Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:37]2[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:36])[N:11]([CH:21]2[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:30]3([CH:34]=[O:35])[CH2:33][CH2:32][CH2:31]3)[CH3:29])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[CH3:45][Mg]Br.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:37]2[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:36])[N:11]([CH:21]2[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:30]3([CH:34]([OH:35])[CH3:45])[CH2:31][CH2:32][CH2:33]3)[CH3:29])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC(OC(C)C3(C=O)CCC3)CC2)c2ncnn12
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC(OC(C)C3(C(C)O)CCC3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
3′-Fluoro-4′-[(4-{4-[1-(1-formylcyclobutyl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (14 g) was dissolved in tetrahydrofuran (150 mL), methylmagnesium bromide (35 mL, 1.0 M tetrahydrofuran solution) was added dropwise at 0° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (13 g, 90%).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11](OS(C(F)(F)F)(=O)=O)=[C:10]([C:27]2[O:31][N:30]=[C:29]([CH3:32])[CH:28]=2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C1COCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[C:10]([C:27]2[O:31][N:30]=[C:29]([CH3:32])[CH:28]=2)[C:9]1=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(-c2c(OS(=O)(=O)C(F)(F)F)c3cc(Cl)ccc3n(Cc3ccccc3)c2=O)on1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Product: Cc1cc(-c2c(N3CCCCC3)c3cc(Cl)ccc3n(Cc3ccccc3)c2=O)on1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 1-benzyl-6-chloro-3-(3-methyl-isoxazol-5-yl)-2-oxo-1,2-dihydro-quinolin-4-yl ester (25 mg, 0.050 mmol) in 1 ml of THF was added piperidine (17 mg, 0.20 mmol). The mixture was stirred at rt for 16 h. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (20% EtOAc/hexanes) gave 21.0 mg (97%) of product as a yellow green oil: 1H-NMR (CDCl3; 400 MHz) δ 7.93 (d, 1H, J=2.6 Hz), 7.37 (dd, 1H, J=9.0, 2.3 Hz), 7.18-7.33 (m, 6H), 6.56 (s, 1H), 5.50 (s, 2H), 2.99 (m, 4H), 2.40 (s, 3H), 1.64-1.76 (m, 6H). Mass spectrum (ESI, m/z): Calcd. for C25H24ClN3O2, 434.2 (M+H), found 434.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=O)=[CH:5][N:4]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]([Cl:16])[CH:12]2[CH2:14][CH2:13]2)=[CH:5][N:4]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1ccc(NC(=O)C2CC2)cn1
Solvent: ClCCl
Product: COc1ccc(N=C(Cl)C2CC2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2-methoxy-5-pyridyl)-cyclopropane carboxamide (5.0 g, 0.026 mol) was added portionwise to stirred solution of phosphorus pentachloride (5.42 g, 0.026 mol) in dichloromethane (25 ml) under a nitrogen atmosphere at room temperature. After complete addition the mixture was stirred at room temperature for one hour and then heated at reflux for a further one hour. The reaction mixture was then evaporated under vacuum to give a solid product which was washed with diethyl ether (50 ml) and air dried to give N-(2-methoxy-5-pyridyl)-cyclopropylmethanimidoyl chloride as the hydrochloride salt (6.2 g, 97%) which was used in Stage 3 without further purification or characterisation.
