Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].[F-].[Cs+].C[Si](C)(C)[C:15]1SC=[N:17][CH:16]=1>C1COCC1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]([C:3]2[CH:10]=[CH:9][C:15]([C:16]#[N:17])=[CH:5][CH:4]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: C[Si](C)(C)c1cncs1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1ccc(C(=O)c2ccc(C#N)cc2)cc1

Procedure:
15.7 g of 4-cyanobenzaldehyde and 9.1 g of caesium fluoride are added to a solution of 9.4 g of 5-trimethylsilylthiazole in 0.56 l of THF, and the mixture is heated under reflux for 16 hours. The solid material is filtered off and the solvent is concentrated. Column chromatography (SiO2, hexane/ethyl acetate 1:2) yields first (a) 5-(4-cyanobenzoyl)-thiazole [Rf hexane/ethyl acetate 1:2)=0.65], m.p. (after crystallisation from ethyl acetate) 181°-182°; 1H-NMR (CDCl3): δ (ppm)=8.88 and 8 (m,4H), 8.36 (s,1H), 9.14 (s,1H), and then (b)4-(α-hydroxy-5-thiazolylmethyl)-benzonitrile [Rf (hexane/ethyl acetate 1:2)=0.35], m.p. (after crystallisation from toluene) 115°-117°; 1H-NMR (CDCl3): δ (ppm)=3.05 (d,1H), 6.2 (d,1H), 7.58 and 7.7 (m,4H), 7.73 (s,1H), 8.78 (s,1H).
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([C:7]([N:9]2[CH2:21][CH2:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][C:11]=3[CH2:10]2)=[O:8])=[CH:5][CH:4]=1)#[N:2].CC(C)([O-])C.[K+].[C:30]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br)#[N:31].C(O)(=O)C>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[CH2:21][CH2:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:35][C:34]4[CH:37]=[CH:38][CH:39]=[C:32]([C:30]#[N:31])[CH:33]=4)[C:11]=3[CH2:10]2)=[O:8])=[CH:22][CH:23]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)N2CCc3c([nH]c4ccccc34)C2)cc1
Reactant: N#Cc1cccc(CBr)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: N#Cc1ccc(C(=O)N2CCc3c(n(Cc4cccc(C#N)c4)c4ccccc34)C2)cc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 63.4 %

Procedure:
150 mg (0.5 mmol) of 2-(4-cyano-benzoyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole were dissolved in 5 ml of dimethylformamide. 60 mg of potassium tert-butoxide were added and the mixture was stirred for 5 minutes, treated with 100 mg of 3-cyano-benzyl bromide and slowly heated up to 80° C. The mixture was acidified by addition of acetic acid and evaporated under reduced pressure. The residue was partitioned between methylene chloride and 10% aqueous sodium carbonate solution, dried and evaporated. Chromatography of the residue over 12 g of silica gel using 10% (v/v) of ethyl acetate in methylene chloride and crystallization from ethyl acetate/hexane yielded 132 mg of 2-(4-cyano-benzoyl)-9-(3-cyano-benzyl) -1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole with m.p. 178-180° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:21][CH:20]=3)[C:16]([C:17]#[N:18])=[C:12]2[NH:11][CH2:10][CH2:9]1.ClCCC(NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C(N)=O)=C3NCC2)C=CC=1)=[O:37]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:21][CH:20]=3)[C:16]([C:17]([NH2:18])=[O:37])=[C:12]2[NH:11][CH2:10][CH2:9]1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Reactant: N#Cc1c(-c2ccc(OCc3ccccc3)cc2)nn2c1NCCC2c1ccccc1N
Product: NC(=O)c1c(-c2ccc(OCc3ccccc3)cc2)nn2c1NCCC2c1ccccc1N

Procedure:
The desired product was prepared from 7-(2-aminophenyl)-2-(4-(benzyloxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile using the procedure similar to step 2 for compound 2. 1H NMR (400 MHz, DMSO-d6) δ 7.47-7.33 (m, 7H), 7.06 (d, J=8.4 Hz, 2H), 6.96 (t, J=7.6 Hz, 1H), 6.75 (br s, 1H), 6.68 (d, J=7.6 Hz, 1H), 6.50 (t, J=7.6 Hz, 1H), 6.28 (d, J=7.6 Hz, 1H), 5.59-5.54 (m, 1H), 5.19 (br s, 2H), 5.12 (s, 2H), 3.30-3.20 (m, 1H), 3.02-2.92 (m, 1H), 2.25-2.14 (m, 1H) and 2.13-2.03 (m, 1H). MS (ESI) m/e [M+1]+ 439.9.
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11](=[O:30])[CH:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C>C(Cl)Cl>[CH:4]1([S:7]([NH:10][C:11](=[O:30])[CH:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])(=[O:9])=[O:8])[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1
Reactant: CCN(CC)C(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)NS(=O)(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 141.3 %

