Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:12]=[CH:11][C:10]=1[CH:25]=[CH:26][C:27]1[S:31][C:30]([CH:32]=O)=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([C:36]1[C:37](=[C:52]([C:55]#[N:56])[C:53]#[N:54])[O:38][C:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:42]([F:45])([F:44])[F:43])[C:40]=1[CH3:41])#[N:35]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:12]=[CH:11][C:10]=1[CH:25]=[CH:26][C:27]1[S:31][C:30]([CH:32]=[CH:41][C:40]2[C:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:42]([F:45])([F:43])[F:44])[O:38][C:37](=[C:52]([C:55]#[N:56])[C:53]#[N:54])[C:36]=2[C:34]#[N:35])=[CH:29][CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Reactant: CCCCN(CCCCO)c1ccc(C=Cc2ccc(C=O)s2)c(OCc2ccccc2)c1
Solvent: CCO
Product: CCCCN(CCCCO)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)s2)c(OCc2ccccc2)c1
Temperature: 65 °C
Yield: 60.9 %

Procedure:
In 8 ml of ethanol were dissolved 155 mg (0.33 mmol) of 5-[2-[2-benzyloxy-4-[butyl(4-hydroxybutyl)amino]phenyl]vinyl]thiophene-2-carboaldehyde and 116 mg (0.37 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene]propanedinitrile. The mixture was stirred with heating at 65° C. for 1 hour. The tar-like matter was separated by decantation, purified by silica gel column chromatography, crystallized in methanol, and separated by filtration to give 153 mg of a dark brown crystal having amp of 181-183° C. (yield: 60.2%).
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:15][CH:14]2[CH:11]([CH2:12][NH:13]2)[CH2:10]1)=[O:8].C1(C2C=CC=CC=2)[C:23]([C:28](O)=[O:29])=CC=CC=1>>[CH:11]12[CH2:12][NH:13][CH:14]1[CH2:15][N:9]([C:7]([C:2]1[C:1]3[C:6](=[CH:19][CH:20]=[CH:21][CH:16]=3)[CH:5]=[CH:4][C:3]=1[O:29][CH2:28][CH3:23])=[O:8])[CH2:10]2
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNC2C1
Product: CCOc1ccc2ccccc2c1C(=O)N1CC2CNC2C1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 19, substituting 2-ethoxy-naphthalene-1-carboxylic acid for biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for C18H20N2O2, 296.37; m/z found, 297.2 [M+H]+.
Reaction SMILES: [N+]([O-])(O)=O.[F:5][C:6]([F:21])([O:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([NH2:20])=[NH:19])[CH:14]=[CH:15][CH:16]=1)[CH:7]([F:9])[F:8].CN(C)[CH:24]=[CH:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:35][CH3:36])[CH:29]=1)=O.[OH-].[Na+]>CC(O)C>[F:5][C:6]([F:21])([O:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]2[N:20]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:35][CH3:36])[CH:29]=3)[CH:25]=[CH:24][N:19]=2)[CH:14]=[CH:15][CH:16]=1)[CH:7]([F:8])[F:9]
Reactant: CCOc1cccc(C(=O)C=CN(C)C)c1
Reactant: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)O
Product: CCOc1cccc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)c1
Temperature: 25 °C

Procedure:
926.1 mg (3.69 mmol) of 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidine nitrate are added to a solution of 801.1 mg (3.69 mmol) of 3-dimethylamino-1-(3-ethoxy-phenyl)-2-propen-1-one in 10 ml of 2-propanol. After the addition of 162.2 mg (4.05 mmol) of sodium hydroxide, the reaction mixture is boiled under reflux for 20 h. After cooling to RT, the reaction product is isolated by filtration and washed with 1-propanol, ethyl acetate and water. After chromatography (hexane:ethyl acetate=7:3), N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3-ethoxy-phenyl)-2-pyrimidineamine is obtained; Rf =0.72 (methylene chloride:methanol=98:2), m.p. 88°-96°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:34])[NH:28]2>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:11]([NH:22][C:23]1[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]3[C:24]=1[CH:25]=[CH:26][C:27](=[O:34])[NH:28]3)[C:10]([OH:17])([C:13]([F:16])([F:14])[F:15])[CH2:9][C:8]2([CH3:18])[CH3:19]
Reactant: COc1c(Cl)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Cc1ccc2[nH]c(=O)ccc2c1N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1c(Cl)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1c(C)ccc2[nH]c(=O)ccc12
Yield: 1.4 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 500 mg of 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 300 mg of 5-amino-6-methylquinolin-2(1H)-one. 10 mg of the title compound is obtained by reaction of 80 mg of the imine with 2.5 ml of titanium tetrachloride solution (1 M in dichloromethane) in 4.3 ml of dichloromethane.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]1=[O:22]>C(Cl)(Cl)Cl>[Cl:3][CH2:6][CH2:7][N:8]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]1=[O:22]
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(-c2ccccc2)c(=O)n(CCO)c1C
Solvent: ClC(Cl)Cl
Product: Cc1nc(-c2ccccc2)c(=O)n(CCCl)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.7 %

