Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([N:17]([CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)[C@H:18]([C:20]([NH:22][CH:23]([C:32](=[O:45])[CH2:33][O:34][C:35](=[O:44])[C:36]1[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:43])[CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[O:21])[CH3:19])=[O:16].C(O)(C(F)(F)F)=O>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([N:17]([CH:46]1[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]1)[C@H:18]([C:20]([NH:22][CH:23]([C:32](=[O:45])[CH2:33][O:34][C:35](=[O:44])[C:36]1[C:37]([Cl:43])=[CH:38][CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:24][C:25]([OH:27])=[O:26])=[O:21])[CH3:19])=[O:16]
Reactant: CC(C)Cc1c(C(=O)N(C2CCCCC2)[C@@H](C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COC(=O)c2c(Cl)cccc2Cl)n(C)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1c(C(=O)N(C2CCCCC2)[C@@H](C)C(=O)NC(CC(=O)O)C(=O)COC(=O)c2c(Cl)cccc2Cl)n(C)c2ccccc12

Procedure:
Treatment of N-[(1-methyl-3-isobutyl-indole-2-carbonyl)cyclohexylalaninyl]-3-amino-5-(2,6-dichlorobenzoyl)oxy-4-oxo-pentanoic acid, tert-butyl ester with TFA as described in Example 80 gave the titled product (54.2 mg) as a white powder. MS C35H41Cl2N3O7, [M+H]+ =686, [M−H]−=684. TLC (CH2Cl2/MeOH, 90/10): Rf=0.30.
Reaction SMILES: [CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[C:14]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:15]=4[N:16]=[CH:17][N:18]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1>C(O)(C)C>[CH:1]1([C@H:4]([N:8]2[CH:12]=[C:11]([C:13]3[C:14]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[C:15]=4[N:16]=[CH:17][N:18]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4CC4)c3)ncnc21
Solvent: CC(C)O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H](CC#N)C4CC4)c3)ncnc21
Reaction time: 0.18 h

Procedure:
A slurry of 1.5 Kg of 20-micron Chiralcel® OD chiral stationary phase (CSP) made by Daicel in 3.0 L of isopropanol (IPA) was packed into a PROCHROM Dynamic Axial Compression Column LC110-1 (11 cm ID×25 cm L; Column Void Vol.: approximate 1.5 L) under 150 bar of packing pressure. The packed column was then installed no a Novasep Hipersep HPLC unit. The column and HPLC system were flushed with methanol (17 L) and the mobile phase made by a mixture of isopropanol and hexane (2:8 by volume, 17 L). The feed solution was then prepared by dissolving 3-cyclopropyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (28, racemic SEM-protected compound, 2500 g, 6.119 mol) in the mobile phase to a concentration of 80 g/L. The feed solution (120 mL per injection) was then sequentially injected into the preparative HPLC chiral column for separation. The chiral column was eluted with the mobile phase at a flow rate of 570 mL/min at room temperature. The column elution was monitored by UV at wavelength 330 nm. Under these conditions, a baseline separation of the two enantiomers was achieved. The cycle time for each injection was 11 minutes and a total of 261 injections were performed for this separation process. Fractions for Peak 1 (the undesired (S)-enantiomer, (S)-29) and Peak 2 (the desired (R)-enantiomer, (R)-29) were collected separately from each injection, and fractions collected for each peak were continuously concentrated at 40° C. under reduced pressure (40-120 bar). The residue from each evaporator was further dried under high vacuum to constant weight to afford (3R)-3-cyclopropyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile ((R)-29, 1150 g, 1250 g theoretical, 92%) from Peak 2 as a light yellow oil which solidified upon standing at room temperature in vacuo and (3S)-cyclopropyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile ((S)-29, 1200 g, 1250 g theoretical, 96%) from Peak 1 as an yellow oil which solidified upon standing at room temperature in vacuo.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][CH:7]=1.[CH3:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[C:16]=1[C:17]([O:19][CH3:20])=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[CH3:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:2][C:3]3[N:4]=[C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[O:6][CH:7]=3)[CH:28]=2)[C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: ClCc1coc(-c2ccccc2)n1
Reactant: COC(=O)c1c(C)cccc1COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1c(C)cccc1COc1cccc(OCc2coc(-c3ccccc3)n2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloromethyl-2-phenyl-oxazole (100 mg, 0.5 mmol, example 19) in DMF (2 mL) is added methyl 2-methyl-6-[(3-hydroxy-phenoxy)-methyl]-benzoate (136 mg, 0.5 mmol, example 5) followed by K2CO3 (75 mg, 0.54 mmol). The resulting mixture is heated to 60° C. and stirred at this temperature for 8 h. This mixture is then cooled to room temperature, diluted with ether, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 20% ethyl acetate in hexanes) to give the title compound. MS (ESI) 429 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([N:7]1[CH2:11][CH2:10][CH2:9][CH:8]1[C:12](=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16])[C:3]([O:5]C)=O.[CH3:18][CH:19]([CH3:24])[CH2:20][CH2:21][Mg]Cl>C1COCC1>[CH3:18][C:19]([CH3:24])([CH2:20][CH3:21])[C:3](=[O:5])[C:2]([N:7]1[CH2:11][CH2:10][CH2:9][CH:8]1[C:12](=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16])=[O:1]
Reactant: CC(C)CC[Mg]Cl
Reactant: C=CCCC(=O)C1CCCN1C(=O)C(=O)OC
Solvent: C1CCOC1
Product: C=CCCC(=O)C1CCCN1C(=O)C(=O)C(C)(C)CC
Reaction time: 2.5 h

