Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[CH:10][NH:9][N:8]=2)=[CH:4][CH:3]=1.I[CH:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH:19]([N:9]1[CH:10]=[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:8]1)([CH3:21])[CH3:20].[CH:19]([N:8]1[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:10]=[N:9]1)([CH3:21])[CH3:20]
Reactant: CC(C)I
Reactant: Clc1ccc(-c2n[nH]cc2-c2ccncc2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(-c2ccncc2)c(-c2ccc(Cl)s2)n1
Product: CC(C)n1ncc(-c2ccncc2)c1-c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %
Yield: 10 %

Procedure:
To a solution of 4-[3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (1.9 mmol) in 10 mL N,N-dimethylformamide were added 2-iodopropane (2.9 mmol) and cesium carbonate (2.1 mmol). The reaction mixture was stirred overnight at room temperature and the solvent was then evaporated. The residue was diluted with water and extracted three times with ethyl acetate. The combined organic extracts were dried over MgSO4 filtered and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:ethyl acetate 20:1 to 5:1) to afford 0.37 g of 4-[1-isopropyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (61% yield) and 63 mg of 4-[1-isopropyl-5-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (10% yield).
Reaction SMILES: [CH2:1]([P:3]([OH:5])[OH:4])[CH3:2].[CH:6](=[O:9])[CH:7]=[CH2:8].[O-]S(OOS([O-])(=O)=O)(=O)=O.[Na+].[Na+]>O>[CH2:1]([P:3]([CH2:8][CH2:7][CH:6]=[O:9])(=[O:5])[OH:4])[CH3:2]
Reactant: C=CC=O
Reactant: CCP(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCP(=O)(O)CCC=O
Temperature: 100 °C
Yield: 74.9 %

Procedure:
564 g (6 mol) of ethylphosphonous acid (produced as in Example 1) are dissolved in 860 g of water and initially charged to a 5 l five-neck flask equipped with thermometer, reflux condenser, high-performance stirrer and dropping funnel. The reaction mixture is heated to 100° C. and 392 g (7 mol) of 2-propenal and 500 g of a 5% strength sodium peroxodisulfate solution (1.5 mol % based on 2-propenal) is added dropwise at atmospheric pressure over 1 h. Then, the water is distilled off in vacuo. The residue is taken up in tetrahydrofuran and the insoluble salts are filtered off. The solvent of the filtrate is removed in vacuo to leave 675 g (75% of theory) of ethyl(2-formylethyl)phosphinic acid as oil.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH2:16][CH3:17])[C:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([O:29][CH:30]([CH3:32])[CH3:31])[CH:20]=1)=[N:10][CH2:9][CH2:8]2)[CH3:3].[Na]>CO.C(OCC)C.C(OC(C)C)(C)C>[ClH:1].[CH2:2]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH2:16][CH3:17])[CH:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([O:29][CH:30]([CH3:32])[CH3:31])[CH:20]=1)[NH:10][CH2:9][CH2:8]2)[CH3:3]
Reactant: CCOc1cc2c(cc1OCC)C(Cc1ccc(OC(C)C)c(OC(C)C)c1)=NCC2
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: CCOCC
Solvent: CC(C)OC(C)C
Product: CCOc1cc2c(cc1OCC)C(Cc1ccc(OC(C)C)c(OC(C)C)c1)NCC2
Yield: 92.4 %