Procedure:
Thionylchloride (0.42 ml, 6.0 mM) was added dropwise under ice-cooling to compound 109 (1.22 g, 50 mM) dissolved in chloroform (10 ml), and stirred at room temperature for 3 hours. Chloroform was added to the reaction mixture, whereafter the mixture was washed with dilute aqueous K2CO3 and the resultant aqueous layer extracted with further chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 25 g), and eluted with chloroform to obtain compound 612 (0.59 g, yield: 42.7%).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[O:28]([CH:35]([CH3:39])[C:36](Cl)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:25]([N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:22])[F:21])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:2])=[O:27])[CH:6]=1)[C:36](=[O:37])[CH:35]([O:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH3:39])[CH3:26]
Reactant: CC(Oc1ccccc1)C(=O)Cl
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)C(C)Oc1ccccc1

Procedure:
(2′-{[Ethyl-(2-phenoxy-propionyl)-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-45) was prepared by following the procedures outlined in Example 1 and using (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 2-phenoxypropionyl chloride.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH2:17][C@H:18]([N:20]([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH2:38][CH3:39])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])[CH:7]=[C:8]2[C:12]=1[N:11]([CH2:13][CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]2)(=[O:3])[NH2:2].[C:40](Cl)(=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:40]([O:16][CH2:15][CH2:14][CH2:13][N:11]1[C:12]2[C:8](=[CH:7][C:6]([CH2:17][C@H:18]([N:20]([C:21]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:27])[CH2:28][CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH2:38][CH3:39])[CH3:19])=[CH:5][C:4]=2[C:1](=[O:3])[NH2:2])[CH2:9][CH2:10]1)(=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)[C@H](C)Cc1cc2c(c(C(N)=O)c1)N(CCCO)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)[C@H](C)Cc1cc2c(c(C(N)=O)c1)N(CCCOC(=O)C(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl (R)-N-[2-[7-carbamoyl-1-(3-hydroxy-propyl)-2,3-dihydro-1H-indol-5-yl]-1-methylethyl]-N-[2-(2-ethoxyphenoxy)ethyl]carbamate (6.24 g) was dissolved in dry pyridine (9.4 ml), and pivaloyl chloride (1.54 ml) was added to the solution. The mixture was stirred overnight at room temperature, and a saturated aqueous sodium bicarbonate solution was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by column chromatography on aminopropyl silica gel (eluent:hexane/ethyl acetate=1/1) to give colorless amorphous (R)-3-[5-[2-[N-(tert-butoxycarbonyl)-N-[2-(2-ethoxyphenoxy)ethyl]amino]-propyl]-7-carbamoyl-2,3-dihydro-1H-indol-1-yl]propyl pivalate (4.30 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(F)c(Br)c1
Reaction time: 3 h

Procedure:
3-Bromo-4-fluorobenzaldehyde (0.300 g, 1.48 mmol) was dissolved in methanol (3 mL). Sodium borohydride (0.0671 g, 1.77 mmol) was added. After 3 h, the reaction was quenched with methanol (1 mL), and the mixture was concentrated. The residue was taken up in 2:1 EtOAc-hexane (60 mL). The organic layer was extracted with dilute NaHCO3 (6 mL) then half-saturated brine (6 mL), then was dried over sodium sulfate and concentrated. The material was purified through silica gel (45 mL) using 30% to 40% EtOAc-hexane to afford the title compound.
Reaction SMILES: Cl.O1[C:6]2([CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][CH2:7]2)[O:5]CC1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>O>[C:16]1([CH2:15][CH2:14][CH2:13][NH:12][CH:9]2[CH2:10][CH2:11][C:6](=[O:5])[CH2:7][CH2:8]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(CCCNC2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1CCC(NCCCc2ccccc2)CC1
Reaction time: 48 h

