Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.OC1C2N=NNC=2C=CC=1.[F:33][C:34]([F:44])([F:43])[C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>CN(C=O)C>[F:33][C:34]([F:43])([F:44])[C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:2]=2[NH2:1])=[CH:37][CH:36]=1
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: Nc1c(O)cccc1C(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
2-amino-3-hydroxybenzoic acid (2 g, 13 mmol) was dissolved in 20 ml of DMF and at 0° C. EDCI (2.7 g, 1.2 equiv.), hydroxybenzotriazole (1.9 g, 1.2 equiv.) and 4-trifluoromethylbenzylamine (2 ml, 1.2 equiv.) were added. The mixture was stirred at rt for 20 hours. The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from EtOAc/ether gave 3.5 g of a beige solid. Yield=86% 1HNMR (DMSO, 200 MHz) δ 4.49 (2H, d, J=5.6 Hz), 6.00 (2H, bs), 6.41 (1H, t, J=8 Hz), 6.76 (1H, d, J=7.6 Hz), 7.11 (1H, d, J=8.2 Hz), 7.51 (2H, d, J=8 Hz), 7.69 (2H, d, J=8 Hz), 8.81 (1H, bt), 9.58 (1H, bs); [M+1] 311.1 (C15H13F3N2O2 requires 310.27).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42](O)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl.C1C=CC=CC=1>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([O:12][C:4]2[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: COC(=O)c1ccc(F)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 60.8 %

Procedure:
A mixture of methyl 4-fluoro-2-hydroxybenzoate (5.1 g, 30 mmol), triphenylphosphine (9.5 g, 36 mmol), 1-tert-butoxycarbonyl-4-hydroxypiperidine (6 g, 30 mmol), and benzene (10 mL) was heated until all solids dissolved. The solution was cooled to 0° C., then sonicated while adding diethyl azodicarboxylate (6.3 g, 36 mmol) dropwise. After the addition was complete, the reaction mixture was sonicated for an additional 60 min, diluted with CH2Cl2 (25 mL), and purified by flash chromatography, eluting with 10% EtOAc in hexanes to yield the title compound (6.45 g, 61%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.Cl[C:6]1[N:11]=[C:10]([NH:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][N:20]=2)[C:16]#[N:17])[CH:9]=[C:8]([CH:21]2[CH2:26][CH2:25][N:24]([CH:27]3[CH2:30][O:29][CH2:28]3)[CH2:23][CH2:22]2)[CH:7]=1>>[N:1]1([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][N:20]=3)[C:16]#[N:17])[CH:9]=[C:8]([CH:21]3[CH2:22][CH2:23][N:24]([CH:27]4[CH2:30][O:29][CH2:28]4)[CH2:25][CH2:26]3)[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: N#Cc1ccnc(Nc2cc(C3CCN(C4COC4)CC3)cc(Cl)n2)c1
Product: N#Cc1ccnc(Nc2cc(C3CCN(C4COC4)CC3)cc(N3CCC3)n2)c1
Yield: 47 %

Procedure:
Reaction of azetidine with 2-((6-chloro-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-2-yl)amino)isonicotinonitrile (40 mg, 0.11 mmol) following general Buchwald-Hartwig procedure described above afforded the target compound as a colorless solid (19.8 mg, 47%); 1H NMR (400 MHz, DMSO) δ 9.76 (br s, 1H), 8.51 (s, 1H), 8.40 (d, J=5.1 Hz, 1H), 7.18 (d, J=5.1 Hz, 1H), 6.59 (s, 1H), 5.80 (s, 1H), 4.57-4.49 (m, 2H), 4.49-4.40 (m, 2H), 4.00-3.92 (m, 4H), 3.43-3.35 (m, 1H), 2.82-2.73 (m, 2H), 2.40-2.27 (m, 3H), 1.88-1.78 (m, 2H), 1.77-1.68 (m, 2H), 1.68-1.51 (m, 2H); ESI-LRMS m/z [M+1]+=391.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH2:16]([OH:22])[C:17]#[C:18][CH2:19][CH2:20][CH3:21].[H-].[Na+].O>CN(C)C=O>[F:15][C:9]1[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:22][CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH3:21])[N:3]=[CH:4][N:5]=1
Reactant: CCCC#CCO
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC#CCOc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 89.5 %