Procedure:
21 g (0.0455 mole) of 6,7-diethoxy-1-(3',4'-diisopropoxybenzyl)-3,4-dihydroisoquinoline hydrochloride was dissolved in 300 ml of methanol in a 1 liter 3-necked flask. The solution was cooled in an ice/water bath and 2.1 g (0.0555 moles) of sodium borhydride was added in two portions with agitation. Stirring was continued for half an hour, the solvent removed under reduced pressure and the residue obtained taken up in 500 ml of diethyl ether. The ethereal solution was washed 3 times with 200 ml of water, dried over sodium sulphate and the solvent removed under reduced pressure. The oil obtained was dissolved in 20 ml of isopropyl ether, and allowed to crystallize. The product was filtered and re-dissolved in 200 ml of diethyl ether, then a solution of hydrochloric acid in diethyl ether added to pH 2. The solvent was removed under reduced pressure and the residue obtained triturated, firstly in isopropyl ether and then in diethyl ether. After drying, 19.5 g of the title hydrochloride was obtained. Yield=92.5%, m.p. 168° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][Cl:7])=[O:3].[S-:8][C:9]#[N:10].[K+].[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18].O>C(#N)C>[Cl:7][CH2:6][CH2:5][O:4][C:2]([NH:10][C:9]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH2:19])=[S:8])=[O:3]
Reactant: Nc1ccccc1N
Reactant: N#C[S-]
Reactant: O=C(Cl)OCCCl
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Nc1ccccc1NC(=S)NC(=O)OCCCl
Reaction time: 2 h
Yield: 54.4 %

Procedure:
2-Chloroethyl chloroformate (14.3 g; 0.10 mole) was added dropwise to a stirred suspension of potassium thiocyanate (11.7 g; 0.12 mole) in dry acetonitrile (100 ml). The temperature of the reaction mixture rose spontaneously to 40° C. and stirring was continued for two hours at 30° C. to 40° C. The reaction mixture was then filtered and the clear filtrate was added dropwise during fifteen minutes to a stirred suspension of o-phenylenediamine (10.8 g; 0.10 mole) in dry acetonitrile (50 ml), the temperature during the addition being maintained between 15°C. and 20° C. by external cooling. When the addition was complete the reaction mixture was stirred at 30° to 40° C. for two hours, and poured into water (1litre). The crude solid which separated was filtered off, washed with water and crystallised from methanol to give 1-(2-chloroethoxycarbonyl)-3-(2-aminophenyl)thiourea (14.9 g), m.p. 173°-174°C. (with decomposition).
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].F[C:7](F)(F)C(O)=O.[C:13]1(OC)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[CH2:7]([NH:4][S:1]([NH2:5])(=[O:3])=[O:2])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccccc1
Reactant: NS(N)(=O)=O
Solvent: ClCCl
Product: NS(=O)(=O)NCc1ccccc1
Reaction time: 0.83 h
Yield: 90 %

Procedure:
The condensed sulfamide having a t-butoxycarbonyl protecting group obtained as Sample No. 1 of Example 1 is dissolved in a mixture of dichloromethane (15 vol.) and anisole (15 vol.) under ice cooling, and trifluoroacetic acid (15 vol.) is added thereto. The mixture is stirred for 50 minutes, and for 1 hour after the ice bath is removed. The reaction mixture is concentrated. The residue is recrystallized from a mixture of ether and petroleum ether (1:6) to give benzylsulfamide. Colorless crystals. Yield: 90%.
Reaction SMILES: [CH:1](/[N:6]=[C:7]=[O:8])=[CH:2]\[CH:3]=[CH:4]\[CH3:5].[F:9][C:10]1[C:11](=[O:17])[NH:12][C:13](=[O:16])[NH:14][CH:15]=1>CN(C)C(=O)C.C(OCC)(=O)C>[CH:1](/[NH:6][C:7]([N:14]1[CH:15]=[C:10]([F:9])[C:11](=[O:17])[NH:12][C:13]1=[O:16])=[O:8])=[CH:2]\[CH:3]=[CH:4]\[CH3:5]
Reactant: C/C=C/C=C/N=C=O
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: C/C=C/C=C/NC(=O)n1cc(F)c(=O)[nH]c1=O
Reaction time: 3 h