Procedure:
A mixture of (1,4-dioxa-spiro[4.5]dec-8-yl)-(3-phenyl-propyl)-amine hydrochloride (1:1) (3.35 g, 10.7 mmol), H2O (25 ml) and trifluoroacetic acid (2.47 ml, 32.2 mmol) was left at r.t for 48 h. NaHCO3 (10%, 100 ml) was added and the solution was extracted with CH2Cl2. Drying of the organic layer (Na2SO4) and evaporation left 4-(3-phenyl-propylamino)-cyclohexanone as a slightly coloured oil (2.4 g, 97%, MS: m/e=232.2 (M+H+)).
Reaction SMILES: [S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].[F:6][C@@H:7]1[CH2:11][N:10]([C:12](=[O:26])[CH2:13][NH:14][C@@H:15]2[CH2:19][CH2:18][C@H:17]([CH2:20][N:21]3[CH:25]=[N:24][CH:23]=[N:22]3)[CH2:16]2)[C@H:9]([C:27]#[N:28])[CH2:8]1.CO>C(OCC)(=O)C>[S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].[F:6][CH:7]1[CH2:11][N:10]2[C:12](=[O:26])[CH2:13][N:14]([CH:15]3[CH2:19][CH2:18][CH:17]([CH2:20][N:21]4[CH:25]=[N:24][CH:23]=[N:22]4)[CH2:16]3)[C:27](=[NH:28])[CH:9]2[CH2:8]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN[C@@H]1CC[C@H](Cn2cncn2)C1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: N=C1C2CC(F)CN2C(=O)CN1C1CCC(Cn2cncn2)C1
Temperature: 27.5 °C

Procedure:
(2S,4S)-4-fluoro-1-({[(1R,3S)-3-(1H-1,2,4-triazol-1-ylmethyl)-cyclopentyl]amino}acetyl)pyrrolidine-2-carbonitrile mesylate salt was melted at 150-160° C. for 3 to 4 h and the residue was cooled to 25-30° C. To this, a mixture of methanol (100 ml, 2 vol.) and ethyl acetate (250 ml, 5 vol.) was added and heated at 50-55° C. The reaction mixture on cooling to 25-30° C. precipitates 7-fluoro-1-imino-2-[(3S,1R)-3-(1H-1,2,4-triazol-1-ylmethyl)cyclopentyl]-perhydroazolo[1,2-a]pyrazin-4-one mesylate. 1H NMR (300 MHz, DMSO-d6) δ 1.52-1.88 (m, 6H), 2.21-2.40 (m, 5H), 2.77-2.80 (m, 1H), 3.52-3.83 (m, 2H), 3.95-4.00 (d, 1H), 4.18-4.25 (m, 3H), 4.42 (m, 1H), 4.85 (m, 1H), 5.39-5.56 (d, 1H), 7.98 (s, 1H), 8.54 (s, 1H), 9.17 (s, 2H); ESI-MS (m/z) 321 (100%); 13C NMR (300 MHz, DMSO-d6) δ 27.00, 26.71, 32.04, 35.81, 32.54, 37.74, 39.97, 47.06, 51.85, 51.54, 52.80, 56.02, 57.73, 92.12, 89.82, 144.14, 151.43, 161.74, 162.12.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:15]=2)=[CH:9][C:8]=1[Cl:30])[CH3:2].[CH3:32][N:33]1[CH2:38][CH2:37][CH:36]([CH2:39]O)[CH2:35][CH2:34]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:39][CH:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[CH:17]=[C:16]([C:21]#[C:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[CH:15]=2)=[CH:9][C:8]=1[Cl:30])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#Cc3ccc(Cl)cc3)c2)cc1Cl
Reactant: CN1CCC(CO)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(Cl)cc3)cc(OCC3CCN(C)CC3)c2)cc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxyl-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (274 mg; 0.58 mmol) was dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. 1-(Methyl-piperidin-4-yl)-methanol (100 mg; 0.48 mmol) and tributylphosphine (0.21 mL; 0.87 mmol) were added followed by 1,1′-(Azodicarbonyl)dipiperidine (0.22 g; 0.87 mmol) dissolved in THF (10 mL). The reaction mixture was stirred at room temperature for 5 h, filtered, and evaporated in vacuo. The crude product was purified by prep. HPLC (method B). Yield: 250 mg. HPLC-MS: m/z: 663.0 (M+H); Rt: 2.47 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][CH2:6][C:5]2[C:8]([CH:13](O)[C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][N:10]=[C:11]([CH3:12])[C:4]=2[O:3]1.N1C=CC=CC=1.S(Cl)([Cl:31])=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:22])[O:7][CH2:6][C:5]2[C:8]([CH:13]([Cl:31])[C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][N:10]=[C:11]([CH3:12])[C:4]=2[O:3]1
Reactant: O=S(Cl)Cl
Reactant: Cc1ncc(C(O)c2ccc(Cl)cc2)c2c1OC(C)(C)OC2
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ncc(C(Cl)c2ccc(Cl)cc2)c2c1OC(C)(C)OC2