Reaction SMILES: C(OC([N:8]1[CH:13]([CH3:14])[CH2:12][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH:17]=2)[CH2:10][CH:9]1C)=O)(C)(C)C.[F:30][C:31]1[CH:32]=[C:33]([CH2:37][CH2:38][NH2:39])[CH:34]=[CH:35][CH:36]=1>>[CH:10]12[CH2:14][CH:13]([NH:8][CH2:9]1)[CH2:12][N:11]2[CH2:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:39][CH2:38][CH2:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([F:30])[CH:32]=3)[N:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: NCCc1cccc(F)c1
Reactant: CC1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CC(C)N1C(=O)OC(C)(C)C
Product: Fc1cccc(CCNc2nccc(-c3cccc(CN4CC5CC4CN5)c3)n2)c1

Procedure:
Intermediate 142 was coupled with 2-(3-fluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 404. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.45 (s, 1H) 8.36 (d, 2H) 7.89 (d, 1H) 7.73 (t, 1H) 7.54 (d, 1H) 7.27 (q, 1H) 7.10 (m, 2H) 6.91 (t, 1H) 4.63 (q, 2H) 4.61 (d, 2H) 3.92 (m, 3H) 3.78 (d, 1H) 3.59 (t, 2H) 3.07 (t, 2H) 2.76 (d, 1H) 2.33 (d, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]2[S:22][CH:23]([CH2:26][C:27](O)=[O:28])[CH2:24][N:25]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:53][CH2:54][C:55]([CH3:58])([OH:57])[CH3:56]>CN(C)C=O.C(OCC)(=O)C.O>[OH:57][C:55]([CH3:58])([CH3:56])[CH2:54][NH:53][C:27](=[O:28])[CH2:26][CH:23]1[S:22][C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([O:11][C:8]2[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:20][CH:19]=3)=[N:25][CH2:24]1
Reactant: CC(C)(O)CN
Reactant: CS(=O)(=O)c1ccc(Oc2ccc3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(O)CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)ccc3[nH]2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
To a solution of [2-(5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (600 mg) in N,N-dimethylformamide (10 mL) were added 1-hydroxybenzotriazole monohydrate (319 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (400 mg), and 1-amino-2-methyl-2-propanol (242 mg), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate) and crystallized from acetonitrile to give the title compound (601 mg, yield 86%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][C:22]#[CH:23].C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:23][C:22]#[CH:21])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: C#CCBr
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: C#CCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide is alkylated using 3-bromo-propyne and K2CO3. After aqueous work-up the crude material (5.11 g) is de-acetylated in MeOH (180 ml) using DBU (1,3 ml) at reflux. After aqueous work-up 5-amino-3,3-dimethyl-6-nitro-1-prop-2-ynyl-1,3-dihydro-indol-2-one (4.32 g) is obtained and used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=3)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26]([NH:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[CH:39]=[C:38]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=4)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=3)[CH:3]=2)[CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1F
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)c2)c1

Procedure:
3′-[4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidine (example E.101) (0.415 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as white foam (0.43 g), which was subsequently deprotected.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:15])=[C:8]([C:12]=1[CH2:13][CH3:14])[C:9]([OH:11])=[O:10])([O-:3])=[O:2].Cl[C:17]([O:19][CH2:20][CH3:21])=O>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:15]=[C:17]([O:19][CH2:20][CH3:21])[O:10][C:9](=[O:11])[C:8]=2[C:12]=1[CH2:13][CH3:14])([O-:3])=[O:2]
Reactant: CCOC(=O)Cl
Reactant: CCc1c([N+](=O)[O-])ccc(N)c1C(=O)O
Solvent: c1ccncc1
Product: CCOc1nc2ccc([N+](=O)[O-])c(CC)c2c(=O)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