Procedure:
To a suspension of the compound (1.37 g) obtained in Example 188 (2) in methylene chloride (50 mL) were added oxalyl chloride (800 μL) and DMF in catalytic amount under ice-cooling, and the mixture was stirred at room temperature for 1.5 hr. After concentration under reduced pressure, methylene chloride (8 mL) was added to the residue. Under ice-cooling, the solution was added dropwise to a mixture of the above-mentioned compound (760 mg) in THF (50 mL) and 4-dimethylaminopyridine (1.71 g). After stirring at room temperature for 17 hr, dilute hydrochloric acid (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL×2). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give the title compound (1.67 g) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1.Cl.[OH-].[Na+]>C(O)C>[F:27][C:24]([F:25])([F:26])[C:20]1[CH:19]=[C:18]2[C:23]([C:14]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([N:2]([CH3:12])[CH3:1])=[O:11])=[CH:5][CH:6]=3)=[CH:15][CH:16]=[N:17]2)=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: CN(C)C(=O)c1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)C(=O)c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1

Procedure:
A mixture of 0.1 mole of N,N-dimethyl-p-aminobenzamide, 0.1 mole of 4-chloro-7-trifluoromethylquinoline, 8 ml. of concentrated hydrochloric acid and 500 ml. of absolute ethanol is heated at reflux for 19 hours, after which 100 ml. of 2.5N sodium hydroxide is added. The mixture is cooled and filtered and the filter cake is recrystallized from methanol. There is thus obtained p-[(7-trifluoromethyl-4-quinolyl)amino]-N,N-dimethylbenzamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]1[CH2:31][C@@H:30]([NH2:32])[C@H:29]([NH2:33])[CH2:28][CH2:27]1.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:32][CH:30]1[CH2:31][CH2:26][CH2:27][CH2:28][CH:29]1[NH2:33])=[O:20]
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: NC1CCCCC1NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.4 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), (-)-R,R-1,2-diaminocyclohexane (0.314 g, 2.75 mmol), triethylamine (0.306 g, 3.06 mmol) and benzene (30 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-aminocyclohexyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.110 g, 8.4% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[O:22]1[CH2:23][CH2:24][N:19]([CH2:2][CH2:3][O:4][C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:20][CH2:21]1
Reactant: C1COCCN1
Reactant: ClCCOc1ccccc1C=Cc1ccccn1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: C(=Cc1ccccc1OCCN1CCOCC1)c1ccccn1

Procedure:
2-[o-(β-Morpholino-ethoxy)-styryl]-pyridine was prepared from 2-[o-(β-chloro-ethoxy)-styryl]-pyridine (m.p. 57°-58° C.) and morpholine, and the free base was converted into its dihydrochloride, yielding 53% of theory of the compound of the formula ##STR10## which had a melting point of 248° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:34])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C2(CC(c3cccc(F)c3)Oc3ccc(Br)cc32)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CC(c1cccc(F)c1)Oc1ccc(Br)cc12
Yield: 11.2 %

Procedure:
A suspension of 6-bromo-2-(3-fluorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (300 mg, 0.77 mmol) and Lawesson's reagent (312 mg, 0.77 mmol) in dry 1,4-dioxane (10 mL) was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(3-fluorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidine]-5′-one (35 mg, 17%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[NH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:29][CH:30](Cl)[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:15][CH2:37][C:34]2[CH:35]=[CH:36][C:31]([CH2:30][Cl:29])=[CH:32][CH:33]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N=C(Nc1ccccc1-c1ccccc1)Nc1ccccc1-c1ccccc1
Reactant: Cc1ccc(C(Cl)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: ClCc1ccc(CN=C(Nc2ccccc2-c2ccccc2)Nc2ccccc2-c2ccccc2)cc1
Yield: 20.6 %

Procedure:
10.9 g (0.03 mole) of N,N'-bis-(2-phenylphenyl) guanidine, 5.7 g (0.033 mole) of α,α-dichloro-p-xylene and 2.1 g (0.015 mole) of anhydrous potassium carbonate were added to 50 ml of toluene. The thus-formed mixture was then refluxed under heating for 10 hours. After the mixture had been allowed to cool, the insoluble substance was removed by filtration. The thus-obtained filtrate was washed with water and then concentrated for the purpose of recovering the solvent and unreacted raw materials to obtain a slightly brown powder. The power was then recrystallized from acetone to obtain 3.1 g of white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[CH2:10][C@H:9]2[CH3:22])=[C:4]2[N:23]=[CH:24][CH:25]=[CH:26][C:3]=12.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][C@H:9]1[N:8]([C:5]2[N:6]=[N:7][C:2]([C:32]3[CH:33]=[CH:34][C:29]([C:28]([F:39])([F:38])[F:27])=[CH:30][CH:31]=3)=[C:3]3[CH:26]=[CH:25][CH:24]=[N:23][C:4]=23)[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10]1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(Cl)c2cccnc12
Reactant: OB(O)c1ccc(C(F)(F)F)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+]
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccc(C(F)(F)F)cc2)c2cccnc12

