Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[Cl:22].[Cl:23][C:24]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=[CH:26][C:25]=1/[N:39]=[C:40]1/[C:41]2[CH:51]=[CH:50][CH:49]=[CH:48][C:42]=2[N:43]([CH3:47])[C:44](=[O:46])[O:45]/1.CCO.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Cl:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([N:39]2[C:40](=[O:45])[C:41]4[C:42](=[CH:48][CH:49]=[CH:50][CH:51]=4)[N:43]([CH3:47])[C:44]2=[O:46])[C:24]=1[Cl:23])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3
Reactant: Cn1c(=O)o/c(=N\c2cccc(B3OC(C)(C)C(C)(C)O3)c2Cl)c2ccccc21
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cn1c(=O)n(-c2cccc(-c3c(Cl)cc(C(N)=O)c4[nH]c5cc(C(C)(C)O)ccc5c34)c2Cl)c(=O)c2ccccc21
Temperature: 90 °C
Yield: 4.5 %

Procedure:
A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 3] (36 mg, 0.094 mmol), (Z)-4-((2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-1-methyl-1H-benzo[d][1,3]oxazin-2(4H)-one [Intermediate 40] (42.8 mg, 0.104 mmol), EtOH (1 mL), toluene (1 mL) and 2 M aqueous Na2CO3 (0.16 mL, 0.311 mmol) was bubbled with nitrogen for 5 min. The mixture was treated with tetrakis(triphenylphosphine)palladium (8.7 mg, 7.55 μmol), and the reaction vessel was sealed and heated at 90° C. for 16 h. The cooled mixture was partitioned between EtOAc and water, and the organic phase was dried and concentrated. The residue was purified by column chromatography on silica gel (4 g), eluting with MeOH-DCM containing 1% TEA (gradient from 0-5%). The resulting material was further purified using preparative HPLC (PHENOMENEX® Axia C18 30×100 mm), eluting with MeCN-water containing 0.1% TFA (gradient from 20-100%, 30 mL/min) The appropriate fractions were treated with saturated aqueous NaHCO3 and concentrated. The residue was partitioned between EtOAc and water, and the organic phase was washed with brine, dried and concentrated to give 3-chloro-4-(2-chloro-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a white solid (2.5 mg, 4% yield). Mass spectrum m/z 569 (M+H—H2O)+. 1H NMR (400 MHz, chloroform-d) δ 8.38-8.23 (m, 1H), 7.73 (d, J=1.5 Hz, 2H), 7.70-7.66 (m, 1H), 7.64 (s, 1H), 7.60-7.55 (m, 1H), 7.51-7.45 (m, 1H), 7.37-7.28 (m, 2H), 7.26-7.20 (m, 1H), 7.10-6.78 (m, 1H), 3.70 (s, 2H), 3.67 (s, 1H), 1.65 (s, 4H), 1.64 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[Br:15]Br>C(O)(=O)C>[Br:15][CH:8]([C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=1)[CH2:9][C:10]([OH:12])=[O:11]
Reactant: BrBr
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Solvent: CC(=O)O
Product: O=C(O)CC(Br)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3-(4-fluorobenzoyl)propionic acid (0.01 mole) and bromine (0.012 mole) in acetic acid is stirred at room temperature for 16 hours. The solvent is removed to give 3-bromo-3-(4-fluorobenzoyl)propionic acid.
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C[CH2:16][Mg:17][Cl:18])C=CC=CC=1.C1(CC[Mg]Br)C=CC=CC=1.C1(CCC[Mg]Br)C=CC=CC=1.C[Mg]Cl>>[CH2:16]([Mg:17][Cl:18])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cl[Mg]CCc1ccccc1
Reactant: Cl[Mg]c1ccccc1
Agent: Br[Mg]CCCc1ccccc1
Agent: Br[Mg]CCc1ccccc1
Agent: C[Mg]Cl
Product: Cl[Mg]Cc1ccccc1

Procedure:
The same procedures as described in Preparation Example 1 were repeated using phenyl magnesium chloride, 2-phenylethyl magnesium chloride, 2-phenylethyl magnesium bromide, 3-phenylpropyl magnesium bromide and methyl magnesium chloride, respectively, in place of benzyl magnesium chloride to obtain functionalized amines. Each compound obtained in Preparation Examples 4 to 7 and physical properties thereof are given below in table 4.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:52]>>[NH2:52][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCNC(=O)CCCCCn1c(COCC)nc2cnc3ccccc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCCNC(=O)CCCCCn1c(COCC)nc2c(N)nc3ccccc3c21

