Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH:7]=[C:8]1[N:12]([CH3:13])[CH2:11][CH2:10][S:9]1>C(O)C>[C:4]([N:7]=[C:8]1[N:12]([CH3:13])[CH2:11][CH2:10][S:9]1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: CN1CCSC1=N
Reactant: C=C1CC(=O)O1
Solvent: CCO
Product: CC(=O)CC(=O)N=C1SCCN1C
Temperature: 25 °C

Procedure:
A solution of 13 g. of diketene in 100 ml. of ethanol was added dropwise to an ice-cold solution of 18 g. of 2-imino-3-methylthiazolidine in 100 ml. of ethanol. The mixture was allowed to warm spontaneously to room temperature and then evaporated to dryness. The residue was triturated with ether, collected on a filter and dried in a dessicator to give 2-acetoacetylimino-3-methylthiazolidine, m.p. 43°-45° C.
Reaction SMILES: O.[NH2:2]N.C[N:5](C)/[CH:6]=[CH:7]/[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]3[CH:23]=[CH:22][C:21]([I:24])=[CH:20][N:19]3[CH:25]=2)=[CH:12][CH:11]=1)=O>C(O)C>[I:24][C:21]1[CH:22]=[CH:23][C:18]2[N:19]([CH:25]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([C:8]4[CH:7]=[CH:6][NH:5][N:2]=4)=[CH:11][CH:12]=3)[N:17]=2)[CH:20]=1
Reactant: CN(C)/C=C/C(=O)c1ccc(-c2cn3cc(I)ccc3n2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Ic1ccc2nc(-c3ccc(-c4cc[nH]n4)cc3)cn2c1

Procedure:
Hydrazine monohydrate (100 μL) was added to a solution (30 mL) of (E)-3-(dimethylamino)-1-[4-(6-iodoimidazo[1,2-a]pyridin-2-yl)phenyl]-2-propen-1-one (344 mg) in ethanol, and the mixture was refluxed for 3 hours. The reaction mixture was left to cool, and the precipitated matter was recovered through filtration and dried, to thereby yield the title compound (290 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[Cl:21])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH:22]O>>[CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N+:10]([O-:22])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[Cl:21])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OO
Reactant: CCOC(=O)N1CCc2nc3ccccc3c(Cl)c2CC1
Product: CCOC(=O)N1CCc2c(Cl)c3ccccc3[n+]([O-])c2CC1
Yield: 29 %

Procedure:
11-Chloro-1,2,4,5-tetrahydro-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester-6-oxide was prepared from 11-chloro-1,2,4,5-tetrahydro-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester and 30% hydrogen peroxide analogous to Example 163. Yield: 29% of theory; m.p. 170° C.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][CH2:10][C@@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]2[C:18](=[O:35])[CH2:19][NH:20][C:21](=[O:34])[NH:22][C:23]2[CH:24]=[C:25]([CH2:29][C:30]([O:32]C)=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CO.O>[C:12]1([C@H:9]2[CH2:10][CH2:11][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]2[C:18](=[O:35])[CH2:19][NH:20][C:21](=[O:34])[NH:22][C:23]2[CH:24]=[C:25]([CH2:29][C:30]([OH:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)CC[C@H]2c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)CC[C@H]2c2ccccc2)c1
Yield: 11.7 %

Procedure:
By proceeding in a fashion similar to that described in Example 9, but starting from 10.6 g of methyl cis-3-{3-[2-(2,5-diphenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenylacetate in solution in 150 cm3 of methanol and 1.7 g of potassium hydroxide dissolved in 30 cm3 of water and after treatment and recrystallization in ethanol, 1.2 g of cis-3-{3-[2-(2,5-diphenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenylacetic acid, melting at 152° C., are obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:48]=[CH:49][C:50]=1[F:51])[O:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]3[CH2:46][CH:45]3C)=[O:43])[N:40]=2)[N:37]=1>CN(C)C(=O)C.O1CCCC1>[CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([C:13]([NH:27][C:28]2[CH:29]=[C:30]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]5[CH2:46][CH2:45]5)=[O:43])[N:40]=4)[N:37]=3)[CH:48]=[CH:49][C:50]=2[F:51])=[O:15])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CC1C(=O)Nc1cn2nc(Oc3ccc(F)c(N)c3)ccc2n1
Reactant: O=C(O)c1ccn(Cc2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F)c1ccn(Cc2ccccc2)c1
Yield: 24.3 %