Procedure:
88 mg (0.275 mmole) of (+)-2,2,8-trimethyl-5-(4-chloro-α-hydroxybenzyl)-pyrido-[4,3-e]-1,3-dioxane are poured into a 5 ml flask, dissolved in 1 ml of methylene chloride and the flask is sealed under an atmosphere of nitrogen. 22 μl (0.27 mmole) of anhydrous pyridine are injected via a glass syringe. 36 μl (0.54 mmole) of thionyl chloride are then added dropwise. At disappearance (2 hours later) of the starting material (checked by TLC), the solvent is evaporated off under reduced pressure.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:6]([CH3:22])=[C:7]2[C:11](=[C:12]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]=1[CH3:14])[NH:10][CH2:9][CH2:8]2)[CH3:3].I[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].CCOC(C)=O>CN(C=O)C>[CH2:24]([N:10]1[C:11]2[C:7](=[C:6]([CH3:22])[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])=[C:13]([CH3:14])[C:12]=2[NH:15][C:16](=[O:21])[C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:8][CH2:9]1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: Cc1c(CN(C)C)c(C)c(NC(=O)C(C)(C)C)c2c1CCN2
Reactant: CCCCCCCCI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCN1CCc2c(C)c(CN(C)C)c(C)c(NC(=O)C(C)(C)C)c21
Reaction time: 0.5 h
Yield: 120.4 %

Procedure:
N-(5-Dimethylaminomethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (700 mg) was dissolved in DMF (7 ml) and Na (P=60%, 160 mg) was added under a nitrogen atmosphere at 5° C. After stirring at the same temperature for 30 min, 1-iodooctane (240 mg) was added, which was followed by stirring at 30° C. for 3 hr. AcOEt (200 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3 /MeOH=10/1-3/1) to give 500 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH:9]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][CH2:3][CH:4]1[CH:9]([NH:10][C:11](=[O:12])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7][NH:6][CH2:5]1
Reactant: COCC1CN(C(=O)OC(C)(C)C)CCC1NC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCC1CNCCC1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,1-dimethylethyl 3-[(methyloxy)methyl]-4-[(phenylcarbonyl)amino]-1-piperidinecarboxylate D34 (0.8 g) was dissolved in dichloromethane (25 ml). Trifluoroacetic acid (10 ml) was then added dropwise at room temperature. The reaction mixture was then stirred at room temperature for 3 hours, solvent was removed. A light yellow oil was obtained of desired product D35 in 0.6 g. LCMS [M+H] 249.1@1.20 min (5 min run)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:14])(=[O:13])[NH:11][CH3:12])=[O:4].[H-].[Na+].[CH2:17]([O:19][C:20](=[O:23])[CH2:21]I)[CH3:18]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:14])(=[O:13])[N:11]([CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:23])[CH3:12])=[O:4]
Reactant: CCOC(=O)CI
Reactant: CNS(=O)(=O)c1ccsc1C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C)S(=O)(=O)c1ccsc1C(=O)OC

Procedure:
43.5 G. (0.184 mol) of the obtained 3-methylsulfamoyl-thiophene-2-carboxylic acid methyl ester are dissolved in 400 ml. of absolute dimethylformamide are added dropwise at 0° C. during 1 hour to a stirred suspension of 4.5 g. (0.187 mol) of sodium hydride in 50 ml. of absolute dimethylformamide. Then, 40 g. (0.187 mol) of iodoacetic acid ethyl ester dissolved in 50 ml. of absolute dimethylformamide are added dropwise during 2 hours while cooling at 0°-5° C. and the mixture allowed to react for a further 1 hour [until a moistened pH paper shows a pH of 7-8]. The mixture is evaporated in vacuo and the residue taken up with 300 ml. of 0.5-N hydrochloric acid and 300 ml. of methylene chloride. The organic phase is separated, the aqueous phase is back-extracted twice with a small amount of methylene chloride and the combined organic phases are shaken out twice with 100 ml. each time of a 5% sodium bicarbonate solution [the aqueous phases are back-extracted once each time with a small amount of methylene chloride]. The combined organic phases are dried over sodium sulfate and evaporated. The crystalline residue is digested with a small amount of cold ethanol for purification. There is obtained 3-(N-carbethoxymethyl-N-methylsulfamoyl)-thiophene-2-carboxylic acid methyl ester of melting point 83°-85° C.
Reaction SMILES: [CH2:1]([C:4]1[O:8][C:7]([NH2:9])=[N:6][N:5]=1)[CH2:2][CH3:3].[C:10]1([CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:20]1([CH:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:17]([NH:9][C:7]2[O:8][C:4]([CH2:1][CH2:2][CH3:3])=[N:5][N:6]=2)=[O:18])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCCc1nnc(N)o1
Product: CCCc1nnc(NC(=O)C(c2ccccc2)c2ccccc2)o1