Procedure:
In 9 ml of N,N-dimethylformamide were dissolved 217 mg of 4-chloro-6-(2,3-difluorophenyl)pyrimidine and 141 mg of 2-hexyn-1-ol, to which 58 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 7 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 247 mg of 4-(2,3-difluorophenyl)-6-(2-hexynyloxy)pyrimidine (the present compound (118)).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([C:19]([OH:21])=O)[N:15]4[CH3:18])=[C:11]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:10]=3)[C:7]3[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[I-].ClC1C=CC=C[N+]=1C.CCN(C(C)C)C(C)C.[NH:50]1[CH2:53][CH:52]([N:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)[CH2:51]1>CN(C=O)C>[CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([C:19]([N:50]5[CH2:53][CH:52]([N:54]6[CH2:59][CH2:58][O:57][CH2:56][CH2:55]6)[CH2:51]5)=[O:21])[N:15]4[CH3:18])=[C:11]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:10]=3)[C:7]3[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: C1CN(C2CNC2)CCO1
Reactant: Cn1c(C(=O)O)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(C(=O)N2CC(N3CCOCC3)C2)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Reaction time: 18 h
Yield: 44.8 %

Procedure:
To a mixture of 2-(2-cyclopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carboxylic acid (500 mg, 1.19 mmol), 2-chloro-1-methylpyridinium iodide (729 mg, 2.86 mmol) and DIPEA (500 μL, 2.87 mmol) in DMF (10 mL) was added 4-azetidin-3-ylmorpholine (288 mg, 2.0 mmol) and the resulting mixture allowed to stir at r.t for 18 h. The reaction mixture was concentrated in vacuo and the resulting residue dissolved in EtOAc which was washed with H2O and brine, then dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-5%) affording 799 as a cream solid (290 mg, 45%). LCMS (method G): RT 5.90 min, [M+H]+ 544.5. 1H NMR (CDCl3, 400 MHz): δ 7.99-7.99 (1 H, m), 7.67-7.67 (1 H, m), 7.28-7.20 (2 H, m), 4.73-4.72 (1 H, m), 4.70-4.00 (4 H, brd s), 4.53-4.51 (1 H, m), 4.29-4.21 (1 H, m), 4.18-4.08 (4 H, m), 3.87 (4 H, t, J=4.67 Hz), 3.78 (4 H, t, J=4.60 Hz), 3.30-3.30 (1 H, m), 2.88-2.88 (1 H, m), 2.47-2.45 (4 H, m), 1.35-1.34 (2 H, m), 1.06-1.05 (2 H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[NH:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1.C([BH3-])#N.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH:23]([N:49]5[CH2:53][CH2:52][CH2:51][CH2:50]5)[CH2:22][CH2:21]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OC1CCN(c2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1
Reactant: C1CCNC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Product: Fc1ccc(Nc2ncnc3cnc(N4CCC(N5CCCC5)CC4)nc23)cc1Cl

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-[4-hydroxy-1-piperidinyl]pyrimido[5,4-d]pyrimidine by oxidation with Dess-Martin reagent and subsequent reductive amination with pyrrolidine and sodium cyanoborohydride. Melting point: 202°-204° C.; Rf : 0.58 (alumina; petroleum ether/ethyl acetate/methanol=10:10:1)
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:11]=[CH:12][C:13]2[N:14]([CH:25]=[N:26][CH:27]=2)[C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24])=[O:9])=C.Cl.O1CCOCC1>CO.ClCCl>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:11]=[CH:12][C:13]2[N:14]([CH:25]=[N:26][CH:27]=2)[C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24])=[O:9]
Reactant: C=COCCONC(=O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(NOCCO)c1ncc2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To a solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid (2-vinyloxy-ethoxy)-amide (24.0 mg, 0.05 mmol) in methanol (0.5 mL) and dichloromethane (1.0 mL) was added 4M HCl in 1,4-dioxane (30 μL, 0.1 mmol, 2.5 eq.), and the reaction was stirred at ambient temperature under N2 for 2 h. The reaction mixture was concentrated in vacuo then poured into ethyl acetate. The organic layer was washed with a saturated solution of sodium bicarbonate, water, and brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 25%, methanol in dichloromethane) to afford the title compound as yellow solid (11.6 mg, 51%). 1H NMR (MeOD, 400 MHz) δ ppm 8.74 (s, 1H), 7.87 (s, 1H), 7.84 (s, 1H), 7.62 (dd, J=10.20, 1.82 Hz, 1H), 7.48 (d, J=8.41 Hz, 1H), 6.61 (t, J=8.53 Hz, 1H), 4.05 (t, J=4.80 Hz, 2H), 3.78 (t, J=4.80 Hz, 2H)); LCMS (method E1): RT=4.33 min, [M+H]+=458.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:12][C@H:11]2[C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>O=[Pt]=O.CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[CH2:12][C@H:11]2[C:13]([OH:15])=[O:14])=[CH:8][CH:9]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Reaction time: 1 h
Yield: 101.8 %