A solution of 1.3 g (6.2 mmoles) of 5-nitro-6-ethyl-2-aminobenzoic acid in 40 mL of dry pyridine was cooled in an ice-water bath under inert atmosphere. Ethyl chloroformate, 2 mL (21 mmoles), was added dropwise over a five-minute period. A mild exotherm was observed and a solid separated from solution immediately upon addition. The suspension was stirred in the ice-water bath for 60 minutes, then warmed to room temperature and stirred under inert atmosphere overnight. Approximately half the pyridine was removed in vacuo, and the residual mixture was poured over ice. The precipitated solid, an orange brown color, was collected and air-dried. 0.76 g (47% yield) 6-nitro-5-ethyl-2-ethoxy-3,1-benzoxazin-4-one was obtained. NMR(CDCl3): 1.36(t,3H,J=7.5 Hz), 1.47(t,3H,J=7.2 Hz), 3.27(q,2H,J=7.2 Hz), 4.56(q,2H, J=7.5 Hz), 7.36(d,1H,J=9.0 Hz), 7.98(d,1H,J=9.0 Hz). MS(m/z): 282(M+ +H2O).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:18])[N:5]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:6]1=[N:7]2.FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([OH:18])[N:5]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:6]1=[N:7]2
Reactant: O=c1c2c(Cl)cc(Cl)cc2nc2n1CCCCC2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: OC1c2c(Cl)cc(Cl)cc2N=C2CCCCCN21

Procedure:
To a solution of 1 g of 1,3-dichloro-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one in 30 mL of hot triethylsilane was added 5 m of trifluoroacetic acid and the mixture was stirred at 100° C.-110° C. under nitrogen. More triethylsilane and trifluoroacetic acid were added until the reaction was substantially complete as evidenced by TLC (basified aliquot extracted into CHCl3). Then all volatiles were removed in vacuo and the residue was basified, extracted into chloroform, and chromatographed using 20:1 chloroform:methanol on a silica gel column. Concentration of the corresponding fractions provided the desired 1,3-dichloro-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazolin-12-ol as a greyish-white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:22]1([CH2:21][CH2:20][CH2:19][O:18][C:15]2[CH:16]=[CH:17][C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:7][CH:8]=3)=[CH:13][CH:14]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: ClCCCOc1ccc(-c2ccc(OCCCN3CCCCC3)cc2)cc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cc(-c2ccc(OCCCN3CCCC3)cc2)ccc1OCCCN1CCCCC1
Yield: 33 %

Procedure:
Following the procedure described in example 36, but starting from 1-{3-[4′-(3-chloropropoxy)biphenyl-4-yloxy]propyl}piperidine (250 mg), pyrrolidine (138 mg) and potassium carbonate (360 mg) in N,N-dimethylformamide (2 mL) affords 90 mg of 1-(3-{[4′-(3-piperidinopropoxy)biphenyl-4-yl]oxy}propyl)pyrrolidine as white crystals melting at 105-108° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[NH2:23]>CN(C=O)C.CCOC(C)=O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:23][C:22]2[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:20]([O:19][CH3:18])[CH:21]=2)[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2ncnc(Cl)n2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2,4-Dichloro-1,3,5-triazine (1.054 g, 7.028 mmol) was dissolved in DMF (5 ml) and cooled to 0° C. To this solution, DIEA (1.225 ml, 7.028 mmol) and 3,4,5-trimethoxyaniline (1.185 g, 6.47 mmol) were added. The reaction mixture was kept at 0° C. for 15 to 30 min and at RT for 2 h. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, filtered, and evaporated in vacuo. The residue was added to CH2Cl2 and the resulting white precipitate was filtered and dried under reduced pressure to give (4-chloro-[1,3,5]triazin-2-yl)-(3,4,5-trimethoxy-phenyl)amine: MS m/z=279 [M−Cl+OH2]+. Calc'd for C12H13ClN4O3: 296.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:7]2[N:8]([C:16]([NH2:18])=[O:17])[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:5][CH:6]=1.[CH3:19][C:20]1[CH:24]=[CH:23][O:22][C:21]=1[C:25](O)=[O:26].Cl.CN(C)CCCN=C=NCC>ClCCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:19][C:20]1[CH:24]=[CH:23][O:22][C:21]=1[C:25]([NH:1][C:2]1[CH:3]=[C:4]([C:7]2[N:8]([C:16]([NH2:18])=[O:17])[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:5][CH:6]=1)=[O:26]
