Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:33][CH2:32][C:20]2([CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:21]2)[CH2:19][CH2:18]1.[Cl:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[C:39]([O:42][CH3:43])[C:40]=1[OH:41]>>[Cl:34][C:35]1[CH:36]=[C:37]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[N:17]2[CH2:33][CH2:32][C:20]3([CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:21]3)[CH2:19][CH2:18]2)[CH:38]=[C:39]([O:42][CH3:43])[C:40]=1[OH:41]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3c(C(=O)C4CC4)cnc4ccc(Br)cc34)CC2)C1
Reactant: COc1cc(B(O)O)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N4CCC5(CCN(C(=O)OC(C)(C)C)C5)CC4)c3c2)cc(Cl)c1O
Yield: 191.5 %

Procedure:
Following general procedure F, tert-butyl 8-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-yl]-2,8-diazaspiro[4,5]decane-2-carboxylate (50 mg, 0.097 mmol) was reacted with 3-chloro-4-hydroxy-5-methoxyphenylboronic acid (41 mg, 0.161 mmol) to afford the crude product (110 mg) as a brown oil: ESI MS m/z 593 [C33H38ClN3O5+H]+.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([NH:11]N)[C:5]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1)[CH2:2][CH3:3].S(O)(O)(=O)=O.CS[C:35](=[NH:37])[NH2:36]>O>[CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[N:36]=[C:35]([NH2:37])[N:11]=[C:6]2[C:5]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(C)nc(NN)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCc1nc(C)n2nc(N)nc2c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 17.7 %

Procedure:
10 g of 6-n-propyl-2-methyl-4-hydrazino-5-[(2'-cyano-4-biphenylyl)methyl]pyrimidine, prepared in Example 12, and 5 g of 2-methyl-2-thiopseudourea sulphate are heated to reflux for 16 hours. After the addition of water, the crystals formed are drained and washed with ether and then with ethyl acetate before taken up in dilute sodium hydroxide solution and extracted with chloroform. The organic phase is dried over magnesium sulphate and evaporated under vacuum, to give a residue which crystallises in a mixture of isopropyl ether and ethyl acetate to give 1.8 g of 7-n-propyl-5-methyl-2-amino-8-[(2 '-cyano-4-biphenylyl)methyl]-1,2,4-triazolo[1,5-c]pyrimidine in the form of crystals of melting point 150° C.
Reaction SMILES: [CH2:1]([CH:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C(Cl)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19]N1C=CC=CC1=S.C(S)(C)(C)C.O=O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:2]1([CH2:1][CH:8]([OH:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(Cc1ccccc1)Cc1ccccc1
Reactant: On1ccccc1=S
Agent: O=C([O-])[O-]
Agent: O=O
Agent: [K+]
Solvent: c1ccncc1
Solvent: CC(C)(C)S
Solvent: Cc1ccccc1
Product: OC(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
258 mg (1 mmol) of (dibenzyl)acetyl chloride in 1 ml of toluene are added at room temperature to 140 mg (1.1 mmol) of N-hydroxypyridine-2-thione and 0.1 ml of pyridine in 5 ml of toluene. The mixture is maintained with stirring for 30 minutes. The filtered solution is added dropwise during 20 minutes to 1 ml of t-butylmercaptan in 20 ml of toluene at 80° C., and a vigorous stream of oxygen is passed into this solution. The reaction is continued for 1 hour at 80° C., and the reaction mixture is then stirred for 2 hours at room temperature before being poured into 10 ml of a saturated solution of potassium carbonate. The organic phase is again washed twice with potassium carbonate (2×10 ml), then with 10 ml of water, twice with 10 ml of HCl (2N) and finally with twice 10 ml of water before being dried over sodium sulfate, filtered and evaporated to dryness. The crude product obtained is filtered on silica (100% CH2Cl2) to give 174 mg of the corresponding hydroxylated derivative. Yield 82%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[O:9])=[C:4]([Cl:17])[CH:3]=1.Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][N:27]1[C:31](=[O:32])[CH2:30][N:29]([CH3:33])[C:28]1=[O:34].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:17][C:4]1[CH:3]=[C:2]([NH:1][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][CH2:26][N:27]2[C:31](=[O:32])[CH2:30][N:29]([CH3:33])[C:28]2=[O:34])[CH:7]=[CH:6][C:5]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[O:9]
Reactant: Cc1ccccc1C(=O)c1ccc(N)cc1Cl
Reactant: CN1CC(=O)N(CCc2ccccc2Br)C1=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2CCN2C(=O)CN(C)C2=O)cc1Cl
Temperature: 120 °C
Reaction time: 72 h