Procedure:
6-[2-(Ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-N-propylhexanamide (4.1 g, 11 mmol) was treated with mCPBA (5.74 g, 33.3 mmol) followed by ammonium hydroxide (50 mL) and p-toluenesulfonyl chloride (2.85 g, 14.9 mmol) according to the method described in Part D of Example 8. The crude product was purified by column chromatography on silica gel (eluting with 97:3 dichloromethane:methanol) followed by recrystallization from methanol:water to provide 0.548 g of 6-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-N-propylhexanamide as beige needles, mp 161-162° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:15])[C:8]([C:12]([OH:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.O.C([O-])(O)=O.[Na+].[CH3:22][CH2:23]O>S(=O)(=O)(O)O>[CH2:22]([O:13][C:12]([C:8]1[C:7]([OH:15])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:9]=1)=[O:14])[CH3:23]
Reactant: CCO
Reactant: O=C(O)c1cc2cc(Br)ccc2cc1O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc2cc(Br)ccc2cc1O
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of 81 g (0.3 mol) of 7-bromo-3-hydroxy-2-naphthoic acid in 600 ml dried EtOH and 60 ml conc. sulfuric acid was heated at reflux for 16 hours. The mixture was cooled to room temperature and treated with water (4000 ml) and neutralised with NaHCO3. The solid was separated by filtration and dried in a drying chamber afforded 75.3 g (85%) of the titled compound.
Reaction SMILES: [CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1.[NH2:22][C@@H:23]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:24][C@H:25]([OH:44])[C@@H:26]([NH:34][C:35]([O:37][CH2:38][C:39]1[S:43][CH:42]=[N:41][CH:40]=1)=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C1COCC1>[CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:19]([NH:22][C@@H:23]([CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[CH2:24][C@H:25]([OH:44])[C@@H:26]([NH:34][C:35]([O:37][CH2:38][C:39]1[S:43][CH:42]=[N:41][CH:40]=1)=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:21])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:10])[CH3:11])[S:7][CH:8]=1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Yield: 74.6 %

Procedure:
A solution of 70 mg (0.223 mmol) of N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine, 79 mg (0.186 mmol) of (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane, 30 mg (0.223 mmol) of 1-hydroxybenzotriazole hydrate, and 51 mg (0.266 mmol) of N-ethyl-N'-dimethylaminopropyl carbodiimide in 2 ml of THF was stirred at ambient temperature for 16 h. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel chromatography using 97:3 CH2Cl2 :CH3OH to provide 100 mg (74%) of the desired compound (Rf 0.4, 95:5 CH2Cl2 :CH3OH) as a solid. 1H NMR (d6 -DMSO) δ0.73 (d, J=7 Hz, 6H), 1.30 (d, J=7 Hz, 6H), 1.45 (m, 2H), 1.87 (m, 1H), 2,5-2.7 (m, 4H), 2.87 (s, 3H), 3.23 (heptet, J=7 Hz, 1H), 3.57 (m, 1H), 3.81 (m, 1H), 3.93 (m, 1H), 4.15 (m, 1H), 4.44 (AA', 2H), 4.62 (d, J=6 Hz, 1H), 5.13 (AA', 2H), 6.01 (d, J=9 Hz, 1H), 6.89 (d, J=9 Hz, 1H), 7.1-7.2 (m, 11H), 7.68 (d, J=9 Hz, 1H), 7.85 (s, 1H), 9.05 (s, 1H). Mass spectrum: (M+H)+ =721. Anal. Calcd for C37H48N6O5S2.0.5H2O: C, 60.88; H, 6.77; N, 11.51. Found: C, 60.68; H, 6.53; N, 11.36.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)=O>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)=[S:10]
Reactant: O=C(Nc1ccc(F)cc1F)c1ccccn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(NC(=S)c2ccccn2)c(F)c1
Yield: 94.7 %