Reactant: Cc1ccoc1C(=O)O
Reactant: NC(=O)n1c(-c2cc(N)cs2)cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Cc1ccoc1C(=O)Nc1csc(-c2cc3ccccc3n2C(N)=O)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To the solution of 2-(4-amino-2-thienyl)-1H-indole-1-carboxamide (51.4 mg, 0.2 mmol, 1 eq) and 3-methyl-furan-2-carboxylic acid (25.2 mg, 1 eq) in anhydrous DCE (2 mL) was added 4-(dimethylamino)pyridine (4.9 mg, 0.2 eq) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (46.1 mg, 1.2 eq). After the reaction was stirred at 60° C. for 1 hour, it was diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. The upper clear solution was decanted, concentrated, and the oily residue was subject to a gradient column chromatography (EtOAc-Hex 1:100 to 1:2) to yield 2-{4-[(3-methyl-2-furoyl)amino]-2-thienyl}-1H-indole-1-carboxamide as a yellow solid in amount of 42 mg.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10]([F:21])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[CH2:15]4)[CH:12]=3)[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.N.C[N:29](C)C=O>>[NH2:29][C:9]1[C:10]([F:21])=[C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[CH2:15]2)[CH:12]=[C:13]2[C:8]=1[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5][N:4]2[CH:1]1[CH2:2][CH2:3]1
Reactant: CN(C)C=O
Reactant: CC1CN(c2cc3c(c(F)c2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1
Agent: N
Product: CC1CN(c2cc3c(c(N)c2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1

Procedure:
In a sealed tube, 1-cyclopropyl-5,6-difluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was aminated with ammonia/dimethylformamide as in Example 13 to give 5-amino-1-cyclopropyl-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. m.p. 181°-183° C.
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[CH3:8][C:9](=[CH:11][CH2:12][CH2:13]/[C:14](=[CH:16]/[CH2:17]O)/[CH3:15])[CH3:10].C(O)(=O)C(O)=O>>[CH3:6][C:5]([CH2:7][CH2:17][CH:16]=[C:14]([CH3:15])[CH2:13][CH2:12][CH:11]=[C:9]([CH3:10])[CH3:8])=[CH:4][C:2](=[O:1])[CH3:3]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CC(=O)C=C(C)C
Agent: O=C(O)C(=O)O
Product: CC(=O)C=C(C)CCC=C(C)CCC=C(C)C
Yield: 81 %

Procedure:
800 parts of mesityl oxide and 200 parts of geraniol have 1 part of oxalic acid added to them and the mixture is heated for three hours at a pressure of 50 atmospheres in the vibrated autoclave described in Example 1 at a temperature of 230°C. The reaction mixture is worked up by distillation. 141 parts of 4,8,12-trimethyl-3,7,11-tridecatrien-2-one is obtained with a boiling point of 92° to 94°C at 10-4 mm. The yield is 81% of theory at a conversion of 57% based on geraniol.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][CH:19]([CH2:22]O)[CH2:20]O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.Cl.[NH2:32][C:33]1[NH:37][N:36]=[CH:35][C:34]=1[C:38]([OH:40])=[O:39]>ClCCl>[CH2:11]([O:18][C:19]1[CH:20]=[N:32][C:33]2[N:37]([N:36]=[CH:35][C:34]=2[C:38]([OH:40])=[O:39])[CH:22]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1[nH]ncc1C(=O)O
Reactant: OCC(CO)OCc1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C(O)c1cnn2cc(OCc3ccccc3)cnc12
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 8.8 %

Procedure:
To solution of oxalyl chloride (0.6 mL, 6.87 mmol) in anhydrous dichloromethane (15 mL), cooled at −78° C., was added, dropwise, a solution of anhydrous dimethyl sulfoxide (1.2 mL, 16.5 mmol) in dichloromethane (2 mL) and the resulting mixture was stirred for 10 minutes at −78° C. A solution of 2-benzyloxy-1,3-propanediol (0.5 g, 2.75 mmol) in dichloromethane (2 mL) was then added dropwise at −78° C. and the reaction mixture was stirred for 15 minutes. Triethylamine (4.6 mL, 33 mmol) was then added dropwise at −78° C. and the resulting mixture was stirred for 1 hour. The cold bath was removed and an aqueous solution of hydrochloric acid (6 M, 6 mL, 36 mmol) was added, followed by 5-amino-1H-pyrazole-4-carboxylic acid (0.35 g, 2.75 mmol) and the reaction mixture was heated at 70° C. for 1 hour. The solid formed was collected by filtration, washed with water and dried under vacuum. The solid residue (0.53 g) was then washed with dichloromethane to give 65 mg (9% yield) of 6-benzyloxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid. MS=270 [M+H]+.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].C[Mg]Br.[CH2:8](OCC)C.[CH2:13]([C@H:15]1[C:19](=[O:20])[CH2:18][CH2:17][N:16]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH3:14]>>[CH2:13]([C@H:15]1[C@:19]([OH:20])([CH3:8])[CH2:18][CH2:17][N:16]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH3:14]