Procedure:
Using 1-benzyl-1H-pyrrole-3-carboxylic acid (276 mg, 1.37 mmol), tetrahydrofuran (3.0 mL), N,N-dimethylformamide (20 μL, 0.26 mmol), oxalyl chloride (120 μL, 1.37 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methylcyclopropanecarboxamide (300 mg, 0.92 mmol) and N,N-dimethylacetamide (6.0 mL), and in the same manner as in Example 249, the title compound (114 mg, 24%) was obtained as a white powder.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([OH:3])=O.C(N(CC)CC)C.ClC(OCC)=O.[C:27]1([CH2:33][CH2:34][NH2:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[C:27]1([CH2:33][CH2:34][NH:35][C:1]([C:4]2[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=2)=[O:3])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: NCCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc(C(=O)NCCc2ccccc2)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
20.1 g (0.1 mol) of 4-carboxybenzenesulfonamide were suspended in 300 ml of anhydrous tetrahydrofuran and treated dropwise at 0° C. with stirring with 15.2 ml (0.11 mol) of triethylamine. After 30 min, 10.5 ml (0.11 mol) of ethyl chloroformate were added dropwise at 0° C., the mixture was stirred at this temperature for 1 h, cooled to -10° C. and 12.1 g (0.1 mol, 12.5 ml) of 2-phenylethylamine in 30 ml of anhydrous tetrahydrofuran were added dropwise. After 1 h at 0° C., the mixture was warmed to 20° C. and concentrated in vacuo, the solid residue was treated with water, filtered off with suction and recrystallized from ethanol, and 20.4 g of product were obtained, M.p. 243°-245° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].Cl[C:12]1[N:13]=[CH:14][C:15]2[CH:20]=[C:19]([C:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH:26]=3)[NH:18][C:16]=2[N:17]=1>C(O)CCC>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:14]2[C:15]3[CH:20]=[C:19]([C:21]4[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH:26]=4)[NH:18][C:16]=3[N:17]=[CH:12][N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3cnc(Cl)nc3[nH]2)CC1
Reactant: COc1ccc(N)cc1I
Solvent: CCCCO
Product: COc1ccc(Nc2ncnc3[nH]c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc23)cc1I
Temperature: 95 °C

Procedure:
3-Iodo-4-methoxyaniline (0.670 g, 2.0 mmol) was added to a solution of tert-butyl 4-(chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (0.598 g, 2.4 mmol) in n-butanol (10 mL). The mixture was heated to 95° C. for 15 h. The solvent was removed and the residue was purified by silica gel chromatography (5% MeOH in dichloromethane) to afford the title compound. 1H-NMR (DMSO-d6, 400 MHz): δ=1.43 (s, 9H), 2.46 (m, 2H), 3.56 (m, 2H), 3.80 (s, 3H), 4.03 (m, 2H), 6.38 (s, 1H), 6.72 (s, 1H), 7.00 (d, J=9.2 Hz, 1H), 7.85 (dd, J=2.8, 8.8 Hz, 1H), 8.34 (s, 1H), 9.27 (s, 1H), 11.93 (s, 1H). MS (ES+): m/z 547.91 [MH+]. HPLC: tR=3.39 min (ZQ2000, polar—5 min).
Reaction SMILES: C([O:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:11][C:10]=1[CH2:30][CH2:31][CH3:32])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:30]([C:10]1[CH:11]=[C:12]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:9]4[CH:29]=[CH:28][CH:12]=[CH:11][CH:10]=4)=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])[CH:28]=[CH:29][C:9]=1[OH:8])[CH2:31][CH3:32]
Reactant: CCCc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCc1cc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)ccc1O