Procedure:
A solution of methyl 2-oxo-2-(2-pent-4-enoylpyrrolidinyl)acetate (21.0 g; 88 mmol) in 150 ml THF was cooled to −78° C., under nitrogen, and treated with 200 ml (180 mmol) of 0.9 M 3,3-dimethylpropyl magnesium chloride. After stirring for 2.5 hours, TLC indicated that the reaction was complete. It was quenched with 300 ml of saturated NH4Cl followed by 200 ml of ethyl acetate. The layers were separated and the aqueous layer was extracted once more with 300 ml of ethyl acetate. The combined organic layers were dried over MgSO4, filtered, concentrated, and the product purified on silica gel with 20% ethyl acetate in hexane, to obtain 3,3-dimethyl-1-(2-pent-4-enoylpyrrolidinyl)pentane-1,2-dione as a light yellow oil, 21.0 g (85%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[C:30]([O:43][CH2:44][C:45]([F:48])([F:47])[F:46])[CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:11][CH:12]([CH3:15])[CH3:13])[CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[C:30]([O:43][CH2:44][C:45]([F:48])([F:46])[F:47])[CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(OCC(F)(F)F)c2)CCN3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(OCC(F)(F)F)c2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 180.6 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.45 g) and isobutylaldehyde (0.32 ml) were dissolved in 1,2-dichloroethane (15 ml), and to the solution, triacetoxy sodium borohydride (0.7 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The mixture was neutralized with solution of sodium bicarbonate, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off to give crude crystals, which were recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 23) (0.44 g) as yellow crystals.
Reaction SMILES: [N:1]1([C:6]2[CH:10]=[CH:9][S:8][C:7]=2[C:11](N2CCOCC2)=[O:12])[CH:5]=[CH:4][CH:3]=[CH:2]1.N1(C2C=CSC=2C(N2CCCCC2)=O)C=CC=C1>>[S:8]1[C:7]2[C:11](=[O:12])[C:5]3[N:1]([CH:2]=[CH:3][CH:4]=3)[C:6]=2[CH:10]=[CH:9]1
Reactant: O=C(c1sccc1-n1cccc1)N1CCOCC1
Agent: O=C(c1sccc1-n1cccc1)N1CCCCC1
Product: O=C1c2sccc2-n2cccc21

Procedure:
This compound can also be obtained by using N-[3-(pyrrol-1-yl)thiophen-2-ylcarbonyl]morpholine (Preparation 12) and N-[3-(pyrrol-1-yl)thiophen-2-ylcarbonyl]piperidine (Preparation 13) as starting materials.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10]([CH3:20])[C:9](=[O:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1.Br[CH2:23][CH2:24][Cl:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][N:2]([CH2:3][C:4]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10]([CH3:20])[C:9](=[O:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH2:23][CH2:24][Cl:25]
Reactant: CNCc1cccc2c(=O)c(C)c(-c3ccccc3)oc12
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)oc2c(CN(C)CCCl)cccc2c1=O
Reaction time: 12 h