Procedure:
To the above solution of trans,trans-1,3-pentadienyl isocyanate was added a solution of 5-fluorouracil (2.6 g.) in N,N-dimethylacetamide (15 ml.) at 80° C. and stirred for 3 hours at the same temperature. The resultant mixture was diluted with ethyl acetate (100 ml.), washed with water (4 times), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was recrystallized from diethyl ether to give 1-[N-(trans,trans-1,3-pentadienyl)carbamoyl]-5-fluorouracil.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[Mg]Br>>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:11]([C:10]1[CH:9]=[N:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:14][CH:13]=1)[OH:12]
Reactant: O=Cc1ccc(-c2ccccc2)nc1
Reactant: Br[Mg]c1ccco1
Product: OC(c1ccc(-c2ccccc2)nc1)c1ccco1

Procedure:
Synthesized using compound 43b (650 mg, 3.75 mmol) and furan-2-ylmagnesium bromide (1.85 g, 10.8 mmol, 2 M in THF) according to Method D. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (6:1) as eluent. Yellow solid. Yield: 631 mg, 67%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=3.62 (br. s., 1H), 5.86 (s, 1H), 6.17 (d, J=3.4 Hz, 1H), 6.33 (dd, J=3.0, 1.8 Hz, 1H), 7.33-7.51 (m, 4H), 7.69 (d, J=7.9 Hz, 1H), 7.83 (dd, J=8.2, 1.8 Hz, 1H), 7.88-7.99 (m, 2H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=66.7, 106.7, 109.3, 119.4, 126.0, 127.7, 128.0, 134.0, 134.3, 137.9, 141.8, 147.1, 154.1, 156.1; (ESI): m/z=251.87 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][CH:22]([N:25]5[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26]5)[CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.[C:32](OC(=O)C)(=[O:34])[CH3:33].CCOCC>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:31])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:20][CH2:21][CH:22]([N:25]5[CH2:29][CH2:28][CH:27]([NH:30][C:32](=[O:34])[CH3:33])[CH2:26]5)[CH2:23][CH2:24]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N5CCC(N)C5)CC4)n3)ccc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)NC1CCN(C2CCN(c3nc(-c4ccc5c(c4)C(C)(C)CCC5(C)C)cs3)CC2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
150 mg (0.32 mmol) of 1-{1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-yl}pyrrolidin-3-ylamine were dissolved in 1 ml of pyridine, and 90 μl of acetic anhydride were added. The reaction mixture was stirred at RT for 15 h and subsequently evaporated. The residue was taken up in ethyl acetate, washed with sat. NaHCO3 solution, dried over Na2SO4 and evaporated. The oil obtained in this way was stirred with ether, and the precipitate formed was filtered off with suction, washed with ether and dried.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[NH2:16])[CH2:6]1)(=[O:3])[CH3:2].[CH3:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[C:21](Cl)=[O:22]>>[C:1]([O:4][CH:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[NH:16][C:21](=[O:22])[C:20]2[CH:24]=[C:25]([CH3:27])[CH:26]=[C:18]([CH3:17])[CH:19]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCN([C@H]2CCCC[C@H]2N)C1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Product: CC(=O)OC1CCN([C@H]2CCCC[C@H]2NC(=O)c2cc(C)cc(C)c2)C1

Procedure:
Following the procedure of Example 1b, using cis-N-[2-(3-acetyloxy-1-pyrrolidinyl)cyclohexyl]amine and 3,5-dimethylbenzoyl chloride there is obtained as product cis-N-[2-(3-acetyloxy-1-pyrrolidinyl)cyclohexyl]-3,5-dimethylbenzamide.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][NH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.NC1C=C([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)C=CC=1CN.C1N=CN(C(N2C=NC=C2)=O)C=1>>[O:12]=[C:8]1[NH:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([N:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]3)=[CH:3][CH:4]=2)[NH:9]1
Reactant: O=C1NCc2ccc(Br)cc2N1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(CN)c(N)c2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)NC(=O)NC3)CC1
Yield: 75 %

