Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:26][C:23]=1[CH:24]=O.C[O-].[Li+]>CN(C=O)C.CO>[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:26][C:23]=1/[CH:24]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: COc1cc(OC)c(N2CCCC2)cc1C=O
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2ccccn2)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(OC)c(N2CCCC2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.9 %

Procedure:
A solution 4-acetyl-N-pyridin-2-ylbenzenesulfonamide (Ex-5A, 588 mg, 2.13 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-yl-benzaldehyde (Ex-38B, 500 mg, 2.13 mmol) in DMF (9.3 mL) and MeOH (4.0 mL) was treated with lithium methoxide (243 mg, 6.39 mmol) and stirred for 20 h at room temperature under nitrogen. The reaction mixture was quenched with water (25 mL) and extracted ethyl acetate (3×50 mL). The product precipitated out of the organic phase to give 535 mg (51%) of the title compound as a red solid, mp 124–128° C. 1H-NMR (300 MHz, DMSO-d6) 8.16 (d, 2H, J=8.7), 8.02 (d, 1H, J=15.9 Hz), 7.95 (m, 3H), 7.70 (t, 1H, J=7.80 Hz), 7.61 (d, 1H, J=16.2 Hz), 7.18 (d, 1H, J=8.70 Hz), 7.15 (s, 1H), 6.83 (t, 1H, J=6.0 Hz), 6.66 (s, 1H), 3.84 (s, 6H), 3.13 (m, 4H), 1.18 (m, 4H). HRMS (ESI) Calcd. for C26H27N3O5S: 494.1750 [(M+H)+]; Found: 494.1750.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:10]1[S:11][C:12]([S:33][CH3:34])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:31]O)[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])(C)(C)C.C(OP([CH2:44][P:45]([O:50]CC)([O:47]CC)=[O:46])(=O)OCC)C.[H-].[Na+].C(Cl)(Cl)Cl.[F:59][C:60]([F:65])([F:64])[C:61]([OH:63])=[O:62]>ClCCl.C1COCC1.[O-2].[O-2].[Mn+4]>[F:59][C:60]([F:65])([F:64])[C:61]([OH:63])=[O:62].[C:8]([C:10]1[S:11][C:12]([S:33][CH3:34])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3/[CH:31]=[CH:44]\[P:45](=[O:46])([OH:47])[OH:50])[CH:21]=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH:14]=1)(=[NH:7])[NH2:9]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2CO)c1
Agent: [Mn+4]
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2/C=C\P(=O)(O)O)c1
Reaction time: 0.5 h
Yield: 57 %

Procedure:
Manganese dioxide (0.041 g, 0.470 mmol) was added to a solution of ({[4-(2′-hydroxymethyl-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.025 g, 0.047 mmol) [example 213, step b] in dichloromethane [5 mL] and refluxed for 3 hours. The reaction was filtered through Celite and evaporated. The crude residue was dissolved in anhydrous THF [2 mL] and added to a solution of (diethoxy-phosphorylmethyl)-phosphonic acid diethyl ester (0.011 g, 0.061 mmol) and sodium hydride (0.003 g, 0.056 mmol) in THF [2 mL] at room temperature and stirred for 0.5 hours. A solution of 1N NaOH/MeOH (1/1) [10 mL] was added and the crude product was extracted with ether, dried with magnesium sulfate and evaporated. Column chromatography (50% EtOAc in hexanes) of the residue yielded the title compound (0.019 g, 57%) as a solid. ESI-MS (m/z): Calcd. for C30H37N2O7PS3: 664.15; found: 664.8.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.C1(S([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[C:19]([C:26]3[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=3)=[CH:18]2)(=O)=O)C=CC=CC=1>>[O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:28]2[N:27]=[C:26]([C:19]3[C:20]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[NH:17][CH:18]=3)[CH:31]=[CH:30][N:29]=2)[CH2:3][CH2:2]1
Reactant: NC1CCOCC1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: c1cnc2[nH]cc(-c3ccnc(NC4CCOCC4)n3)c2c1
Yield: 83.7 %