Procedure:
Lawesson's reagent (29.8 g, 74 mmol) and N-(2,4-difluorophenyl)-2-pyridinecarboxamide (14.37 g, 61 mmol) were combined in toluene (185 mL) and refluxed for 3 hours. After evaporation of the solvent, the residue was dissolved in dichloromethane, preadsorbed on silica gel, and flash chromatographed (eluted with 2% ethyl acetate in petroleum ether) to provide N-(2,4-difluorophenyl)-2-pyridinecarbothioamide as a yellow solid (14.45 g, 94%) m.p. 124°-129° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:15]([NH:16][C:17]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)=[O:18])[C:14](=[O:29])[N:13]([CH2:30][C:31]([O:33]CC)=O)[C:12]3[CH:36]=[CH:37][CH:38]=[CH:39][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[NH3:40]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH:15]([NH:16][C:17]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)=[O:18])[C:14](=[O:29])[N:13]([CH2:30][C:31]([NH2:40])=[O:33])[C:12]3[CH:36]=[CH:37][CH:38]=[CH:39][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)CN1C(=O)C(NC(=O)c2ccc3ccccc3c2)C(c2ccc(OC)cc2)Sc2ccccc21
Reactant: N
Solvent: CO
Product: COc1ccc(C2Sc3ccccc3N(CC(N)=O)C(=O)C2NC(=O)c2ccc3ccccc3c2)cc1
Reaction time: 72 h

Procedure:
In 500 ml of methanol is dissolved 1.8 g of ethyl 2-p-methoxyphenyl- 3-(2-naphthalenecarboxamido)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, into which ammonia gas is blown under ice-cooling for about 1 hour. After the mixture is allowed to stand still at room temperature for 3 days, the reaction mixture is concentrated under reduced pressure to the volume of about 50 ml to give crystals. The crystals are collected by filtration to give 1.2 g of 2-p-methoxyphenyl-3-(2-naphthalenecarboxamido)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, m.p. 243°-245° C.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:14]([OH:16])=O)[CH3:3].C(N1C=CN=C1)([N:19]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:14]([NH2:19])=[O:16])[CH3:3]
Reactant: CC(C)Oc1c(C(=O)O)oc2ccccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Oc1c(C(N)=O)oc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A suspension of 3-(1-methylethoxy)-2-benzofurancarboxylic acid (200 mg, 0.91 mmol) and 1,1'-carbonyldiimidazole (191 mg, 1.18 mmol) in 5 mL of tetrahydrofuran is heated at reflux for 1 hour. The reaction solution is cooled to room temperature and aqueous ammonium hydroxide (3 mL) is added and the reaction mixture is stirred at room temperature for 2 hours. The reaction is diluted with ethyl acetate and washed with 1N HCl, saturated aqueous NaHCO3, and brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography eluting with ethyl acetate:hexane (1:1) provides 3-(1-methylethoxy)-2-benzofurancarboxamide in 77% yield; mp=82°-83° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:7](=[O:15])[C:6]=2[CH:16]=1.[N+:17]([C:20]1[C:25](F)=[CH:24][CH:23]=[CH:22][N:21]=1)([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:25]3[C:20]([N+:17]([O-:19])=[O:18])=[N:21][CH:22]=[CH:23][CH:24]=3)([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:7](=[O:15])[C:6]=2[CH:16]=1
Reactant: CCOC(=O)C1Oc2ccc(Br)cc2C1=O
Reactant: O=[N+]([O-])c1ncccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C1(c2cccnc2[N+](=O)[O-])Oc2ccc(Br)cc2C1=O
Temperature: 87.5 °C