Procedure:
A mixture of 22 g of Intermediate XX, 66 ml of 1-bromo-2-chloroethane and 11 g of anhydrous potassium carbonate in 88 ml of dimethylformamide was stirred at 20°-25° C. for 12 hours. The reaction mixture was then poured into 600 ml of water and extracted with dichloromethane. The organic layer was washed with water, dried on anhydrous sodium sulfate and acidified with ethanolic hydrogen chloride. The solvent and the excess 1-bromo-2-chloroethane were distilled off in vacuo at 70°-80° C. The residue was taken up in cold 1N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic solution was washed with water, dried on anhydrous sodium sulfate and evaporated to dryness in vacuo at 25°-30° C. The crude title product was purified by flash chromatography on silica gel, eluting with ethyl acetate:petroleum ether 7:3, to give 18 g of the title compound melting at 118°-120° C. after crystallization from ethanol.
Reaction SMILES: [ClH:1].[N:2]1([C:11](=[O:34])/[CH:12]=[CH:13]/[C@@H:14]([NH:17][C:18]([C:20]2([NH:26]C(=O)OC(C)(C)C)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:19])[CH2:15][CH3:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1>C(O)(C)C>[ClH:1].[NH2:26][C:20]1([C:18]([NH:17][C@@H:14]([CH2:15][CH3:16])/[CH:13]=[CH:12]/[C:11]([N:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)=[O:34])=[O:19])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CC[C@@H](/C=C/C(=O)N1CCc2ccccc21)NC(=O)C1(NC(=O)OC(C)(C)C)CCOCC1
Agent: Cl
Solvent: CC(C)O
Product: CC[C@@H](/C=C/C(=O)N1CCc2ccccc21)NC(=O)C1(N)CCOCC1
Temperature: 65 °C
Yield: 89.4 %

Procedure:
A solution of concentrated aq. HCl (0.23 mL, 2.76 mmol) was added to a solution of 1,1-dimethylethyl [4-({[(1S,2E)-4-(2,3-dihydro-1H-indol-1-yl)-1-ethyl-4-oxo-2-buten-1-yl]amino}carbonyl)tetrahydro-2H-pyran-4-yl]carbamate (251 mg, 0.549 mmol) in isopropanol (2.5 mL). The reaction flask was fitted with an air condenser, and the reaction mixture was heated to 65° C. (bath temp) for 1 h 45 min. The solvent was evaporated under reduced pressure. Water (5 mL) was added to the residue, and the mixture was concentrated under reduced pressure at 65° C. Water (2 mL) was added to the residue, and the mixture was lyophilized, giving 193.3 mg (89%) of the title compound. LC-MS m/z 358 (M+H)+, 0.68 (ret time). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.14 (br. s., 1H); 7.25 (d, J=7.03 Hz, 1H); 7.18 (t, J=7.53 Hz, 1H); 7.02-7.09 (m, 1H); 6.83 (dd, J=15.18, 6.65 Hz, 1H); 6.49 (d, J=14.8 Hz, 1H); 4.56 (d, J=7.28 Hz, 1H); 4.22 (br. s., 2H); 3.95 (d, J=7.53 Hz, 1H); 3.88-3.94 (m, 1H); 3.71-3.78 (m, 2H); 3.23 (br. s., 2H); 2.39-2.46 (m, 2H); 1.79-1.86 (m, 2H); 1.75 (s, 1H); 1.72 (d, J=8.28 Hz, 1H); 1.00 (t, J=7.40 Hz, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([O:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(O)cc1
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Product: CCCCOC(=O)c1nc(Oc2ccc(OC)cc2)c2ccccc2c1O

Procedure:
Synthesized from 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and 4-methoxy-phenol in analogy to Example D-20 d); MS-(+)-ion: M+1=368.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[O:17])=[C:12]([Cl:25])[CH:11]=1.[F:26][C:27]([F:34])([F:33])[CH2:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])=[O:17])=[C:12]([Cl:25])[CH:11]=2)=[C:2]([NH:1][S:29]([CH2:28][C:27]([F:34])([F:33])[F:26])(=[O:31])=[O:30])[CH:7]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2N)cc1Cl
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2NS(=O)(=O)CC(F)(F)F)cc1Cl
Reaction time: 4 h

Procedure:
The reaction was conducted as described in the preparation of compound 179 using {4-[(2-amino-4-bromophenyl)amino]-2-chlorophenyl}(2-methylphenyl)methanone (0.15 g, 0.35 mmol)(disclosed in WO 01/05744) in pyridine (0.47 mL) and trifluoroethanesulfonyl chloride (0.059 mL, 0.53 mmol). The reaction time was 4 h. Work up as described in the preparation of compound 179 afforded the title compound as brown crystals.
Reaction SMILES: [CH2:1]([C:5]1([N:26]([CH3:28])[CH3:27])[CH2:10][CH2:9][C:8]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH3:20])=[CH:17][C:16]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:15][CH:14]=3)=[CH:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]>C(O)C.[Pd]>[CH2:1]([C:5]1([N:26]([CH3:28])[CH3:27])[CH2:6][CH2:7][CH:8]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH3:20])=[CH:17][C:16]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:15][CH:14]=3)[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(N(C)C)CC=C(c2[nH]c3ccc(OC(F)(F)F)cc3c2C)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCCC1(N(C)C)CCC(c2[nH]c3ccc(OC(F)(F)F)cc3c2C)CC1
Reaction time: 1.5 h