Procedure:
A Fischer-Porter bottle containing racemic-(trans)-2-(4-nitrophenyl)cyclopropanecarboxylic acid (V-2) (4.60 g, 22.22 mmol), PtO2 (0.16 g, 0.70 mmol), ethyl acetate (70 mL) and MeOH (50 mL) was purged with N2 (3x's) then charged with 40 psig H2 at RT. After 1 h, the bottle was carefully vented and the suspension was filtered through Celite. The solution was concentrated to give the title compound as a white powder (4.01 g, ˜100%). 1H NMR (400 MHz, DMSO) δ 6.79 (d, J=8.6 Hz, 2H), 6.47 (d, J=8.6, 2H), 5.02 (bs, 2H), 2.21-2.16 (m, 1H), 1.61-1.56 (m, 1H), 1.31-1.28 (m, 1H), 1.19-1.14 (m, 1H). ES-MS m/z 176.3 (MH−).
Reaction SMILES: [NH:1]1[CH:5]([C:6]([OH:8])=O)[CH2:4][CH2:3][C:2]1=[O:9].[CH3:10][N:11]([CH2:13][CH2:14][CH2:15][NH2:16])[CH3:12]>>[CH3:10][N:11]([CH3:12])[CH2:13][CH2:14][CH2:15][NH:16][C:6]([CH:5]1[CH2:4][CH2:3][C:2](=[O:9])[NH:1]1)=[O:8]
Reactant: O=C1CCC(C(=O)O)N1
Reactant: CN(C)CCCN
Product: CN(C)CCCNC(=O)C1CCC(=O)N1
Temperature: 165 °C

Procedure:
129 Grams of 2-pyrrolidone-5-carboxylic acid were slowly added to 133 g of dimethylaminopropylamine with mixing. This mixture was then stirred and heated for 8-10 hours at 165° C. The excess amine was then distilled off having the title product in the form of an amber colored water-soluble solid.
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:4]=1[CH2:21][C:22]1[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=1[O:30][CH3:31].[CH2:32]([OH:35])[CH2:33][OH:34]>>[CH3:31][O:30][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([O:28][CH3:29])[C:22]=1[CH2:21][C:4]1[C:5]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[N:6][CH:7]=[N:8][C:3]=1[O:34][CH2:33][CH2:32][OH:35]
Reactant: OCCO
Reactant: C=Cc1ccc(S(=O)(=O)Nc2ncnc(Cl)c2Cc2c(OC)cccc2OC)cc1
Agent: [Na]
Product: C=Cc1ccc(S(=O)(=O)Nc2ncnc(OCCO)c2Cc2c(OC)cccc2OC)cc1
Temperature: 150 °C

Procedure:
60 mg of sodium were added to 2 ml of ethylene glycol at 70° C. Thereafter, 223 mg of N-[6-chloro-5-(2,6-dimethoxybenzyl)-4-pyrimidinyl]-p-vinyl-benzenesulfonamide were added and the reaction mixture was heated at 150° C. for 4.5 hours. The ethylene glycol was distilled under reduced pressure, the residue was taken up in EtOAc/H2O and extracted once with ethyl acetate. Thereafter, the aqueous phase was acidified with 1N HCl and extracted four times with ethyl acetate. The organic phase was dried, filtered and concentrated under reduced pressure. The residue was chromatographed over 50 g of SiO2 with methylene chloride/ethyl acetate 1:1. There were obtained 50 mg of N-[5-(2,6-dimethoxybenzyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-p-vinylbenzenesulfonamide, melting point 138°-139° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH3:21])[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[O:15]1.[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1.CCCCCC.ClCCl.C(N(CC)CC)C.CN(C)P(N(C)C)(N(C)C)=O>[CH3:13][C:14]1([CH3:21])[C:18](=[O:19])[CH:17]=[C:16](/[CH:20]=[CH:27]/[C:26]2[CH:29]=[CH:30][C:23]([Br:22])=[CH:24][CH:25]=2)[O:15]1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC1=CC(=O)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OC(/C=C/c2ccc(Br)cc2)=CC1=O
Reaction time: 0.25 h
Yield: 38.7 %

