mmol), EDC (332 mg, 1.73 mmol) and HOBt.H2O (20.0 mg, 0.16 mmol). The reaction was stirred overnight then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound (346 mg, 83%). LCMS (Method 1): Rt 0.37 min, m/z 267.1 [MH+].