Procedure:
(±)-N-[1-Butyl-4-(3-methyl-5-trifluoromethoxy-1H-indol-2-yl)cyclohex-3-enyl]-N,N-dimethylamine (320 mg, 0.81 mmol) was dissolved in ethanol (50 ml), and Pd/C (5%, 140 mg) was added under argon. Hydrogenation was carried out under 3 bar for 1.5 h. The catalyst was then filtered off with suction over Celite and the filtrate was concentrated. The solid pale brown residue (341 mg) was separated by chromatography [silica gel 60 (30 g); ethyl acetate/methanol (1:1; 500 ml); (1:2; 300 ml)]. 1-Butyl-N,N-dimethyl-4-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)cyclohexanamine (less polar diastereoisomer) was obtained in a yield of 28 mg (9%) and the more polar diastereoisomer in a yield of 237 mg (75%), in each case as a colourless solid.
Reaction SMILES: [CH2:1]([C:3]([CH2:5][CH3:6])=[O:4])[CH3:2].[Cl-].[CH3:8][N:9]([CH3:16])[CH:10]=NC=[N+](C)C.C[O-].[Na+]>CO>[CH3:8][N:9]([CH3:16])[CH:10]=[C:1]([CH3:2])[C:3](=[O:4])[CH2:5][CH3:6]
Reactant: CCC(=O)CC
Reactant: CN(C)C=NC=[N+](C)C
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCC(=O)C(C)=CN(C)C

Procedure:
Diethyl ketone (29.71 g; 0.345 mol) and [3-(dimethylamino)-2-azaprop-2-en-1-ylidene]dimethyl-ammonium chloride (37.64 g; 0.230 mol) were added to a solution of 30% of sodium methoxide in methanol (41.41 g; 0.230 mol) and methanol (305 ml) at 20° C. under N2. The reaction mixture was refluxed for 18 h and then concentrated under reduced pressure. The residue was dissolved in dichloromethane (300 ml) and washed with saturated sodium bisulphite solution (3×100 ml). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. This gave 26.60 g of product, which comprised 42% by weight of 1-(dimethylamino)-2-methylpent-1-en-3-one (corresponding to a yield of 34%).
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C(=O)([O-])O.[Na+].[CH3:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH2:25][C:26]3[N:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][CH:27]=3)=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:16]2)=[CH:12][CH:11]=1>C(O)C>[CH3:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH2:25][C:26]3[N:31]=[C:30]([C:32](=[N:3][OH:2])[NH2:33])[CH:29]=[CH:28][CH:27]=3)=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:16]2)=[CH:12][CH:11]=1
Reactant: Cc1ccc2c(Cc3cccc(C#N)n3)c(-c3ccccc3)[nH]c2c1
Reactant: [NH3+]O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2c(Cc3cccc(C(N)=NO)n3)c(-c3ccccc3)[nH]c2c1
Yield: 90.4 %

Procedure:
To a suspension of hydroxylammonium chloride (27.6 mg) in ethanol (1 mL) was added sodium hydrogen carbonate (33.4 mg), and this mixture was heated under reflux for 45 minutes. Then, a solution of 6-(6-methyl-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carbonitrile (61 mg) in ethanol (1.3 mL) was added dropwise thereto under ice-cooling, and the mixture was heated under reflux for additional 3.5 hours. The reaction mixture was left to be cooled and concentrated under reduced pressure. To the residue was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (60.8 mg). 1H-NMR (CDCl3) δ ppm: 2.47 (3H, s), 4.42 (2H, s), 5.64 (2H, br s), 6.48-6.84 (1H, br), 6.90-6.97 (1H, m), 7.08-7.14 (1H, m), 7.18-7.23 (1H, m), 7.32-7.49 (4H, m), 7.52 (1H, t, J=7.8 Hz), 7.54-7.61 (2H, m), 7.66-7.74 (1H, m), 8.06 (1H, br s). ESI-MS (m/z): 357 (M+H)+
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:14][N:15]3[C:20](Cl)=[CH:19][CH:18]=[CH:17][C:16]=23)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:29][Zn]C>O1CCCC1>[CH2:1]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:14][N:15]3[C:20]([CH3:29])=[CH:19][CH:18]=[CH:17][C:16]=23)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Zn]C
Reactant: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)n1
Solvent: C1CCOC1
Product: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(C)cccc23)n1
Temperature: 60 °C
Yield: 32 %