Procedure:
To a solution of dry diisopropylamine (3.3 mL, 24 mM) in dry tetrahydrofuran (25 mL) at -78° C., was added dropwise a 2.3N solution of n-butyllithium in hexane (10.4 mL, 24 mM). After the reaction solution was stirred for 15 minutes, a solution of 2,2,5-trimethyl-3(2H)-furanone (2.0 g, 16 mM) in tetrahydrofuran (10 mL) was added dropwise. Hexamethylphosphoramide (4.4 mL, 24 mM) was then added dropwise for 30 minutes. Finally, p-bromobenzaldehyde (3.6 g, 19.2 mM) in tetrahydrofuran (10 mL) was added in one portion. The reaction solution was stirred 10 minutes when trifluoroacetic anhydride (5.6 mL, 40 mM) was added in one portion. Again, the reaction solution was stirred for 15 minutes when triethylamine (5.9 mL, 47.6 mM) was added and was allowed to room temperature. The reaction mixture was then partitioned between saturated aqueous sodium chloride (50 mL) and diethyl ether (50 mL). The layers were separated. The organic layers were then washed with saturated aqueous sodium chloride (2×25 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give dark liquid. After the crude product was dissolved in dichloromethane (100 mL), trifluoroacetic anhydride (5.6 mL, 40 mM) was added. After thirty minutes, triethylamine (2.75 mL, 20 mM) was added. The resulting mixture was stirred for one hour, washed with 1N aqueous hydrochloric acid, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford an amber oil. The crude oil was purified by chromatography (silica gel, petroleum ether-ethyl acetate) to give yellow-brown crystals (1.8 g, 39%). Recrystallization from hexane gave an analytically pure product, m.p. 109°-110° C.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:8]=2[CH2:7][CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[OH:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:14][C:13]1[C:8]2[CH2:7][CH2:6][C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[C:3](=[CH:2][C:23]3[CH:24]=[CH:25][C:20]([OH:19])=[CH:21][CH:22]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: Clc1cccc2c1CCc1ccccc1C2=CBr
Reactant: OB(O)c1ccc(O)cc1
Product: Oc1ccc(C=C2c3ccccc3CCc3c(Cl)cccc32)cc1

Procedure:
Following procedures essentially as described in Example 219, below, and using 5-bromomethylene-1-chloro-10,11dihydro-5H-dibenzo[a,d]cycloheptene (100 mg, 0.313 mmol) and 4-hydroxyphenylboronic acid (47 mg, 0.344 mmol), affords 84 mg (81%) of a mixture of geometric isomers of the title compound as a brown oil. MS (ES) 331 (M−H); HPLC shows 97% purity.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)([F:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20]([O:22]CCCC)=[CH2:21].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(O)=O.[Na+]>C(O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=2)([F:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(Br)cc2)C1
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CCO
Product: CC(=O)c1ccc(C2(F)CN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 96 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
In 100 mL autoclave vessel, a solution of 3-(4-bromo-phenyl)-3-fluoro-azetidine-1-carboxylic acid tert-butyl ester (Intermediate from Step 5a; 5 g, 15.142 mmol, 1 eq) in ethanol (17.5 mL) was degassed with nitrogen gas for 30 minutes at room temperature. TEA (3.79 mL, 27.256 mmol, 1.8 eq), butyl vinyl ether (BVE, 3.91 mL, 30.282 mmol, 2 eq), 1,3-bis(diphenylphosphino)propane (DPPP, 0.375 g, 0.909 mmol, 0.06 eq) were added followed by addition of Pd(OAc)2 (0.102 g, 0.454 mmol, 0.03 eq.) at room temperature. Resulting reaction mixture was heated at 96° C. for 16 hours in an autoclave. After complete consumption of starting material, the reaction mixture was quenched with 1N HCl (5 mL, pH˜2-3) and stirred for 2 hours at room temperature. After 2 hours, the pH of reaction mixture was adjusted to 7 by addition of saturated NaHCO3 solution and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (250 mL), dried over sodium sulphate and concentrated under reduced pressure to get crude compound as dark brown sticky oil (6.1 g, Crude). Crude compound was purified by column chromatography on silica gel using 230-400 silica mesh. Desired compound was eluted in 10% ethyl acetate in n-hexane to give product as off white semisolid (2.56 g, 57.66%). 1H NMR (400 MHz, CDCl3) δ: 1.46 (s, 9H), 2.61 (s, 3H), 4.20 (dd, J1=0.88 Hz, J2=10.28 Hz, 1H), 4.24 (dd, J1=0.92 Hz, J2=10.36 Hz, 1H), 4.39 (dd, J1=1.28 Hz, J2=10.24 Hz, 1H), 4.44 (dd, J1=1.28 Hz, J2=10.20 Hz, 1H), 7.55 (dd, J1=1.48 Hz, J2=8.48 Hz, 2H), 8.00 (d, J=7.96 Hz, 2H), LC-MS (m/z): 294.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:12]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].S(OOS([O-])(=O)=O)([O-])(=O)=[O:19].[K+].[K+]>FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[OH:19][C:9]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([CH3:1])[C:12]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1cccc(OS(C)(=O)=O)c1C
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: Cl[Ru]Cl
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccc(C(C)C)cc1
Product: CCOC(=O)c1c(O)ccc(OS(C)(=O)=O)c1C
Temperature: 90 °C
Reaction time: 22 h
Yield: 39.5 %