Reactant: CCOCC
Reactant: CC[C@H]1C(=O)CCN1C(=O)OCc1ccccc1
Agent: C[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Product: CC[C@@H]1N(C(=O)OCc2ccccc2)CC[C@]1(C)O

Procedure:
By an operation in the same manner as in Reference Example 3 and using cerium chloride (11.69 g), 3 mol/L methylmagnesium bromide-diethyl ether solution (13.55 mL) and benzyl (2S)-2-ethyl-3-oxopyrrolidine-1-carboxylate (3.35 g), the title compound was obtained as colorless oil (yield: 2.84 g, yield: 84%).
Reaction SMILES: C(S[C:4]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7]2=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]2[N:5]=1)C.[CH2:32]([C:34]1NC2=NC=CC(C)=C2N=1)[CH3:33]>>[CH3:12][C:11]1[CH:10]=[CH:9][N:8]=[C:7]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:31][N:30]=[N:29][N:28]=4)=[CH:17][CH:16]=3)[C:4]([C:33]#[C:32][CH3:34])=[N:5][C:6]=12
Reactant: CCc1nc2c(C)ccnc2[nH]1
Reactant: CCSc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Product: CC#Cc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
2-Ethylthio-7-methyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine p0 3-{(2'-Carboxybiphenyl-4-yl)methyl{-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:11]>>[C:1]1([S:7]([NH2:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N
Product: NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
200 ml of aq. NH3 is cooled to −10° C. and treated with benzenesulfonylchloride (13 g, 73 mmol). The resulting mixture is stirred at this temperature for 3 h. When TLC confirmed the completion of the reaction, the reaction mixture is warmed to rt, and the resulting solid is filtered, washed with water and dried under vacuum to afford the title compound (11.1 g, 96%). LC/MS: (ES+): 158.2, (ES−): 156.2.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].[C:16]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([NH:24][C:8]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])=[CH:25][CH:26]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(Cl)c1cccnc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)c2cccnc2F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 2-fluoropyridine-3-carbonyl chloride (3.2 g, 20 mmol, Step D) and NaHCO3 (4 g, 48 mmol) in CH2Cl2 added in dropwise a solution of 4-tert butylaniline (3.0 g, 20 mmol). After the addition, the suspension was stirred at RT for 5 h. Solid inorganic salts were removed via filtration. The filtrate was concentrated to afford a brown solid as desired compound. MS:273 (M+H). Calc'd. for C16H17FN2O—272.33.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].C(N(CC)CC)C.Cl.[F:20][C:21]1([F:26])[CH2:24][CH:23]([NH2:25])[CH2:22]1>ClCCl>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:25][CH:23]1[CH2:24][C:21]([F:26])([F:20])[CH2:22]1)=[O:7]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: NC1CC(F)(F)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CC(F)(F)C1)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
3-(Chloromethyl)benzoyl chloride (13.93 mmol, 2.63 g) was stirred in dichloromethane (50 ml) at 0° C. Triethylamine (41.8 mmol, 5.81 ml, 4.23 g) and 3,3-difluorocyclobutanamine hydrochloride (13.93 mmol, 2 g) were combined in dichloromethane and added dropwise. The reaction mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was washed with water, dried over sodium sulfate and concentrated under vacuum to afford the title compound (3.33 g). MS (ESI) m/z 260.3 [M+H]+