Procedure:
To a solution of N-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamine (80 mg, 0.20 mmol) in tetrahydrofuran (1 mL) was added dimethylzinc (304 μL, 2.0 M in toluene, 0.60 mmol) and tetrakis(triphenyl-phosphine)palladium(0) (23 mg, 0.02 mmol). The reaction mixture was heated at 60° C. for 16 hours. The reaction mixture was cooled, then quenched with ice water. The resultant mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (3:1 hexanes:ethyl acetate) provided N-butyl-4-[2-(4-fluorophenyl)-7-methylpyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamine (24 mg, 32%) as a yellow solid. Rf 0.33 (2:1 hexanes:ethyl acetate);
Reaction SMILES: [CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[CH:7]1([C:13]2[N:14]([CH3:26])[N+:15]([CH3:25])=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20](C)[CH2:19]3)[CH:17]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[Cl-]>>[CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[CH3:26][N+:14]1[N:15]([CH3:25])[C:16]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]2[CH3:1])=[CH:17][C:13]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC1CCCN(c2cc(C3CCCCC3)n(C)[n+]2C)C1
Agent: COS(=O)(=O)[O-]
Agent: [Cl-]
Product: CC1CCCCN1c1cc(-c2ccccc2)[n+](C)n1C

Procedure:
3-Cyclohexyl-1,2-dimethyl-5-(3-methylpiperidino)pyrazolium methyl sulfate (and chloride)
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([F:26])[F:25])=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C.[Cu]I>[F:25][CH:24]([F:26])[C:21]1[CH:22]=[CH:23][C:18]([O:1][C:2]2[C:7]3[CH:8]=[C:9]([CH3:11])[O:10][C:6]=3[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1cc(O)c2cc(C)oc2c1
Reactant: FC(F)c1ccc(Br)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(Oc2ccc(C(F)F)cc2)c2cc(C)oc2c1
Temperature: 160 °C
Yield: 41 %

Procedure:
A mixture of ethyl 4-hydroxy-2-methyl-1-benzofuran-6-carboxylate (252c) (1.10 g, 5 mmol), 1-bromo-4-(difluoromethyl)benzene (1.24 g, 6 mmol), Cs2CO3 (2.44 g, 7.5 mmol) and CuI (5 mg, 0.03 mmol) in DMF (5 mL) was heated in a microwave at 160° C. for 60 minutes. Water was then added and the product was extracted with CHCl3 (3×), dried over MgSO4 and concentrated to give an oil residue. The oil was purified via silica gel chromatography using hexanes/EtOAc (100/0 to70/30) to give the title compound (710 mg, 41%) as a yellow solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.38 (t, J=7.06 Hz, 3 H) 2.44 (s, 3 H) 4.37 (q, J=7.06 Hz, 2 H) 6.22 (d, J=0.94 Hz, 1 H) 6.63 (t, J=56.61 Hz, 1 H) 7.03 (d, J=8.29 Hz, 2 H) 7.46 (d, J=8.29 Hz, 2 H) 7.55 (d, J=1.13 Hz, 1 H) 7.89-8.05 (m, 1 H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[OH:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)Oc1ccc2c(c1)CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Oc1ccc2c(c1)CCC2O
Reaction time: 2 h
Yield: 84.3 %

Procedure:
To a solution of acetic acid 1-oxo-indan-5-yl ester (2700 mg, 14.2 mmol) in MeOH (20 mL) at 0° C. was added sodium borohydride (760 mg, 20 mmol). The reaction mixture was stirred for 2 hours, quenched with saturated aqueous NH4Cl (20 mL) and diluted with ethyl acetate (500 mL). The organic solution was washed with saturated aqueous NaHCO3 (50 mL) and saturated aqueous NaCl (50 mL), dried (Na2SO4) and concentrated in vacuo to give 2.3 grams of the desired product. 1H NMR (250 MHz, CDCl3): d 7.35 (d, 2 H), 6.90 (m, 2 H), 5.2 (t, 1 H), 3.0 (m, 1 H), 2.8 (m, 1 H), 2.5 (m, 1 H), 2.3 (s, 3 H), 1.95 (1 H, m).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1NC(=O)OC1C=CC=CC=1.C([N:23](CC)CC)C.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>ClCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:23][C:29](=[O:30])[O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: O=C(Nc1ccc2ccccc2n1)Oc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccnc2ccccc12)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Quinolin-4-amine (A) (76 mg, 0.53 mmol) was dissolved in dichloromethane. To the reaction mixture was added triethylamine (0.09 mL, 0.63 mmol) and phenyl chloroformate (0.07 mL, 0.55 mmol) and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to afford the crude phenyl quinolin-4-ylcarbamate which was directly used for next step without purification.