Procedure:
A mixture of (4-amino-2-chlorophenyl)(2-methylphenyl)methanone (61 mg. 0.25 mmol) (disclosed in WO 01/42189 A1), compound 436 (89 mg, 0.30 mmol), BINAP (5 mg), Pd2(dba)3 (5 mg) and Cs2CO3 (114 mg, 0.35 mmol) in 1,4-dioxane (5 ml) was heated to 120° C. under stirring for 3 days. The reaction mixture was filtered. The obtained solution was concentrated in vacuo. The residue was purified by chromatography (petroleum ether/ethyl acetate 1:1) to provide the desired product, which was not pure. The impure product was further purified by preparative TLC (petroleum ether/ethyl acetate 2:1) to give the pure title compound as brownish oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[CH:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:29])C=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>ClCCl>[CH2:1]([O:8][CH2:9][CH:10]1[O:29][CH:11]1[CH2:12][O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C(=CCOCc1ccccc1)COCc1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(COCC2OC2COCc2ccccc2)cc1
Yield: 67.1 %

Procedure:
To a solution of 6.0 g (0.022 mol) of 1,4-bis-(benzyloxy)-2-butene in 80 ml of dichloromethane was added 5.4 g (0.022 mol) of m-chloroperbenzoic acid (purity: 70%) in four portions under ice-cooling and stirring. The resulting mixture was stirred at the same temperature for 1 hour. After filtering off the white precipitate thus formed, the filtrate was poured into a 10% aqueous solution of sodium hydrosulfite. The mixture was extracted with dichloromethane, washed with water and dried. After distilling off the solvent, the obtained residue was purified by column chromatography (silica gel, hexane/ether) to thereby give 4.2 g of 1,4-bis(benzyloxy)-2,3-epoxybutane as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:3]=1[NH:4][CH:5]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].[C:30](O)(=O)C.C(N)=N>C(OCCO)C>[C:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:11]([CH:5]([N:4]2[C:3]3[CH:23]=[CH:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][C:2]=3[N:1]=[CH:30]2)[CH2:6][C:7]([O:9][CH3:10])=[O:8])=[CH:16][CH:15]=1
Reactant: COC(=O)CC(Nc1ccc([N+](=O)[O-])cc1N)c1ccc(-c2ccccc2)cc1
Reactant: CC(=O)O
Agent: N=CN
Solvent: CCOCCO
Product: COC(=O)CC(c1ccc(-c2ccccc2)cc1)n1cnc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C

Procedure:
To a solution of methyl 3-(2-amino-4-nitroanilino)-3-(1,1′-biphenyl)-4-ylpropanoate (60 mg, 153 μmol) in 2-ethoxyethanol (1 mL) was added formamidine acetate (48 mg, 461 μmol). The solution was heated to reflux for 6 hours, then cooled to room temperature, and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane, to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=6.11 min, MH+ 402].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]([CH3:15])[CH2:13][C:12]3[C:8]4[C:9](=[N:16][CH:17]=[CH:18][C:7]=4[C:6]=2[CH:19]=1)[NH:10][CH:11]=3.[H-].[Na+].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]([CH3:15])[CH2:13][C:12]3[C:8]4[C:9](=[N:16][CH:17]=[CH:18][C:7]=4[C:6]=2[CH:19]=1)[N:10]([S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)(=[O:30])=[O:29])[CH:11]=3
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1Cc2c[nH]c3nccc(c23)-c2cc(F)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc3c4c(ccnc42)-c2cc(F)ccc2N(C)C3)cc1
Reaction time: 0.5 h