Procedure:
A solution of 4-[2-(4-benzyloxy-3-propylphenoxy)ethyl]-5-methyl-2-phenyloxazole (3.16 mmol) in ethanol (100 mL) was treated with 5% Pd/C (160 mg) and hydrogen (60 psi) at ambient temperature for 18 h. The mixture was filtered and concentrated in vacuo to give a tan solid.
Reaction SMILES: N1C=CN=C1.Cl[Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[CH3:14][O:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH2:24][OH:25])[CH:21]=[CH:22][CH:23]=1>ClCCl>[CH3:11][C:10]([Si:7]([CH3:9])([CH3:8])[O:25][CH2:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH2:16][O:15][CH3:14])[CH:19]=1)([CH3:13])[CH3:12]
Reactant: COCOc1cccc(CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COCOc1cccc(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Yield: 102.2 %

Procedure:
In a 100 ml round-bottomed flask (3-{[(methyloxy)methyl]oxy}phenyl)methanol (Intermediate 95, 3.5 g) was dissolved in dichloromethane (20 ml) to give a colourless solution. 1H-imidazole (1.700 g, 24.97 mmol) and chloro(1,1-dimethylethyl)dimethylsilane (3.64 g, 24.14 mmol) were added. The reaction mixture immediately became a white suspension and was stirred at room temperature. After overnight stirring the reaction was completed. The reaction mixture was then quenched with 10 ml of water and diluted with 10 ml of dichloromethane. The phases were separated through a separating funnel. The organic phase was dried using a hydrophobic frit and evaporated under vacuum to give 6.0082 g of the crude product as a colourless oil which was purified via Biotage SP1 (with cyclohexane/EtOAc as eluents from 1:0 to 5:1 in 10 CV; then 5:1 for 5 CV; then from 5:1 to 1:1 in 5 CV; 100 g SNAP Silica column). Two fractions of the title compound were collected: 1.70 g of a colourless oil (purity: 93%) and 3.70 g of a colourless oil (purity: 98%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3](=[O:12])[C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>CO>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:4][C:3](=[O:12])[C:2]([F:13])([F:14])[F:1])[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(C#Cc1ccccc1)C(F)(F)F
Solvent: CO
Product: O=C(C=C(Nc1cccc(Cl)c1)c1ccccc1)C(F)(F)F

Procedure:
Into a 1-Neck round-bottom flask was added 1,1,1-trifluoro-4-phenyl-but-3-yn-2-one (2.0 g, 0.01 mole), methanol (5 mL) and m-chloroaniline (0.961 mL, 0.0091 mol). The reaction was stirred. TLC (SiO2, hexanes/methylene chloride 1:1) indicated near reaction completion after 1 h. After 1.5 h the product was concentrated in vacuo to afford an orange oil, which was placed on high vacuum overnight, affording a yellow gum. The crude product was chromatographed on Silica gel with hexanes, Methylene Chloride 2:1, and place on high vacuum for 2 h to afford the title compound as a yellow gum; 1H NMR (CDCl3, 400 MHz) δ 5.74 (s, 1H), 6.67-6.69 (m, 1H), 6.85 (nm, 1H), 7.08-7.10 (m, 1H), 7.31-7.39 (m, 4H), 7.43-7.47 (tt, 1H), 12.39 (bs, 1H)
Reaction SMILES: [N:1]([CH2:4][CH:5]([C:7]1[CH:12]=[C:11]([S:13](=[O:16])(=[O:15])[NH2:14])[CH:10]=[CH:9][C:8]=1[Cl:17])[OH:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N>N1C=CC=CC=1>[NH2:1][CH2:4][CH:5]([C:7]1[CH:12]=[C:11]([S:13](=[O:16])(=[O:15])[NH2:14])[CH:10]=[CH:9][C:8]=1[Cl:17])[OH:6]
Reactant: [N-]=[N+]=NCC(O)c1cc(S(N)(=O)=O)ccc1Cl
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: NCC(O)c1cc(S(N)(=O)=O)ccc1Cl
Temperature: 25 °C
Reaction time: 9 h
Yield: 42.6 %