Procedure:
To a solution of ethyl 2-methyl-3-[(methylsulfonyl)oxy]benzoate (116b, 3.0 g, 12 mmol) in trifluoroacetic acid (35 mL) and trifluoroacetic anhydride (15 mL) was added potassium persulfate (3.5 g, 13 mmol) and dichloro(p-cymene)ruthenium(II) dimer (0.36 g, 0.59 mmol). The resulting mixture was stirred at 90° C. in a sealed tube for 22 hours. The reaction mixture was concentrated under vacuum then diluted with water (50 mL) and extracted with dichloromethane (2×75 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, concentrated under vacuum, and purified by column chromatography (40% EtOAc/Heptane) to give ethyl 6-hydroxy-2-methyl-3-[(methylsulfonyl)oxy]benzoate (116c, 1.3 g, 41% yield) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][CH3:6].Cl[CH2:8][CH2:9][CH2:10][OH:11].[OH-].[Na+]>>[OH:11][CH2:10][CH2:9][CH2:8][N:5]([CH3:6])[CH2:4][CH2:3][CH2:2][OH:1]
Reactant: CNCCCO
Reactant: OCCCCl
Agent: [Na+]
Agent: [OH-]
Product: CN(CCCO)CCCO
Temperature: 25 °C

Procedure:
To this aqueous N-(3-hydroxypropyl)methylamine solution is added a second 249.5 g portion of 3-chloro-1-propanol, and the resulting mixture is heated under reflux at a temperature of approximately 105° C. for a period of about 5 hours, during which time about 195 grams of a 50% aqueous sodium hydroxide solution is added slowly at a rate sufficient to maintain the pH between about 8 and 9. The reaction mixture is cooled to room temperature, filtered, and the filtered aqueous solution is extracted with three 500 ml-portions of n-butanol. The butanol extracts are combined, evaporated to a small volume in vacuo, and the residual slurry is triturated with 300 ml of ethyl ether. The resulting ethereal slurry is filtered, thereby removing insoluble inorganic solid material, and the latter is washed with 100 ml of ethyl ether. The ether solution and washings are combined, the ether is evaporated therefrom in vacuo, and the residual oil is distilled in vacuo to give about 123 grams of N,N-bis(3-hydroxypropyl)methylamine; b.p. 110° C. at 150 microns pressure.
Reaction SMILES: [CH2:1]([O:3][C:4](OCC)([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[CH2:5][CH3:6])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH3:6])=[CH:8][CH:9]=1
Reactant: CCOC(CC)(OCC)c1ccc(OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CC=C(OCC)c1ccc(OC)cc1
Temperature: 140 °C
Yield: 74.6 %

Procedure:
103.3 g of p-methoxy-propiophenone diethyl ketal are treated with 1.1 g of p-toluenesulphonic acid and heated in a distillation apparatus to 140° C. (oil bath temperature). In so doing, the ethanol formed is distilled off continuously at atmospheric pressure. 20 g of ethanol are distilled off within 31/2 hours. Subsequently, the mixture remaining is distilled in a high vacuum over a 15 cm column. There are obtained 62.2 g of 1-(p-methoxyphenyl)-1-ethoxy-1-propene (yield: 74.8% of theory). B.p.=78°-79° C. 0.3 mmHg; nD20 =1.5315: d420 =1.0175.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][NH2:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl-].[CH:28]1([S:31](C2CC2)(=[O:33])=[O:32])[CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:19][NH:20][S:31]([CH:28]4[CH2:30][CH2:29]4)(=[O:33])=[O:32])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: NC[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: O=S(=O)(C1CC1)C1CC1
Agent: [Cl-]
Product: O=S(=O)(NC[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1)C1CC1

Procedure:
Prepared according to the procedure described for Example 1 from (1R)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-ethan-2-amine (40a, 31 mg, 0.09 mmol) cyclopropylsulphone chloride (28 μl, 0.27 mmol). Yield: 10 mg (25%).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][NH2:15]>C1COCC1>[CH3:14][NH:15][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CN
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]

Procedure:
4-Methylamino-3-nitro-benzoic acid (25 g) was prepared by following general procedure A starting from 4-fluoro-3-nitro-benzoic acid (25 g) and 2 M methylamine in THF (100 mL).