Procedure:
A mixture of ethyl 5-bromo-3-oxo-2,3-dihydro-1-benzofuran-2-carboxylate (1.42 g, 5.0 mmol), 2-nitro-3-fluoropyridine (0.71 g, 5 mmol) and potassium carbonate (0.83 g, 6.0 mmol) in DMSO (15 mL) is heated at 85-90° C. for 18 h. The mixture is cooled to ambient temperature and partitioned between EtOAc and brine. The layers are separated and the aqueous layer is further extracted with EtOAc. The combined organic extracts are dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient elution with hexanes-EtOAc) to afford the title compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:1][C:13]1[S:9][C:10]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:12]=1
Reactant: c1csc(-c2cccs2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Brc1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
N-Bromosuccinimide (NBS, 1.12 g, 6.3 mmol) was added in small portions to a stirred solution of 1.0 g {6.01 mmol} of 2,2'-bithiophene in 10 ml of glacial acetic acid and 10 ml of chloroform. After stirring for 1 h at room temperature, the mixture was poured into ice-water and extracted into chloroform (75 ml). The organic layer was washed with aqueous sodium bicarbonate solution, water, and then dried over magnesium sulfate and evaporated. The residue was subjected to flash chromatography on silica gel using hexane to give 1.3 g (88%) of a light green solid, m.p. 55-56° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:48])([CH3:47])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=2)[CH:9]=1.C1C(=O)N([Br:56])C(=O)C1>C(#N)C>[CH3:46][Si:43]([CH3:45])([CH3:44])[CH2:42][CH2:41][O:40][CH2:39][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:47])[CH3:48])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:33]=2)[C:9]=1[Br:56]
Reactant: COC(=O)Cc1ccc(Cc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)Cc1ccc(Cc2nc3c(-c4cnc5ccccc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 2-(4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)phenyl)acetate (150 mg, 0.22 mmol) was dissolved in ACN (10 mL). NBS (40 mg, 0.22 mmol) was added and the mixture was stirred at room temperature for 1 h. After concentration, the product that resulted, methyl 2-(4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)phenyl)acetate was used in the next step without further purification HPLC-MS tR=2.66 min (UV254 nm); mass calculated for formula C37H48BrN5O4Si2 761.2, observed LCMS m/z 762.2 (M+H).
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[Li+].CC([N-]C(C)C)C.Br[CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31]>C1COCC1>[CH3:31][C:30]([CH3:32])=[CH:29][CH2:28][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:2]1
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)=CCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC=C(C)C)CCCN(C(=O)OC(C)(C)C)C1
Temperature: -55 °C
Reaction time: 4 h

Procedure:
To a solution of 1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (2.6 g, 10.0 mmol) in THF (30 mL) was slowly added LDA (6.7 mL, 12.0 mmol, 1.8 M solution in heptane/tetrahydrofuran/ethylbenzene) at −78° C. and the mixture was slowly warmed to −55° C. over 1 h. To this mixture, 1-bromo-3-methyl-2-butene (1.55 g, 10.5 mmol) was slowly added and the reaction was warmed to room temperature and stirred for 4 h. The mixture was quenched with saturated NH4Cl and extracted with diethyl ether, and the combined extracts were washed with brine, dried and concentrated. The product (2.75 g, 85%) was purified by CombiFlash eluted with hexane/ethyl acetate.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)[CH2:3][CH2:4]Cl.[I-].[Na+].[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>C(O)(C)C>[O:1]=[C:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)[CH2:3][CH2:4][N:28]1[CH2:29][CH2:30][N:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:26][CH2:27]1
Reactant: O=C1CCc2cc(C(=O)CCCl)ccc2N1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)O
Product: O=C1CCc2cc(C(=O)CCN3CCN(c4ccccc4)CC3)ccc2N1
Reaction time: 2 h

Procedure:
2.4 Grams of 6-(1-oxo-3-chloropropyl)-3,4-dihydrocarbostyril and 1.6 g of sodium iodide were mixed with 60 ml of isopropanol and the mixture was stirred at 40°-50° C. for 2 hours. Then to this reaction mixture were added 2.0 g of 4-phenylpiperazine and 3.0 g of DBU (1,5-diazabicyclo[5,4,0] undecane-5) and refluxed by heating for 6 hours. Then the reaction mixture was poured into 100 ml of 5%-sodium hydrogencarbonate solution and stirred at a room temperature for 1 hour. The insoluble matters were collected by filtration, washed with water and dried, then recrystallized from ethanol-chloroform to obtain 1.9 g of 6-[1-oxo-3-(4-phenylpiperazinyl)-propyl]-3,4-dihydrocarbostyril in colorless flake-like crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH3:2].[C:11]([Si:15]([CH3:23])([CH3:22])[O:16][CH2:17][CH2:18][C@@H:19]1[CH2:21][O:20]1)([CH3:14])([CH3:13])[CH3:12]>CCO.O>[C:11]([Si:15]([CH3:23])([CH3:22])[O:16][CH2:17][CH2:18][C@@H:19]([OH:20])[CH2:21][NH:8][C:7]1[CH:9]=[CH:10][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1)([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CO1
Reactant: CCOc1ccc(N)cc1
Solvent: CCO
Solvent: O
Product: CCOc1ccc(NC[C@H](O)CCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 80 °C
Yield: 62 %