Procedure:
Using the procedure of example 1, tetrahydropyran-4-ylamine (0.8 g) was reacted with compound 1f (1.8 g) to provide compound 60 (1.2 g, 42%). 1H NMR (400 MHz, DMSO) δ 12.20 (s, 1H), 8.95 (s, 1H), 8.39 (s, 1H), 8.30 (d, 1H), 8.15 (d, 1H), 7.20 (m, 1 H), 7.06 (d, 1H), 7.04 (d, 1H), 4.00 (m, 1H), 3.90 (m, 2H), 3.45 (m, 2H), 1.90 (m, 2 H), 1.55 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.CC1(C)N([O])C(C)(C)CCC1.[Br-].[K+].Cl[O-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH:16]=[O:17])=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(CCCO)cc2)nc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Product: Cc1ccc(-c2ccc(CCC=O)cc2)nc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of the compound obtained from step d above (1.4 g) in dichloromethane (20 mL), 2,2,6,6,-tetramethylpiperidine N-oxyl (9.6 mg) and potassium bromide (73.4 mg) were added at 0° C. under nitrogen atmosphere. Sodium hypochlorite (13.7 mL, 4% solution) was added at pH 8-9 (maintained by adding aqueous sodium bicarbonate solution). The reaction was stirred for 20 minutes at 0° C. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, water, and brine. The organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the title compound (0.9 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]1[C:20]2[C:15](=[C:16]([O:21]C)[N:17]=[CH:18][CH:19]=2)[N:14]([CH3:23])[CH:13]=1.[F:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[F:31].C([O-])([O-])=O.[Cs+].[Cs+].Cl>CS(C)=O.O1CCOCC1>[F:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][C:30]=1[F:31])[O:32][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:4][C:3]=1[C:12]1[C:20]2[CH:19]=[CH:18][NH:17][C:16](=[O:21])[C:15]=2[N:14]([CH3:23])[CH:13]=1
Reactant: Oc1ccc(F)c(F)c1
Reactant: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3F)cn(C)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)c(F)c2)c2cc[nH]c(=O)c21
Yield: 38.8 %

Procedure:
A mixture of Example 17C (0.1 g, 0.299 mmol), 3,4-difluorophenol (0.058 g, 0.449 mmol) and Cs2CO3 (0.146 g, 0.449 mmol) in DMSO (5 mL) was stirred at 110° C. for 12 hours, cooled and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), filtered, and concentrated. The resulting residue (0.13 g, 0.405 mmol) and 4M HCl in dioxane (4 M, 13 mL) was heated at 70° C. for 12 hours, cooled and concentrated. The residue was purified by reverse phase HPLC (C18, CH3CN/water (0.1% TFA), 10-100%) to afford the title compound (0.05 g, 0.116 mmol, 38.7%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.00 (d, J=5.3 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.80 (dd, J=8.7, 2.4 Hz, 1H), 7.68 (s, 1H), 7.50 (dd, J=19.6, 9.2 Hz, 1H), 7.40 (ddd, J=11.5, 6.8, 2.9 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H), 7.00 (d, J=7.7 Hz, 1H), 6.95-6.88 (m, 1H), 6.54 (d, J=6.3 Hz, 1H), 4.11 (s, 3H), 3.26 (s, 3H). MS (ESI+) m/z 431.0 (M+H)+.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12]([O:14][C:15](=[O:22])[CH2:16][C:17]([CH:19]1[CH2:21][CH2:20]1)=O)[CH3:13].[N:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])=[N+:24]=[N-:25].O>CN(C=O)C>[CH:19]1([C:17]2[N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:24]=[N:25][C:16]=2[C:15]([O:14][CH2:12][CH3:13])=[O:22])[CH2:21][CH2:20]1
Reactant: [N-]=[N+]=Nc1ccccc1F
Reactant: CCOC(=O)CC(=O)C1CC1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1nnn(-c2ccccc2F)c1C1CC1
Reaction time: 0.25 h

Procedure:
DBU (2.99 ml; 20.06 mmol; 1.10 eq.) was dissolved in DMF (37.5 ml) and put under nitrogen atmosphere. 3-Cyclopropyl-3-oxo-propionic acid ethyl ester (Betapharma, 3.132 g; 20.06 mmol; 1.10 eq.) was added to the mixture and it was stirred for 15 min. Then a solution of 1-azido-2-fluorobenzene prepared according to Platz, M. S. et al. J. Org. Chem. 1989, 54, 5938-5945, (2.5 g; 18.23 mmol; 1 eq.) in DMF (5 mL) was added dropwise to the solution at room temperature. Water (50 mL) was added to the cooled reaction mixture and the aqueous layer was extracted with EtOAc (3×50 mL). Combined organics were washed with water and brine, dried over MgSO4 and concentrated under vacuum affording the title compound as a brown oil. It was used in the next step without further purification. LC/MS (Method B): 276.1 (M+H)+.
Reaction SMILES: [C:1]1([N:7]=[C:8]=S)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:10]([C:12]1[N:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:16](=[O:22])[N:15]([CH3:23])[C:14](=[O:24])[CH:13]=1)[NH2:11]>CN(C=O)C>[CH2:18]([N:17]1[C:12]2=[N:10][NH:11][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]1=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: S=C=Nc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)[nH]nc21
Temperature: 120 °C
Yield: 13.6 %