Procedure:
To a solution of Example 41B (18.49 g, 73.0 mmol) in N,N-dimethylformamide (146 mL) at room temperature under nitrogen was added sodium hydride (4.38 g, 110 mmol) in portions. The mixture was stirred for 30 minutes and p-toluenesulfonyl chloride (15.31 g, 80 mmol) was added in portions over 10 minutes. The mixture was stirred overnight at room temperature, poured into water and filtered. The solid was washed with heptanes and placed in a vacuum oven overnight at 50° C. The residue was taken up in dichloromethane/methanol and concentrated to give a solid containing ˜10% unreacted starting material. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J=5.3 Hz, 1H), 8.01 (d, J=8.4 Hz, 2H), 7.76 (d, J=10.4 Hz, 1H), 7.71 (s, 1H), 7.61 (d, J=5.5 Hz, 1H), 7.41 (d, J=8.1 Hz, 2H), 7.31-7.25 (m, 2H), 4.10 (s, 2H), 2.89 (s, 3H), 2.33 (s, 3H). MS (ESI+) m/z 408.5 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[O:20])[O:5][C:6]=1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[N:16][O:17][CH3:18])[CH2:11][CH2:10]2.C([Sn](CCCC)(CCCC)[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)CCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:18][O:17][N:16]=[C:12]1[C:13]2[C:9](=[CH:8][C:7]([C:6]3[O:5][C:4]([CH:19]=[O:20])=[CH:3][C:2]=3[C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:15][CH:14]=2)[CH2:10][CH2:11]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: CON=C1CCc2cc(-c3oc(C=O)cc3Br)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CON=C1CCc2cc(-c3oc(C=O)cc3-c3ccncc3)ccc21
Yield: 68.7 %