Procedure:
Following the same procedure adopted for the synthesis of compound 13, reaction of compound 20 with CDI afforded 0.73 g (75%) of compound 16 as an off-white solid, m.p. 218-219° C.; IR (KBr) νmax. cm−1: 3211, 3166 (NH), 3037 (Ar—H), 1693 (C═O), 1610, 1519, 1417 (C═C). 1H NMR (500 MHz, CDCl3) δ=1.48 (s, 9H, (CH3)3C); 3.00 (m, 4H, 2CH2); 3.56 (m, 4H, 2CH2); 4.48 (s, 2H, CH2); 6.62 (d, 1H, J=2.5 Hz, H-8); 6.64 (d, 1H, J=8.5 Hz, H-5); 6.74 (dd, 1H, J=2.5, 8.4 Hz, H-6); 7.80 (br.s, 1H, NH); 13C NMR (125.7 MHz, CDCl3) δ=28.65 (CH3)3C), 43.31 (CH2), 43.98 (CH2), 50.63 (CH2), 80.18 (CH3)3C), 115.13 (C-8/C-6), 115.21 (C-8/C-6), 117.59 (C-5), 118.35 (C-5), 130.66 (C-5), 147.20 (C-5), 154.91 (C═O), 155.95 (C═O). Calculated (%) for C17H24N4O3 (332.18); C, 61.43; H, 7.28; N, 16.86. found (%) C, 61.37; H, 7.32; N, 16.80.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[CH3:21][NH:22][CH2:23][CH:24]1[CH:28]([CH3:29])[CH2:27][NH:26][CH2:25]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:1][C:2]1[C:3]([N:26]2[CH2:27][CH:28]([CH3:29])[CH:24]([CH2:23][NH:22][CH3:21])[CH2:25]2)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18]
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: CNCC1CNCC1C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CNCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)CC1C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
A mixture of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (5 ml), 3-methylaminomethyl-4-methylpyrrolidine (0.32 g) and DBU (0.25 g) was refluxed for an hour and allowed to stand overnight at room temperature. The resulting precipitate was collected by filtration, washed with acetonitrile and ether successively and recrystallized from chloroform-methanol-concentrated aqueous ammonia to give the title compound (0.31 g) as pale yellow powder, mp 253°-255° C.
Reaction SMILES: [C:1]([OH:14])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(OC(=O)C)(=O)C.[NH:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)(=O)C>[C:1]([N:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: C1CCCNCC1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCCCCC(=O)N1CCCCCC1
Yield: 83.4 %

Procedure:
A mixture of dodecanoic acid (20.03 g, 0.1M), acetic anhydride (13.27 g, 0.13M), hexahydro-1H-azepine (12.9 g, 0.13M) was heated with distillation of formed acetic acid. The residue on distillation gave 23.46 g (83.5%) of colorless product, b.p. 204-205/7 mm.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:17]([CH:30]([OH:34])[CH:31]([CH3:33])[CH3:32])=[N:16][C:15]=2[N:14]([CH3:35])[C:13]1=[O:36])(C(C)(C)C)(C)C.Cl>C(O)C.O.C(OCC)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:18]2[C:19]3[C:20](=[O:21])[N:12]([CH2:11][CH2:10][CH2:9][OH:8])[C:13](=[O:36])[N:14]([CH3:35])[C:15]=3[N:16]=[C:17]2[CH:30]([OH:34])[CH:31]([CH3:32])[CH3:33])=[CH:28][CH:27]=1
Reactant: CC(C)C(O)c1nc2c(c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C)n1Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CC(C)C(O)c1nc2c(c(=O)n(CCCO)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
Step 2 1-(3-((tert-Butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-8-(1-hydroxy-2-methylpropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.19 g, 0.355 mmol) was dissolved in ethanol (5 mL) and 6 N HCl (0.5 mL) was added. The clear solution was stirred at room temperature for 1 h. The reaction was diluted with water (75 mL) and extracted with DCM (3×50 ml). The combined extracts were dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to yield a white solid. Solid was slurried in diethyl ether (4 mL) and collected to give 7-(4-chlorobenzyl)-8-(1-hydroxy-2-methylpropyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.085 g, 56% yield) as a white solid. LCMS retention time=3.263 min and 94% purity, LCMS MH+ 421. 1H NMR (CDCl3) δ 7.23 (dd, 4H, J=8 Hz and 68 Hz), 5.59 (dd, 2H, J=16 Hz and 40 Hz), 4.43 (t, 1H, J=8 Hz). 4.17 (t, 2H, J=8 Hz), 3.59 (s, 3H), 3.48-3.54 (m, 2H), 3.35-3.40 (m, 1H), 2.48 (d, 1H, J=8 Hz), 2.08-2.16 (m, 1H), 1.85-1.92 (m, 2H), 1.03 (d, 3H, J=8 Hz), 0.82 (d, 3H, J=8 Hz).
Reaction SMILES: [Cl:1][C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.Cl.[CH3:9][C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=1[NH:17][C:18]1[CH2:22][CH2:21][CH2:20][N:19]=1>>[ClH:1].[CH3:9][C:10]1[CH:15]=[C:14]([NH:16][C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH:13]=[CH:12][C:11]=1[NH:17][C:18]1[CH2:22][CH2:21][CH2:20][N:19]=1
Reactant: Cc1cc(N)ccc1NC1=NCCC1
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCOC(=O)Nc1ccc(NC2=NCCC2)c(C)c1