Procedure:
1.35 g (4.9 mmol) of α-azidomethyl-2-chloro-5-sulphamoylbenzenemethanol, 90 ml of anhydrous pyridine and 9.67 g (29.0 mmol) of triphenylphosphine on a carrier are introduced into a 250-ml round-bottomed flask. The mixture is stirred at room temperature for 9 hours, 100 ml of 28% aqueous ammonia are then added, and the suspension is stirred for 16 hours and filtered. The filtrate is concentrated and the residue is recrystallized in methanol. 0.523 g of α-aminomethyl-2-chloro-5-sulphamoylbenzenemethanol is obtained. 1 equivalent of methanesulphonic acid in 2M solution in methanol is added. After recrystallization in methanol and diethyl ether and drying in a desiccator under vacuum over phosphorus pentoxide, 0.439 g of α-aminomethyl-2-chloro-5-sulphamoylbenzenemethanol methanesulphonate is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@@H:7]([CH:20]([CH3:22])[CH3:21])[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:27]>CN(C=O)C.CCOCC>[C:1]([O:5][C:6](=[O:23])[CH:7]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH3:27])[CH:20]([CH3:21])[CH3:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)N[C@@H](C(=O)OC(C)(C)C)C(C)C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N(C)C(C(=O)OC(C)(C)C)C(C)C)cc1
Reaction time: 15 h
Yield: 95.3 %

Procedure:
To a solution of 1.00 g (2.915 mmol) of N-[(4-methoxyphenyl)sulfonyl]-D-valine tert-butyl ester (J. Med. Chem. 1997, 40, 2525) in 10 mL of DMF was added 0.128 g (3.207 mmol) of 60% sodium hydride. After 30 minutes at room temperature 0.45 mL (7.289 mmol) of iodomethane was added and the reaction was stirred for 15 h. The reaction mixture was then diluted with ether and washed with water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 0.993 g (95%) of the N-methyl sulfonamide as a colorless oil. Electrospray Mass Spec: 357.9 (M+H)+
Reaction SMILES: [CH2:1]([C:3]1[NH:7][N:6]=[C:5]([C:8]([NH2:10])=[O:9])[C:4]=1[N+:11]([O-:13])=[O:12])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].CS(O[CH:27]1[CH2:30][N:29]([CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:28]1)(=O)=O>O1CCCC1.O>[CH:31]([N:29]1[CH2:30][CH:27]([N:7]2[C:3]([CH2:1][CH3:2])=[C:4]([N+:11]([O-:13])=[O:12])[C:5]([C:8]([NH2:10])=[O:9])=[N:6]2)[CH2:28]1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCc1[nH]nc(C(N)=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1c([N+](=O)[O-])c(C(N)=O)nn1C1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 30.8 %

Procedure:
5-Ethyl-4-nitro-1H-pyrazole-3-carboxamide (WO 98/49166) (25.0 g, 136 mmol), sodium carbonate (57.6 g, 543 mmol), sodium iodide (40.7 g, 272 mmol) and 1-benzhydryl-3-azetidinyl methanesulfonate (86.2 g, 272 mmol) were suspended in tetrahydrofuran (338 mL) and water (38 mL) and heated under reflux for 5 days. The reaction mixture was then concentrated in vacuo and taken up in ethyl acetate (500 mL) and water (300 mL). The resulting precipitate was filtered, washed with ethyl acetate and water to yield the title compound as a white solid (17 g, 41.9 mmol, 31%): mp 257-260° C.; 1H NMR (400 MHz, DMSO-d6): δ=1.09 (t, 3H, J=7.6 Hz), 2.95 (q, 2H, J=7.3 Hz), 3.43 (t, 2H, J=7.6 Hz), 3.61 (t 2H, J=7.6 Hz), 4.59 (s, 1H), 5.23 (quintet, 1H, J=7.3 Hz), 7.15-7.20 (m, 2H), 7.24-7.31 (m, 4H), 7.43-7.48 (m, 4H), 7.70 (br s, 1H), 7.95 (br s, 1H); LRMS (m/z) (TSP+) 406.2 (MH+).
Reaction SMILES: [OH:1][C@@H:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].Cl.[NH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH:1][C@@H:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:12])=[CH:13][CH:14]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCOC(=O)CCN
Reactant: CCC[C@@H](O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC[C@@H](O)c1ccc(C(=O)NCCC(=O)OCC)cc1
Reaction time: 1 h
Yield: 100.2 %