Procedure:
A degassed mixture of the product of Step 4 (2.0 g, 6.0 mmol) and 4-tributylstannylpyridine (2.5 g, 6.8 mmol) in toluene (100 ml) was treated with triphenylphosphine (156 mg, 0.6 mmol) and palladium acetate (67 mg, 0.3 mmol) then heated under reflux for 60 hours. The reaction mixture was concentrated in vacuo and the product purified by silica gel chromatography eluting with ethyl acetate/hexane (1:1) and then ethyl acetate to give the title compound (1.37 g, 69%); MS(ES+) m/e 333 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([O:21][NH:22][C:23]1[N:28]=[CH:27][N:26]=[C:25]([Cl:29])[C:24]=1[NH:30][CH:31]=O)[CH2:11][CH2:12][P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(OC(OCC)OCC)(=O)C>[Si:1]([O:8][CH2:9][CH:10]([O:21][N:22]1[CH:31]=[N:30][C:24]2[C:23]1=[N:28][CH:27]=[N:26][C:25]=2[Cl:29])[CH2:11][CH2:12][P:13]([O:15][CH2:16][CH3:17])([O:18][CH2:19][CH3:20])=[O:14])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCOP(=O)(CCC(CO[Si](C)(C)C(C)(C)C)ONc1ncnc(Cl)c1NC=O)OCC
Agent: CCOC(OCC)OC(C)=O
Product: CCOP(=O)(CCC(CO[Si](C)(C)C(C)(C)C)On1cnc2c(Cl)ncnc21)OCC
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A solution of 6-[[1-(t-butyldimethylsilyloxymethyl)-3-(diethoxyphosphoryl)propoxy]amino]-4-chloro-5-formamidopyrimidine (0.5 g) in diethoxymethyl acetate (5 ml) was heated at 110° C. for 2 hours. The solvent was evaporated under reduced pressure, the residue dissolved in methanol (5 ml) and 0.880 ammonia (0.1 ml) added. After 30 minutes at ambient temperature, the solvent was evaporated and the residue chromatographed on silica gel using dichloromethane-methanol (98:2) as eluant. This afforded the title compound (0.27 g, 56%) as a yellow oil. IR: υmax (film) 2940, 2870, 1595, 1565, 1440, 1390, 1340, 1250, 1220, 1060, 1030, 970, 930, 840, 790 cm-1. 1H NMR: δH (CDCl3) 0.0 (6H, s, SiMe2), 0.8 (9H, s, SiBut), 1.25 (6H, t, J=7Hz, (OCH2CH3)2), 1.8-2.4 (4H, m, CH2CH2P) 3.8 (2H, d, J=6Hz, CH2OSi), 4.1 (4H, m, (OCH2CH3)2), 4.6 (1H, m, CHON), 8.35 (1H, s), 8.75 (1H, s). Found: C, 45.97; H, 6.89; N, 10.80%. C19H34N4O5PSiCl requires: C, 46.28; H, 6.95; N, 11.36%.
Reaction SMILES: N.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:11][C:12]([C:16]([O:18]CC)=O)=[C:13]([CH3:15])[N:14]=1.COC1C=CC=CC=1C([NH2:27])=O.ClC(C(C)=O)C(OCC)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S>C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:11][C:12]([C:16]([NH2:27])=[O:18])=[C:13]([CH3:15])[N:14]=1
Reactant: CCOC(=O)c1sc(-c2ccccc2OC)nc1C
Reactant: COc1ccccc1C(N)=O
Agent: CCOC(=O)C(Cl)C(C)=O
Agent: N
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CCO
Product: COc1ccccc1-c1nc(C)c(C(N)=O)s1
Yield: 70 %

Procedure:
Into a solvent mixture of 50 ml of aqueous 28% ammonia and 450 ml of ethanol, 13.9 g of ethyl 2-(2-methoxyphenyl)-4-methylthiazole-5-carboxylate which had been prepared by heating a mixture of o-methoxybenzamide, ethyl α-chloroacetoacetate and phosphorus pentasulfide under a reflux condenser for 5 hours was dissolved. Then in a similar manner as in Example 3 the object was obtained as colourless minute aciculate melting at 191° to 192.5° C. in an amount of 8.7 g corresponding to the yield of 70%.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][O:18][C:19]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[N:23]1[CH:22]=[CH:21][C:20]([C:19]2[O:18][CH:17]=[N:16][C:15]=2[C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[CH:25][CH:24]=1
Reactant: c1ccc(COc2ccc(-c3ncoc3-c3ccncc3)cc2)cc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Oc1ccc(-c2ncoc2-c2ccncc2)cc1
Temperature: 60 °C
Yield: 95.9 %

Procedure:
To a solution of 4-(4-(4-(Benzyloxy)phenyl)oxazol-5-yl)pyridine (300 g, 0.91 mmol) was added 20% Pd(OH)2/C (30 mg) and ammonium formate (115 mg, 1.83 mmol) in methanol (8 mL ). The solution was heated at 60° C. for 20 min. The catalyst was removed by filtration and the filtrate was concentrated to give 208 mg (96%) of the title compound. 1H NMR (400 MHz, CDCl3) δ: 6.92 (m, 2H), 7.46 (m, 2H), 7.57 (d, 2H), 8.02 (s, 1H), 8.58 (m, 2H). MS m/z: 239 [M+1]+.
Reaction SMILES: [Cl-].[OH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.C1CCN2C(=NCCC2)CC1.N1C=CC=CC=1.[NH2:24][C:25]1[CH:26]=[C:27]([N:33]2[C:42]3[C:37](=[CH:38][C:39]([F:45])=[C:40](F)[C:41]=3[CH3:43])[C:36](=[O:46])[C:35]([C:47]([OH:49])=[O:48])=[CH:34]2)[C:28]([F:32])=[CH:29][C:30]=1[F:31]>C(OCC)C>[NH2:24][C:25]1[CH:26]=[C:27]([N:33]2[C:42]3[C:37](=[CH:38][C:39]([F:45])=[C:40]([N:5]4[CH2:6][CH:3]([OH:2])[CH2:4]4)[C:41]=3[CH3:43])[C:36](=[O:46])[C:35]([C:47]([OH:49])=[O:48])=[CH:34]2)[C:28]([F:32])=[CH:29][C:30]=1[F:31]
Reactant: OC1CNC1
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1c(N2CC(O)C2)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 40.8 %