Procedure:
The title compound was prepared by the method of Example 21 using 30.5 mmole of ethyl chloroformate and 1.0 g (3.8 mmole) of the product compound of Example 9. Complete reaction, as indicated by thin-layer chromatography (See Example 21), required heating for a second day with an additional 30.5 mmole of ethyl chloroformate. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([C:26]2[CH:31]=[N:30][CH:29]=[C:28](Cl)[N:27]=2)C(=O)C(C)(C)C)=[CH:15][CH:14]=1>CN(C)C=O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:26]2[CH:31]=[N:30][CH:29]=[C:28]([N:4]3[CH:5]=[C:6]4[C:11]([CH:10]=[CH:9][CH:8]=[CH:7]4)=[N:3]3)[N:27]=2)=[CH:17][CH:18]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:26]2[CH:31]=[N:30][CH:29]=[C:28]([N:3]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[N:4]3)[N:27]=2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)C(=O)N(c1ccc(Cl)cc1)c1cncc(Cl)n1
Reactant: c1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(Nc2cncc(-n3cc4ccccc4n3)n2)cc1
Product: Clc1ccc(Nc2cncc(-n3ncc4ccccc43)n2)cc1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 13 %
Yield: 12 %

Procedure:
Sodium hydride (180 mg, 4.50 mmol) was added to a suspension of indazole (543 mg, 4.40 mmol) in N,N-dimethylformamide (5 mL) and the reaction mixture was stirred at 50° C. for 20 minutes. To this suspension N-(4-chloro-phenyl)-N-(6-chloro-pyrazin-2-yl)-2,2-dimethyl-propionamide (300 mg, 0.88 mmol) was added and stirred at 100° C. over night. The reaction mixture was quenched with brine and extracted with ethyl acetate (4×15 mL). The combined organic phases were washed with brine, dried over sodium sulphate, filtrated and evaporated. The crude product was purified by column chromatography with ethyl acetate-heptane as eluent to give (4-chloro-phenyl)-(6-indazol-2-yl-pyrazin-2-yl)-amine (17 mg, 13%, Mp 249-252° C., LC-ESI-HRMS of [M+H]+ shows 322.0864 Da. Calc. 322.085948 Da, dev. 1.4 ppm) as a yellow solid, and (4-chloro-phenyl)-(6-indazol-1-yl-pyrazin-2-yl)-amine (19 mg, 12%, Mp. 204-207° C., LC-ESI-HRMS of [M+H]+ shows 322.0876 Da. Calc. 322.085948 Da, dev. 5.1 ppm) as a brown solid.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH3:21][NH:22][CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[N:22]([CH3:21])[CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: CNCc1cccc2ccccc12
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N(C)Cc2cccc3ccccc23)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and methyl-naphthalen-1-ylmethyl-amine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C24H25NO5 [M+H]+: 408.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:9]([O:14][CH:15]3[CH2:18][N:17]([C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[CH2:16]3)=[N:10][CH:11]=[CH:12][N:13]=2)[CH2:4][CH2:3]1.CCN(CC)CC.[C:36](Cl)(=[O:39])[O:37][CH3:38]>C(Cl)Cl>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[N:17]1[CH2:18][CH:15]([O:14][C:9]2[C:8]([CH:5]3[CH2:6][CH2:7][N:2]([C:36]([O:37][CH3:38])=[O:39])[CH2:3][CH2:4]3)=[N:13][CH:12]=[CH:11][N:10]=2)[CH2:16]1
Reactant: COC(=O)Cl