Procedure:
N,N-dimethylformamide (16.9 mL) was added to a vial containing (R)-4-(1-hydroxybutyl)benzoic acid (2.6 g, 13.5 mmol), ethyl 3-aminopropanoate hydrochloride (4.16 g, 27.1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (10.3 g, 27.1 mmol). Diisopropylethylamine (11.8 mL, 67.7 mmol) was then added. The reaction was stirred for 1 h, and was then concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) afforded (R)-ethyl 3-(4-(1-hydroxybutyl)benzamido)propanoate (3.97 g, 100% yield) as an oil. 1H NMR (400 MHz, CDCl3, δ): 7.75 (d, J=8.2 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 6.83 (br. s., 1H), 4.74 (t, J=8.2 Hz, 1H), 4.18 (q, J=7.1 Hz, 2H), 3.73 (q, J=5.9 Hz, 2H), 2.64 (t, J=6.4 Hz, 2H), 1.87 (br. s., 1H), 1.84-1.62 (m, 2H), 1.49-1.30 (m, 2H), 1.28 (t, J=7.1 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H). MS (M+1): 294.
Reaction SMILES: [CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](=O)[CH:16]=[CH:17]N(C)C)[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[NH2:25][C:26]([NH2:28])=[NH:27]>C(O)C>[CH2:22]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15]3[CH:16]=[CH:17][N:25]=[C:26]([NH2:28])[N:27]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:23][CH3:24]
Reactant: CCCN(CCC)C1CCc2cccc(C(=O)C=CN(C)C)c2C1
Reactant: N=C(N)N
Solvent: CCO
Product: CCCN(CCC)C1CCc2cccc(-c3ccnc(N)n3)c2C1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
2-Di-n-propylamino-8-(1-oxo-3-(dimethylamino)-prop-2-enyl)-1,2,3,4-tetrahydronaphthalene, prepared as in Example 8 (0.18 g; 0.55 mmol) was dissolved in 3 ml of ethanol. To the mixture was added 0.07 g (1.1 mmol) of guanidine, and the mixture was stirred at 60° C. under nitrogen for 18 hours. The mixture then was cooled to room temperature during which a crystalline solid formed. The crystals were filtered, washed with isopropyl alcohol, ether, and dried in vacuo to give 70 mg of the title compound as glistening plates. The product was recrystallized from isopropyl alcohol to obtain colorless crystals, m.p. 188°-189° C. Analysis: Theory: C, 74.04; H, 8.70; N, 17.27; Found: C, 74.30; H, 8.70; N, 17.45.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]1[C:8]([CH2:9][C:10](O)=[O:11])=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[N:5]1>O1CCCC1>[F:24][C:2]([F:1])([F:25])[CH2:3][N:4]1[C:8]([CH2:9][CH2:10][OH:11])=[CH:7][C:6]([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:17][CH:18]=2)=[N:5]1
Reactant: O=C(O)Cc1cc(-c2ccc(OC(F)(F)F)cc2)nn1CC(F)(F)F
Solvent: C1CCOC1
Product: OCCc1cc(-c2ccc(OC(F)(F)F)cc2)nn1CC(F)(F)F

Procedure:
In analogy to the procedure described for example 9 c], [2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-acetic acid was reduced with a 1 M solution of BH3*THF in tetrahydrofuran to give 2-[2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-ethanol as colorless oil.
Reaction SMILES: NN.[C:3]1([C:9]([N:22]=[C:23]=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=[CH:7][CH:6]=[CH:5][CH:4]=1.CC[OH:27]>C1COCC1>[CH3:23][N:22]1[CH2:9][CH2:3][CH2:4][CH2:5][C@H:6]1[CH2:7][OH:27]
Reactant: O=C=NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCO
Agent: NN
Solvent: C1CCOC1
Product: CN1CCCC[C@H]1CO
Reaction time: 8 h