Procedure:
70 mg of 3-hydroxyazetidine monochloride, 200 mg of 1,8-diazabicyclo[5.4.0]-7-undecene, and 200 mg of pyridine were stirred at 80° C., and to this mixture was added 150 mg of 1-(3-amino-4,6-difluorophenyl)-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. The mixture was stirred at 90° C. for 10 minutes. Diethylether was added to the reaction solution, and the solution was decanted. 1 ml of ethanol was added to the residue and the solid precipitate was collected by filtration and dried to obtain 70 mg of the title compound.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][OH:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[N:24]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.N#N>O>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][O:22][N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (2S,4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.0 g, 6.0 mmol) in CH2CT2 (15.0 mL) was added 2-hydroxyisoindolin-1,3-dione (978 mg, 6.0 mmol) and triphenylphosphine (2.36 g, 9.0 mmol). The resultant mixture was cooled to 0° C. and diisopropylazodicarboxylate (1.78 ml, 9.0 mmol) was slowly added drop wise under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. To the reaction mixture, H2O (100 mL) was added and extracted with CH2Cl2. The organic layers washed with brine. Dried over anhydrous Na2SO4, filtered and concentrated to provide yellow oil, which was purified by flash chromatography (50% EtOAc-hexane) to yield (2S,4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-((1,3-dioxoisoindolin-2-yloxy)methyl)pyrrolidine-1-carboxylate as light yellow oil.
Reaction SMILES: N=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[NH:8][C:9]([N:11]1C=CN=C1)=[S:10].Cl[CH2:17][C:18]1[N:19]=[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][N:21]2[CH:29]=1>C(O)CC>[N:11]1[C:9]([S:10][CH2:17][C:18]2[N:19]=[C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][N:21]3[CH:29]=2)=[N:8][N:3]2[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=12
Reactant: ClCc1cn2c(n1)-c1ccccc1C2
Reactant: N=c1ccccn1NC(=S)n1ccnc1
Solvent: CCCO
Product: c1ccc2c(c1)Cn1cc(CSc3nc4ccccn4n3)nc1-2
Yield: 62.4 %

Procedure:
An adaptation of the method described in WO 96801826 was used, Imidazole-1-carbothioic acid (2-imino-2H-pyridin-1-yl)-amide (200 mg, 1.37 mmol) and 2-Chloromethyl-5H-imidazo[2,1-a]isoindole (300 mg, 1.46 mmol) were dissolved in 1-propanol (25 mL) and the mixture was heated to reflux for 2 hours. The solvent was removed under reduced pressure and the residue dissolved in dichloromethane. The solution was washed with water and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by chromatography on silica gel to afford the title compound (273 mg, 62%) as a yellow solid. LC-MS: m/z=321.1 (MH+), tR=1.40 min, method B.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O.OS(O)(=O)=O.[CH:22](=O)[CH2:23][CH2:24][CH3:25]>C(O)C>[CH2:23]([CH:22]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]=2[CH2:3][CH:2]([C:13]([OH:15])=[O:14])[NH:1]1)[CH2:24][CH3:25]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CCCC=O
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CCCC1NC(C(=O)O)Cc2c1[nH]c1ccccc21
Yield: 58 %