Procedure:
The title compound, viscous oil and MS: m/e=322.4 (M+H+) was prepared in accordance with the general method of example 44a from 5-propyl-[1,3,4]oxadiazol-2-ylamine and 2,2-diphenylacetic acid chloride.
Reaction SMILES: O[C:2]1([CH3:11])[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.CCN(S(F)(F)[F:18])CC>C(Cl)Cl>[F:18][C:2]1([CH3:11])[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)C1CC(C)(O)C1
Solvent: ClCCl
Product: CCOC(=O)C1CC(C)(F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
To a solution of ethyl 3-hydroxy-3-methylcyclobutanecarboxylate (500 mg, 3.16 mmol) in DCM (5 mL) was added DAST (0.626 mL, 4.74 mmol) at −78° C. and the reaction mixture was slowly allowed to warm to RT and stir for 3 h. The reaction mixture was diluted with DCM (25 mL), washed with H2O and a saturated aq. solution of NaHCO3, then dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (12 g REDISEP® column, eluting with 25% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 288A as a pale yellow liquid (0.2 g, 40% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.08 (q, J=7.0 Hz, 2H), 3.22-3.09 (m, 1H), 2.60-2.53 (m, 1H), 2.37-2.22 (m, 3H), 1.44 (d, J=18 Hz, 3H), 1.22-1.11 (m, 3H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[CH:17]2.C(=O)([O-])O.[Na+]>CO>[NH:19]1[C:20]2[C:16](=[CH:15][C:14]([NH:13][CH:2]3[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]3[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:22][CH:21]=2)[CH:17]=[N:18]1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: Nc1ccc2[nH]ncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1CCCCC1Nc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.8 %

Procedure:
Ethyl 2-oxocyclohexanecarboxylate (0.85 g) and 5-aminoindazole (0.60 g) were dissolved in methanol (10 ml), and a borane-pyridine complex (0.81 ml) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (10 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel [chloroform/methanol] to give the title compound (1.37 g) as substantially 1:1 enantiomers.
Reaction SMILES: ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH:23]1([C:26]2[CH:31]=[C:30]([O:32][CH2:33][C:34]3[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=3[F:41])[N:29]3[N:42]=[C:43]([CH3:48])[C:44]([C:45](O)=[O:46])=[C:28]3[CH:27]=2)[CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C.[C:58]([O:62][C:63](=[O:72])[NH:64][C:65]([CH3:71])([CH2:68][CH2:69][CH3:70])[CH2:66][NH2:67])([CH3:61])([CH3:60])[CH3:59]>O1CCCC1>[C:58]([O:62][C:63](=[O:72])[NH:64][C:65]([CH3:71])([CH2:68][CH2:69][CH3:70])[CH2:66][NH:67][C:45]([C:44]1[C:43]([CH3:48])=[N:42][N:29]2[C:30]([O:32][CH2:33][C:34]3[C:35]([F:41])=[CH:36][CH:37]=[CH:38][C:39]=3[F:40])=[CH:31][C:26]([CH:23]3[CH2:25][CH2:24]3)=[CH:27][C:28]=12)=[O:46])([CH3:61])([CH3:60])[CH3:59]
Reactant: Cc1nn2c(OCc3c(F)cccc3F)cc(C3CC3)cc2c1C(=O)O
Reactant: CCCC(C)(CN)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(C3CC3)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
76 mg (0.6 mmol) of 1-hydroxy-7-azabenzotriazole and 107 mg (0.6 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to a solution of 167 mg (0.5 mmol) of 5-cyclopropyl-7-[(2,6-difluorobenzyl)oxy]-2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid (Example 149A), 244 μl (1.4 mmol) of N,N-diisopropylethylamine and 121 mg (0.6 mmol) of rac-(1-amino-2-methylpentan-2-yl)carbamic acid tert-butyl ester from Example 152A in 5 ml of tetrahydrofuran. The mixture was stirred at room temperature for 18 h and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was removed and washed with water and saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The residue was purified by chromatography on silica gel (40 g silica gel cartridge, mobile phase: cyclohexane/ethyl acetate, gradient 0% to 100%). This gave 125 mg of the target compound (48% of theory).