Procedure:
Using methods described in Example 6, and starting with (R)-(4-(5-chloropyrido[2,3-d]pyridazin-8-yl)-3-methylpiperazin-1-yl)(phenyl)methanone 79 (180 mg, 489 μmol), tetrakis(triphenylphosphine)palladium (283 mg, 245 μmol), 4-trifluoromethylphenylboronic acid (139 mg, 734 μmol), and 2 M sodium carbonate (489 μl, 979 μmol) afforded (R)-(3-methyl-4-(5-(4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)piperazin-1-yl)(phenyl)methanone 84 after chromatographic purification. MS 477.2 (calc'd) 478.1 (M+H, found).
Reaction SMILES: [CH2:1](O)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.O=S(Cl)[Cl:14]>C1C=CC=CC=1>[Cl:14][CH2:1][C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: ClCc1ccc2c(c1)OCO2

Procedure:
Piperonyl alcohol (45.64 g, 300 mmol) was dissolved in 340 ml of dry benzene, and SOCl2 (37 ml) was added dropwise with stirring. The solution was refluxed for 1 h, cooled and evaporated on the rotary evaporator (bath temperature less than 50° C.!). The resulting dark green residue was used without further purification.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([CH2:25][O:26][C:27](=[O:43])[C@H:28]([CH:40]([CH3:42])[CH3:41])[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:21][C:22]([OH:24])=[O:23])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:62][CH2:63]I>O1CCOCC1>[Cl:62][CH2:63][O:23][C:22](=[O:24])[CH2:21][CH:20]([CH2:25][O:26][C:27](=[O:43])[C@H:28]([CH:40]([CH3:42])[CH3:41])[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:19][O:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: ClCI
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)OCCl

Procedure:
3,3-bis(N-CBz-L-valyloxymethyl)-propionic acid (3 g, 5 mmole) was dissolved in dioxane (20 ml). To the solution was added tetrabutylammonium hydroxide aqueous solution (40%, 3.11 ml, 4.8 mmole). The solution was dried in vacuo, and it was coevaporated with toluene several times. The residue was dissolved in methylene chloride (15 ml) and then chloroiodomethane (7.3 ml, 100 mmole) was added to the solution. The reaction solution was refluxed for 18 hr and then evaporated and the product was isolated with silica gel column chromatography. 900 mg.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:23][CH:22]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O)C1C=CC=CC=1.Cl.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:11][C@@H:12]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:25][CH:26]=1)[C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14]
Reactant: [H][H]
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)CCCOc1ccc(C[C@H](N)C(=O)OC(C)(C)C)cc1
Yield: 99.5 %

Procedure:
100 g (0.206 mol) of tert-butyl (2S)-2-benzyloxycarbonylamino-3-(4-(3-ethoxycarbonylpropyloxy)phenyl)propionate (1.1) from Example 1 were dissolved in 1 liter of methanol, the solution was treated with methanolic hydrogen chloride solution and with 10 g of 20% palladium hydroxide/carbon and hydrogen was passed in for 6 hours. Then the catalyst was filtered off, the solution was evaporated and the residue was treated with tert-butylether. The precipitate formed was filtered off. 72 g (90%) of an amorphous powder were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][C:11]2[C:16]([SH:17])=[N:15][CH:14]=[N:13][C:12]=2[N:18]=1.[CH2:19](N(CC)CC)C.CI>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][C:11]2[C:16]([S:17][CH3:19])=[N:15][CH:14]=[N:13][C:12]=2[N:18]=1
Reactant: CCN(CC)CC
Reactant: Sc1ncnc2nc(-c3c(Cl)cccc3Cl)sc12
Solvent: CI
Solvent: CCO
Product: CSc1ncnc2nc(-c3c(Cl)cccc3Cl)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
To a solution of 2-(2,6-dichlorophenyl)thiazolo[4,5-d]pyrimidine-7-thiol (1.29 g, 4.1 mmol) and triethylamine (1.66 g, 16.4 mmol) in ethanol (20 mL) was added methyl iodide (2.32 g, 16.4 mmol). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0-20% EtOAc/hexane gradient to give the desired compound as a white solid (0.59 g, 44% yield). 1H NMR (500 MHz, CDCl3) δ 9.12 (s, 1H), 7.49-7.47 (M, 2H), 7.45-7.40 (m, 1H), 2.81 (s, 3H). LCMS (ESI) m/z: 328.9 [M+H+].
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12]1.O.C(=O)(O)[O-].[Na+]>ClCCl>[F:7][C@H:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12]1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)N1CC[C@H](F)C1
Temperature: -78 °C