Procedure:
L-tryptophan (5.10 g, 25 mmol), water (300 ml), H2SO4 (0.5M, 50 ml), n-butyraldehyde (10 ml) and ethanol (100 ml) were added in a 250 ml round-bottom flask, and then stirred and reacted at room temperature for 24 h. After filtration, wash with water and drying, white solids (3.75 g, 58%) were obtained.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH:11]=[N:12][N:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:14]=2)[O:4]1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([N:18]1[CH2:19][CH2:20][CH:15]([N:13]2[CH:14]=[C:10]([B:5]3[O:6][C:7]([CH3:8])([CH3:9])[C:3]([CH3:21])([CH3:2])[O:4]3)[CH:11]=[N:12]2)[CH2:16][CH2:17]1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OB(c2cnn(C3CCNCC3)c2)OC1(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OB(c2cnn(C3CCN(S(C)(=O)=O)CC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine hydrochloride (315 mg, 1.0 mmol) and triethylamine (303 mg, 3.0 mmol) in DCM (15 mL) was added methanesulfonyl chloride (230 mg, 2.0 mmol) dropwise, the mixture was stirred at room temperature for 1 hour. Then the mixture was extracted with EA, wash with brine, dried and purified by flash column chromatography, eluting with EA/MeOH, to give product as light yellow solid. MS (m/z): 356 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2Cl)=O)[NH:5][CH:6]=1.O.[NH2:20][NH2:21]>C1(C)C=CC=CC=1.CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[C:4]([C:7]2[C:9]3[C:10](=[CH:11][CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=3)[NH:21][N:20]=2)[NH:5][CH:6]=1
Reactant: NN
Reactant: O=C(c1cc(Br)c[nH]1)c1cc([N+](=O)[O-])ccc1Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc2[nH]nc(-c3cc(Br)c[nH]3)c2c1
Temperature: 110 °C

Procedure:
A mixture of (4-bromo-1H-pyrrol-2-yl)-(2-chloro-5-nitro-phenyl)-methanone (400 mg) and hydrazine hydrate (0.4 mL) in toluene (6 mL) and 1-methyl-2-pyrrolidinone (1.5 mL) was heated at 110° C. for 1 hour. The reaction was concentrated, the residue was triturated with 10% ethyl acetate in DCM to give 210 mg of the titled compound as an orange solid.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[CH2:1]([CH:4]1[CH2:9][CH2:8][C:7]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: C1CCNC1
Reactant: CCCC1CCC(=O)CC1
Solvent: Cc1ccccc1
Product: CCCC1CC=C(N2CCCC2)CC1
Reaction time: 3 h

Procedure:
212 g of 4-propylcyclohexanone and 200 ml of pyrrolidine was dissolved in 600 ml of toluene, and the mixture was heated with stirring for 3 hours, and any azeotropically distilled water was removed. Excess pyrrolidine was then removed by azeotropic distillation with toluene, to obtain 1-(4-propylcyclohexa-1-en-1-yl)-pyrrolidine. The crude product was cooled, as is, to room temperature, a further 800 ml of toluene was added, the mixture was cooled in a water bath, and 120 ml of methyl vinyl ketone was added dropwise over a period of 1 hour at a temperature of 25° C. or lower. Following completion of the addition, the mixture was immediately heated and refluxed for 20 hours. The solution was then cooled to room temperature, a buffer solution of pH 5 prepared from 63 g of sodium acetate, 120 ml of acetic acid and 140 ml of water was added, and the reflux was continued for a further 4 hours. After the solution had been cooled to room temperature, the organic layer was separated and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was then dried over anhydrous sodium sulfate, and the solvent removed by evaporation to obtain 320 g of a crude product of 6-propyl-4,4a,5,6,7,8-hexahydro-3H-naphthalen-2-one.