Procedure:
Following the known procedure of patent EP 0 429 984 A2 (reference example 8). The resolution was identical to the procedure described above except 3 rounds of crystallization were performed. To a mixture of (±)-1-methyl-2-piperidinemethanol (95.6 g, 740 mmol) in EtOH (840 mL) was added dibenzoyl-L-tartaric acid (255 g, 711 mmol). The resulting mixture was slowly heated until a solution was obtained at which time the solution was slowly cooled with gentle stirring. After 12 h the crystals were isolated and dried to provide 79.6 g. This process was repeated: (2) EtOH (335 mL) provided 50.4 g. (3) EtOH (345 mL) provided 35 g. The resulting salt was treated with 3M HCl (134 mL) which was heated to induce it to dissolve. The still warm solution was poured into a separatory funnel and extracted with ethyl acetate. The remaining aqueous layer was adjusted to pH 10 with K2CO3. The solution was extracted with CH2Cl2, dried (MgSO4) and concentrated to give 6 g of the alcohol. This alcohol (6 g, 46.7 mmol) was suspended in CH2Cl2 (100 mL) and SOCl2 (6.8 mL, 93.3 mmol) added dropwise. After stirring for 12 h, the solvent was removed to provide a crude HCl salt. This salt (5.98 g) was dissolved in EtOH (100 mL) and treated with NH2NH2 (19.5 mL, 405 mmol) and heated to reflux for 3 h. Half the solvent was removed, the residue extracted with ether and the extracts dried and concentrated to give 4.55 g of a crude oil. This crude hydrazine (2.01 g, 14.06 mmol) was dissolved in THF (100 mL) and triphenylmethylisocyanate (4.0 g, 14.1 mmol) was added slowly. The solution was then stirred overnight and the solvent removed under reduced pressure and the residue was purified by flash chromatography (CH2Cl2/MeOH/NH4OH) to provide 350 mg of the desired product. 1H NMR (DMSO-d6) δ 1.10 (m, 2H), 1.30-1.56 (m, 4H), 1.95 (t, 1H), 2.15 (s, 1H), 2.18 (s, 3H), 2.71 (d, 1H), 3.25 (q, 1H), 3.55 (q, 1H), 4.80 (s, 2H), 7.12-7.32 (m, 15H), 8.02 (s, H). ESI-MS m/z 429.2 (100, M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:15]Br>C(Cl)Cl>[Br:15][C:10]1[N:9]=[C:8]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=12
Reactant: Clc1nccn2c(C3CCC3)ncc12
Reactant: BrBr
Solvent: ClCCl
Product: Clc1nccn2c(C3CCC3)nc(Br)c12
Reaction time: 0.17 h

Procedure:
To a clear, vigorously stirred and cooled (0° C.) solution of 8-chloro-3-cyclobutylimidazo[1,5-a]pyrazine (0.75 g, 3.6 mmol) in DCM (90 mL) was added Br2 (0.28 mL, 5.4 mmol) in DCM (90 mL) over 34 min. The reaction became a light orange suspension towards the end of the addition. Stirring was continued at the temperature for 10 min then concentrated under reduced pressure at rt. The mixture was diluted with H2O (˜20 mL), basified with 2 M aq NaOH to ˜pH 7-9 and extracted with DCM (3×80 mL). The organic layers were washed (satd aq NaHCO3, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (50 g cartridge, 100% DCM) yielded the title compound as an off-white solid; 1H NMR (400 MHz, CD2Cl2) δ 7.41 (d, J=5.2 Hz, 1H), 7.16 (d, J=5.2 Hz, 1H), 3.70 (qud, J=1.2 Hz, 8.4 Hz, 1H), 2.48-2.33 (m, 4H), 2.13-2.02 (m, 1H), 1.98-1.88 (m, 1H); MS (ES+): m/z 286.1 (90), 288.0 (100) [MH+]; HPLC: tR=3.33 min (OpenLynx, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH3:20])[CH2:16][CH:17]=1.Cl>CO.[Pt]=O>[Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]1
Reactant: CCCN1CC=C(c2cccc(S(C)(=O)=O)c2Cl)CC1
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: CCCN1CCC(c2cccc(S(C)(=O)=O)c2Cl)CC1
Reaction time: 1 h
Yield: 75.4 %

Procedure:
A mixture of 4-[2-chloro-3-(methylsulfonyl)phenyl]-1-propyl-1,2,3,6-tetrahydropyridine (0.46 g, 1.47 mmol), platinum oxide (0.11 g) and hydrochloric acid (0.1 ml, conc) in methanol (30 ml) was hydrogenated at 50 psi for 1 h under hydrogen gas. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated and evaporated to dryness to give 0.48 g of crude product as the hydrochloric acid salt. Purification by flash column chromatography (ethylacetate/methanol, 1:1) gave the title compound (0.35 g, 75%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 250-252° C. MS m/z (relative intensity, 70 eV) 315 (M+, 3), 288 (37), 287 (15), 286 (bp) 129 (7).