Reactant: c1ccc2nc(N3CC(Oc4nccnc4C4CCNCC4)C3)ccc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(c2nccnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a solution of 2-(3-((3-(piperidin-4-yl)pyrazin-2-yl)oxy)azetidin-1-yl)quinoline hydrochloride (see PREPARATION P4.1; 100 mg, 0.29 mmol) in dry DCM (10 mL) was added Et3N (1 mL). The reaction mixture was cooled to 0° C. with an ice bath, and methyl carbonochloridate (54 mg, 0.58 mmol) was added dropped to the reaction mixture. After 1 hour, the reaction mixture was warmed to RT, and stirred overnight. Then the reaction mixture was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product. The crude product was purified via flash chromatography on silica gel (20% to 45% EtOAc in petroleum ether) to give methyl 4-(3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyrazin-2-yl)piperidine-1-carboxylate (93 mg, 0.23 mmol, 79% yield) as a white solid. ESI-MS (M+1): 404 calc. for C23H25N5O2 403.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[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][N:24]([C:35](=[O:37])[CH3:36])[C@@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][C@@H:26]2[OH:34])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.I[CH3:40].[H-].[Na+]>CN(C=O)C.Cl.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:38])[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][N:24]([C:35](=[O:37])[CH3:36])[C@@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][C@@H:26]2[O:34][CH3:40])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(C)=O)[C@@H]2c3ccccc3C[C@@H]2O)c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(C)=O)[C@@H]2c3ccccc3C[C@@H]2OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (2′-{[acetyl-((1R,2S)-2-hydroxy-indan-1-yl)-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.163 g, 0.31 mmol) and iodomethane (0.02 mL, 0.34 mmol) in DMF (1.6 mL) was added sodium hydride (60% in mineral oil; 0.015 g, 0.37 mmol), and the mixture was stirred at room temperature for 1 hour. Once minimal starting material was seen by analytical LCMS, the solution was diluted with aqueous 1N HCl and CH2Cl2. The organic layer was separated, dried over MgSO4., filtered, and concentrated to give the title compound.
Reaction SMILES: [H-].[Na+].CI.[CH2:5]([OH:12])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11].[CH3:13]COCC>CN(C=O)C.O>[CH3:13][O:12][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11]
Reactant: CCOCC
Reactant: C#CCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: C#CCCCCCOC
Yield: 61.7 %

Procedure:
To a slurry of sodium hydride (7.86 g, 197 mmol) in DMF (100 mL) was added methyl iodide (12.29 mL, 197 mmol) followed by a solution of hept-6-yn-1-ol (24.5 g, 197 mmol) in DMF (50 mL). Following the addition the reaction was monitored by TLC. After 2 h additional methyl iodide (6 mL, 50 mmol) was added followed by sodium hydride (1 g, 25 mmol) portions. At 1 h intervals additional sodium hydride (1 g, 25 mmol) portions was added until no alcohol remained as indicated by TLC. Et2O (50 mL) and water (100 mL) was added to the reaction mixture and the layers were separated. The organic layer was washed with brine, dried using Na2SO4, filtered and distilled (145-155° C.) to provide 7-methoxyhept-1-yne (18 g, 121 mmol, 61.7% yield) as a colorless oil.