Procedure:
A 5-L, 3-neck, round bottom flask equipped with mechanical stirrer, thermocouple, addition funnel and nitrogen bubbler was charged with 375 mL (2.84 mol) of (diethylamino)sulfur trifluoride and 400 mL of dichloromethane. The solution was cooled to −78° C. To this was added via addition funnel a solution of 304 g (1.37 mol) of benzyl (3R)-3-hydroxypyrrolidine-1-carboxylate in 400 mL of dichloromethane over a 2-h period keeping the reaction temperature below −70° C. The reaction mixture was allowed to stir and warm slowly to ambient temperature overnight. The reaction mixture was added portion-wise with caution to a large extractor containing ice, water, and saturated aqueous sodium bicarbonate solution. The mixture was extracted with 8 L of ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give a brown oil. Purification by flash chromatography (silica gel, eluting with a 10 to 30% ethyl acetate/hexane gradient) gave the title compound as a brown oil.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH3:19])[C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH:19]=[CH:27][C:26]3[CH:29]=[CH:30][C:23]([F:22])=[CH:24][CH:25]=3)[C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1
Reactant: C#CCOc1ccc2c(C)cc(=O)oc2c1C(C)=O
Reactant: O=Cc1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C#CCOc1ccc2c(C)cc(=O)oc2c1C(=O)C=Cc1ccc(F)cc1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-prop2-ynyloxy-8-acetylcoumarin (1.92 g, 0.0075 mol) and 4-fluorobenzaldehyde (0.93 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by ethanol to give 1.2 g of product m.p. 185-186° C., 1H-NMR (CDCl3) δ: 2.43 (d, J=1.2 Hz, 3H), 2.52 (m, 1H), 4.79 (d, J=1.2 Hz, 2H), 6.17 (d, J=1.2 Hz, 1H), 6.96-7.66 (m, 8H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3S[CH2:19][CH2:18][C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][C:15]=3[CH:26]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].OO.[S:29]([O-:32])([O-])=[O:30].[Na+].[Na+].O>C(O)(=O)C>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[S:29](=[O:32])(=[O:30])[CH2:19][CH2:18][C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][C:15]=3[CH:26]=2)=[CH:9][CH:10]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OCC)CCS3)cc1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OCC)CCS3(=O)=O)cc1
Temperature: 56 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Ethyl 7-(4-propoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate (15 g, 40.707 mmol) was suspended in 135 ml of acetic acid and was heated to 56° C. to dissolve. A solution of 30% hydrogen peroxide (9.5 g, 83.449 mmol) in 15 ml of acetic acid was dropped slowly and then was stirred at 65-70° C. for 3 hours. At that temperature, 60 ml of an aqueous sodium sulfite solution was dropped and disappearance of the peroxide was checked with iodo-starch paper. At that temperature, 15 ml of water was dropped. Crystals were formed and the mixture was cooled and stirred for 2 hours. After filtration, the residue was washed with 15 ml of a mixed solution of acetic acid/water =3/2 and subsequently with 150 ml of water. After vacuum drying (40° C.), 15.4 g (Yield 94%) of ethyl 7-(4-propoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate was obtained as white crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:31]=[CH:30][C:6]([C:7]([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18]4[CH:20]=[C:21]([C:24]([OH:26])=O)[CH:22]=[CH:23][C:17]=4[N:16]4[CH:27]=[CH:28][CH:29]=[C:15]34)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[O:32][CH3:33])[CH3:2].[CH3:34][N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([C:3]1[CH:31]=[CH:30][C:6]([C:7]([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18]4[CH:20]=[C:21]([C:24]([NH:35][CH3:34])=[O:26])[CH:22]=[CH:23][C:17]=4[N:16]4[CH:27]=[CH:28][CH:29]=[C:15]34)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[O:32][CH3:33])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C(=O)O)ccc2-n2cccc23)cc1OC
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C(=O)NC)ccc2-n2cccc23)cc1OC

Procedure:
A solution of 1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxylic acid (40 mg, 0.090 mmol), HATU (34 mg, 0.090 mmol), N-methylamine hydrochloride (6.0 mg, 0.090 mmol) and iPr2NEt (62 μL, 0.36 mmol) in DMF (1 mL) was stirred at room temperature overnight. The reaction mixture was filtered and purified by reverse phase LC-MS (10-99% CH3CN/H2O). Pure fractions were combined and evaporated to yield 1′-(4-ethyl-3-methoxybenzoyl)-N-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxamide. ESI-MS m/z calc. 459.5, found 460.5 (M+1)+; Retention time: 1.73 minutes (3 min run).