Procedure:
Phenyl isothiocyanate (0.17 mL, 1.4 mmol) is added to a solution of 6-hydrazinyl-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione (31 mg, 0.47 mmol) in DMF (10 mL). The reaction mixture is heated at 120° C. for 6 hours, and then evaporated to remove solvent under reduced pressure. The residue is further purified by silica-gel flash chromatography to give 20 mg of product (Yield: 41%). 1H NMR (400 MHz, DMSO-d6) 50.95 (s, 3H), 0.97 (s, 3H), 2.30 (m, 1H), 3.37 (s, 3H), 3.77 (d, 2H), 7.16-7.43 (m, 5H), 7.61 (s, 1H). MS (FAB) m/z 314.3 [M+H]+.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][CH:9]([CH2:12][CH2:13][CH2:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:10]=[O:11].[OH-].[Na+]>CCOCC>[CH3:8][CH:9]([CH2:12][CH2:13][CH2:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:10][OH:11]
Reactant: CC(C)CCCC(C)CCCC(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)CCCC(C)CCCC(C)CO
Reaction time: 1 h

Procedure:
To a solution of 70 ml. of 70% by weight of bis (2-methoxyethoxy) sodium aluminum hydride in toluene (0.25 mol) in 500 ml. of anhydrous diethyl ether was added, dropwise over 1.0 hour, 69.2 g. (0.326 mol.) of (±)-2,6,10-trimethylundecanal. The solution was stirred 1.0 hour, poured onto ice and 10N aqueous NaOH, and worked up with ether and dried as described in Example 2. Distillation of the crude product gave (±)-2,6,10-trimethylundecan-1-ol as a colorless oil; b.p. 96°-98° C./0.20 mmHg.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([N:13]([CH3:15])[CH3:14])[N:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[N:3]=1.[Cl-].[CH3:27][NH2+:28][CH3:29].C(N(CC)C(C)C)(C)C.O>CN1C(=O)N(C)CCC1>[CH3:27][N:28]([CH3:29])[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([N:13]([CH3:15])[CH3:14])[N:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[N:3]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc([N+](=O)[O-])cc2)nc1N(C)C
Reactant: C[NH2+]C
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)Cc1c(N(C)C)nc(Cc2ccc([N+](=O)[O-])cc2)nc1N(C)C
Temperature: 150 °C
Yield: 68.6 %

Procedure:
A mixture of methyl [4-chloro-6-(dimethylamino)-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (7.75 g, 21.25 mmol), dimethylammonium chloride (5.20 g, 63.74 mmol), and N,N-diisopropylethylamine (10.98 g, 84.98 mmol) in DMPU (50 mL) was heated at 150° C. in a sealed tube for 15 hours. After cooling to room temperature, the dark mixture was poured into water and extracted with ethyl acetate. The combined extracts were washed sequentially with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product as a dark oil. Chromatographic purification of this crude product over silica gel eluting with 25% ethyl acetate in n-hexane containing 0.1% triethylamine gave methyl [4,6-bis(dimethylamino)-2-(4-nitro-benzyl)pyrimidin-5-yl]acetate (5.44 g, 69%) as a red colored oil.
Reaction SMILES: S(=O)(=O)(O)O.CO[CH:8](OC)[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:10].C([O-])(O)=O.[Na+]>>[CH3:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[N:11][C:9]([OH:10])=[CH:8]2
Reactant: COC(OC)C(=O)NCc1ccccc1C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cccc2cc(O)ncc12
Temperature: 60 °C
Reaction time: 6 h