Procedure:
A solution of 4-ethoxy-aniline (commercial; 3.2 mL) in EtOH/water (9:1; 150 mL) was reacted with (2R)-2-[2-[[(tert-butyl)dimethylsilyl]oxy]ethyl]-oxirane (prepared according to WO 2007/144423) and further heated at 80° C. overnight. The solvents were removed under reduced pressure and the residue was purified by CC (EA/Hept 1:1), affording a brown oil (5.22 g; 62% yield).
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]#[N:4].Cl.[H][H].N[C@H](CC1C=CC=CC=1)CO>CO.O.[Pd]>[C:6]1([CH2:5][C@@H:2]([NH2:1])[CH2:3][NH2:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: N#C[C@H](N)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Agent: N[C@@H](CO)Cc1ccccc1
Solvent: O
Solvent: CO
Product: NC[C@H](N)Cc1ccccc1
Reaction time: 19 h
Yield: 6 %

Procedure:
To a solution of 9.0 g (49 mmol) of (R)-2-amino-3-phenylpropionitrile.HCl-salt (97.5% e.e.) in 280 mL of methanol-water 1:1 was added 2.2 equiv. of conc. HCl solution and 2.0 g of 5% Pd/C. The solution was hydrogenated for 19 h at 35° C. and 0.9 MPa of hydrogen pressure. Then additional 2 g of Pd/C was added and hydrogenation was continued for 24 h at 3.0 MPa. According to chiral HPLC 91% of (R)-2-amino-3-phenyl-1-propanol was formed together with 6% of (R)-3-phenyl-1,2-diaminopropane The reaction mixture was filtered and partially evaporated. The solution was basified to pH 10 using diluted NaOH solution and extracted with CH2CL2. The organic solution was dried over Na2SO4 and evaporated.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([CH:21]=O)[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[CH2:33]([O:35][C:36]([C@@H:38]1[CH2:43][CH2:42][CH2:41][NH:40][CH2:39]1)=[O:37])[CH3:34].CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([CH2:21][N:40]3[CH2:41][CH2:42][CH2:43][C@@H:38]([C:36]([O:35][CH2:33][CH3:34])=[O:37])[CH2:39]3)[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: C[C@@H](O[C@H]1CC[C@@H](C=O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCOC(=O)[C@@H]1CCCN(C[C@@H]2CC[C@H](O[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H]2c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
To a solution of 9.8 g (22 mmole) of 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(formyl)cyclopentane from Step A in 100 mL of 1,2-dichloroethane was added 8.7 g (28 mmole) of (R)-3-ethoxycarbonylpiperidine hydrochloride and 4.9 mL (28 mmole) of DIPEA. After stirring at room temperature for 10 minutes, 9.2 g (44 mmole) of sodium triacetoxyborohydride was added. The reaction was stirred for 16 hours. The reaction was quenched with sat'd sodium bicarbonate and was extracted twice with methylene chloride. The organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and evaporated. The residue was purified by prep LC (20-30% ethyl acetate/hexanes) to give 10.5 g of title compound.
Reaction SMILES: [CH:1]([O:4][P:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[OH:6])([CH3:3])[CH3:2].[Na].[C:12](#[N:15])[CH:13]=[CH2:14]>>[C:12]([CH2:13][CH2:14][P:5]([C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:6])[O:4][CH:1]([CH3:3])[CH3:2])#[N:15]
Reactant: C=CC#N
Reactant: CC(C)OP(O)C(C)(C)C
Agent: [Na]
Product: CC(C)OP(=O)(CCC#N)C(C)(C)C

Procedure:
To 15.7 g of t-butylphosphonous acid-isopropylester in 6.3 ml of acrylonitrile are added 21 ml of sodium isopropylate (0.25 molar). After the exothermic reaction (the temperature rises to 100°) the suspension is filtered, the filtrate evaporated and the residue distilled to yield isopropyl 2-cyanoethyl(t-butyl)phosphinate as an oil, b.p. 121°/8 Pa, nD20 =1.4480.