Procedure:
Concentrated sulfuric acid (18 M; 7.0 mL) was added to 2,2-dimethoxy-N-(2-methylbenzyl)-acetamide (3.04 g, 13.6 mmol) at ambient temperature, and the solution was stirred overnight at ambient temperature and 6 h at 60° C. The cooled reaction mixture was added to ≈50 mL of ice, and the pH of the yellow mixture was adjusted to 7 with NaHCO3 solution. The yellow precipitate was filtered off, washed with water, and dried in vacuo overnight. The yellow solid thus obtained was triturated from EtOH, the mother liquor was concentrated to give a solid, which was triturated against from EtOH. After four such triturations, the mother liquor was adsorbed onto Hydromatrix and chromatographed on silica gel [20 g/70 mL prepacked cartridge, eluting with DCM→2% MeOH in DCM→3% MeOH in DCM→4% MeOH in DCM]. Fractions containing the title compound were combined and dried in vacuo, giving a yellow oil. It was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ=10.9 (brs, 1H), 8.96 (s, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.42 (dd, J=6.8, 8.0 Hz, 1H), 7.12-6.97 (m, 2H), 6.85 (s, 1H), 2.64 (s, 3H). MS(ES+): m/z=160.06 (100) [MH+]. HPLC: tR=2.27 min (polar—5 min, ZQ3).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[C:11]3[C:15]([CH:16]=[C:17](B4OC(C)(C)CC(C)(C)O4)[CH:18]=2)=[N:14][N:13]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[CH:12]=3)=[O:8])[N:6]=1.Br[C:36]1[CH:37]=[C:38]([NH2:43])[C:39]([Cl:42])=[N:40][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[NH2:43][C:38]1[CH:37]=[C:36]([C:17]2[CH:18]=[C:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)=[O:8])[C:11]3[C:15]([CH:16]=2)=[N:14][N:13]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[CH:12]=3)[CH:41]=[N:40][C:39]=1[Cl:42]
Reactant: Cc1nc(C(=O)Nc2cc(B3OC(C)(C)CC(C)(C)O3)cc3nn(C4CCCCO4)cc23)cs1
Reactant: Nc1cc(Br)cnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(C(=O)Nc2cc(-c3cnc(Cl)c(N)c3)cc3nn(C4CCCCO4)cc23)cs1
Temperature: 140 °C
Yield: 45.9 %

Procedure:
2-Methyl-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1,3-thiazole-4-carboxamide (0.75 g), 5-bromo-2-chloro-3-pyridinamine (0.39 g), sodium carbonate (0.66 g) and Pd(dppf)Cl2 (0.114 g) were weighed to a 10-20 ml microwave vial and 1,4-dioxane (8 ml) then water (8 ml) were added. The reaction was heated at 140° C. for 20 min. The reaction was passed through a 10 g silica cartridge, washing with methanol:DCM (1:1, v/v). The solvent was evaporated and the residue was purified on a 40 g ISCO companion silica cartridge, eluting with 1.5-7.5% methanol in DCM (containing 1% ammonia) at 40 ml/min. Pure fractions were combined and evaporated to dryness to give title compound (335 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]([O:17]C)=[O:16])=[N:4][S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[F:14].C([O-])([O-])=O.[Cs+].[Cs+].ClC1C(C(OC)=O)=NSC=1Cl>COCCOC.O.CCOC(C)=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>[Cl:1][C:2]1[C:3]([C:15]([OH:17])=[O:16])=[N:4][S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[F:14]
Reactant: COC(=O)c1nsc(-c2cccc(Cl)c2F)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC(=O)c1nsc(Cl)c1Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C(O)c1nsc(-c2cccc(Cl)c2F)c1Cl
Temperature: 100 °C
Yield: 37 %

Procedure:
Methyl 4-chloro-5-(3-chloro-2-fluorophenyl)isothiazole-3-carboxylate: To a solution of Intermediate 50A (0.100 g, 0.472 mmol) and Cs2CO3 (0.461 g, 1.415 mmol) in DME (3.02 mL) and water (0.605 mL) was added methyl 4,5-dichloroisothiazole-3-carboxylate (0.100 g, 0.472 mmol). The solution was purged with Ar for 0.5 h. To the solution was added Pd(PPh3)4 (0.054 g, 0.047 mmol). The reaction mixture was then sealed and heated in microwave for 0.5 h at 100° C. The reaction mixture was then diluted with EtOAc and aqueous layer was decanted. The organic layer was concentrated in vacuo, yielding an oily residue which was purified by silica gel column chromatography to provide the desired product (53 mg, 37%) as a white solid. MS(ESI) m/z: 360.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][C:12]([O:14]CC)=O.C1(C)C=CC=CC=1>C(OCC)(=O)C.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[F:8][C:7]1[C:2]2[NH:1][C:12](=[O:14])[CH2:11][CH2:10][NH:9][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCNc1cccc(F)c1N
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1CCNc2cccc(F)c2N1
Temperature: 80 °C
Yield: 96.9 %

Procedure:
A disposable tube was charged with ethyl 3-(2-amino-3-fluorophenylamino)propanoate (800 mg, 3.54 mmol) and a stirbar. Toluene (10 mL) was added, followed by tetraisopropoxytitanium (523 μl, 1.768 mmol), and the solution was stirred at 80° C. 0.5 h. The solution was diluted with ethyl acetate, concentrated with celite, and purified by silica gel chromatography (eluting with hexanes/ethyl acetate) to yield 9-fluoro-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one as a white amorphous solid (0.618 g, 3.43 mmol, 97%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: Cc1ccccc1Cc1cc(Cl)ncn1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(Cc2ccccc2C)ncn1
Temperature: 25 °C
Yield: 108.3 %

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.06 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.08 g of 2-butyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, to which 0.6 ml of a tetrahydrofuran solution containing 0.2 g of 4-chloro-6-(2-methylbenzyl)pyrimidine was slowly added dropwise at room temperature, followed by stirring for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.25 g of 4-(2-butynyloxy)-6-(2-methylbenzyl)pyrimidine (the present compound (92)).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[C:1]([O:5][C:6](=[O:16])[N:7]([C@H:9]1[CH2:10][CH2:11][C@H:12]([O:15][CH2:21][CH2:20][CH2:19][CH2:18][Br:17])[CH2:13][CH2:14]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](O)CC1
Reactant: BrCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](OCCCCBr)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a suspension of 2.0 g (8.7 mmol) trans-(4-Hydroxy-cyclohexyl)-methyl-carbamic acid tert-butyl ester in 56.5 ml (261 mmol, 30 eq) 1,4-Dibromobutane, 0.89 g (2.6 mmol, 0.3 eq) tetrabutylammoniumhydrogensulfate and 56 ml 50% aqueous NaOH were added. The mixture was stirred at RT for 4 days, CH2Cl2 was added and the layers were separated. The inorganic layer was extracted with CH2Cl2, the combined organic layers washed with brine and dried over Na2SO4. The excess of dibromide was removed in vacuo and the residue was purified by column chromatography on silica gel with hexane:EtOAc 4:1 as eluent yielding 2.4 g (76%) trans-[4-(4-Bromo-butoxy)-cyclohexyl]-methyl-carbamic acid tert-butyl ester as light yellow oil, MS: 364 (MH+, 1Br).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].[C:17](OC)(=[O:22])[C:18]([O:20][CH3:21])=[O:19]>C1COCC1>[C:1]1(/[CH:7]=[CH:8]\[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccccc1C=Cc1ccccc1
Reactant: COC(=O)C(=O)OC
Agent: [Mg]
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccccc1/C=C\c1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
A solution of the Grignard agent prepared from part of the mixture of isomers of 1-phenyl-2-(2-bromophenyl)ethylene described above (5.58 g) and magnesium (0.63 g) in dry THF (20 ml) was added dropwise over 30 mins. to a stirred solution of dimethyl oxalate (5.06 g) in dry THF (40 ml) cooled to -15° C. The resulting mixture was stirred at about -15° C. for 30 minutes, then at room temperature for 1 hour, then poured into dilute hydrochlorice acid and extracted with ether. The extracts were washed with water, dried, concentrated under reduced pressure, then chromatographed twice [(i) 30% ether in petrol; (ii) 20% hexane in dichloromethane] to give isomerically pure Z-methyl 2-(2'-phenylethenyl)phenylglyoxalate (1.76 g, 31% yield) as a yellow oil, 1H nmr (CDCl3): delta 3.87 (3H, s), 6.78 centre of 2 doublets, each 1 H, J 12 Hz) p.p.m.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1([C:11](=[O:16])N(OC)C)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Li+].C[Si]([C:23]#[C-:24])(C)C>C1COCC1.[NH4+].[Cl-]>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1([C:11](=[O:16])[C:23]#[CH:24])[CH2:9][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C1(NC(=O)OC(C)(C)C)CC1
Reactant: [C-]#C[Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(=O)C1(NC(=O)OC(C)(C)C)CC1
Reaction time: 2 h
Yield: 12.8 %

Procedure:
To a solution of [1-(Methoxy-methyl-carbamoyl)-cyclopropyl]-carbamic acid tert-butyl ester (5.0 g, 20. mmol) in anhydrous THF (50 mL) at −78° C., was slowly added lithium (trimethylsilyl)acetylide (0.5 M in THF, 81 mL, 41 mmol). The reaction stirred at this temperature for 2 h then an additional amount of lithium (trimethylsilyl)acetylide (0.5 M in THF, 81 mL, 41 mmol) was added and stirring continued for 3 h at −78° C. The reaction was diluted with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The material was purified by flash chromatography (silica, 15% EtOAc/petroleum ether) to give 550 mg of the title compound as a brown syrup, m/z 154.18 [M-t-Bu]+.