Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C1CCCCC1)CC(O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.[CH2:20]1[CH2:24][O:23][CH2:22][CH2:21]1>>[CH:20]1([CH:21]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:22][OH:23])[CH2:24][CH2:22][CH2:21][CH2:20][CH2:24]1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)C1CCCCC1
Agent: B
Product: CC(C)(C)OC(=O)NC(CO)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A solution of N-(t-butyloxycarbonyl)cyclohexylglycine (2.0 g, 7.77 mmol) in anhydrous THF (10 mL) was cooled to 0° C. Borane solution (1 M in THF, 15.5 mL, 15.5 mmol) was added slowly and the reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction was quenched with MeOH (5 mL), volatiles were evaporated and the residue was partitioned between water and EtOAc. The organic layer was washed with saturated NaHCO3/water, brine, dried (sodium sulfate), and evaporated to give tert-butyl 1-cyclohexyl-2-hydroxyethylcarbamate 2a (1.26 g, 66.7%), MS (CI) m/z 144.20 (MH+-Boc).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[O:5][C:6]=1[Br:7].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:44][CH:45]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH2:46][NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:44][CH:45]([CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH2:46][NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:51])[CH3:52])=[O:10])[O:5][C:6]=1[Br:7]
Reactant: CC(C)(C)OC(=O)NCC(N)Cc1ccccc1
Reactant: O=C(O)c1cc(Br)c(Br)o1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(Cc1ccccc1)NC(=O)c1cc(Br)c(Br)o1
Reaction time: 16 h
Yield: 107 %

Procedure:
To a solution of 4,5-dibromo-2-furancarboxylic acid (2.81 g, 10.4 mmol), PyBrOP (5.6 g, 12.0 mmol) and diisopropylethyl amine (4.2 mL, 24.0 mmol) in DCM (70 mL) at 25° C. was added 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate (2.0 g, 8.0 mmol). After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, hexanes/EtOAc, 2:1) affording the title compound (4.3 g, 82%) as a white solid: LC-MS (ES) m/z=503 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([CH2:8][CH:9]2[CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:21]5([C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[CH2:23][C:22]5=[O:30])[CH2:20][O:19][C:17]4=[CH:18][C:11]=3[O:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C-:31]#[N:32].[Na+].O>CN1CCCC1=O.O.O.O.O.O.O.[Ni](Cl)Cl>[O:30]=[C:22]1[CH2:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]21[C:16]1[C:17](=[CH:18][C:11]3[O:10][CH:9]([CH2:8][C:3]4[C:2]([C:31]#[N:32])=[CH:7][CH:6]=[CH:5][N:4]=4)[CH2:14][O:13][C:12]=3[CH:15]=1)[O:19][CH2:20]2
Reactant: O=C1Cc2ccccc2C12COc1cc3c(cc12)OCC(Cc1ncccc1Br)O3
Reactant: [C-]#N
Agent: Cl[Ni]Cl
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cccnc1CC1COc2cc3c(cc2O1)OCC31C(=O)Cc2ccccc21
Temperature: 200 °C
Yield: 289 %

Procedure:
3-[(3-Bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one (0.233 g, 0.500 mmol), nickel (II) chloride hexahydrate (0.113 g, 0.500 mmol), and sodium cyanide (0.050 g, 1.0 mmol) were combined in 1-methyl-2-pyrrolidone (1 mL) and heated at 200° C. for 30 min under microwave irradiation. The reaction mixture was allowed to cool to ambient temperature, poured into water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (3×20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was subjected to column chromatography, and eluted with a 50% to 75% gradient of ethyl acetate in hexanes, to afford 2-[(2′-oxo-2,2′,3,3′-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-3-yl)methyl]pyridine-3-carbonitrile (0.593 g, 29%) as a colorless solid: mp 230-233° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.71 (dd, J=4.8, 1.4 Hz, 1H), 8.38 (dd, J=7.9, 1.5 Hz, 1H), 7.56 (dd, J=7.8, 4.9 Hz, 1H), 7.27-7.15 (m, 2H), 7.04 (d, J=7.5 Hz, 1H), 6.98 (d, J=7.9 Hz, 1H), 6.50 (s, 1H), 6.38 (s, 1H), 5.30 (s, 2H), 4.74 (ABq, 2H), 4.19-4.11 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 177.3, 158.2, 155.0, 153.1, 144.6, 143.1, 142.1, 138.2, 132.4, 129.1, 124.0, 123.4, 121.9, 116.5, 112.2, 109.8, 108.0, 99.1, 79.8, 64.7, 64.1, 57.7, 44.1; MS (ES+) m/z 412.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH3:16])[N:9]=2)[N:3]=1.N/C(=C\C)/C#N.C(OC1N=C(NN)C=CC=1)C.[C:34]([C:42](=[CH:48]OCC)[C:43]([O:45][CH2:46][CH3:47])=[O:44])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:34]([C:42](=[CH:48][NH:7][C:5]1[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH3:16])[N:9]=2)[N:3]=[C:2]([CH3:1])[CH:6]=1)[C:43]([O:45][CH2:46][CH3:47])=[O:44])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1ccccc1
Reactant: CCOc1cccc(-n2nc(C)cc2N)n1
Agent: C/C=C(\N)C#N
Agent: CCOc1cccc(NN)n1
Product: CCOC(=O)C(=CNc1cc(C)nn1-c1cccc(OCC)n1)C(=O)c1ccccc1

Procedure:
Following the procedure described in Reference Example 1-1, 3-methyl-1-(6-ethoxy-2-pyridinyl)-1H-pyrazol-5-amine was prepared from aminocrotononitrile and 6-ethoxy-2-hydrazinopyridine. Following the procedure described in Reference Example 1-2, the compound was subjected to a reaction with ethyl 2-benzoyl-3-ethoxy-2-propenoate to give ethyl 2-benzoyl-3-[[3-methyl-1-(6-ethoxy-2-pyridinyl)-1H-pyrazol-5-yl]amino)-2-propenoate. The compound was treated following the method described in Example 1-4 to give the title compound (35% cyclization yield).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[OH:24][CH2:25][C@H:26]([NH:29][C:30]1[CH2:34][S:33][C:32](=[O:35])[N:31]=1)[C:27]#[CH:28].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:34]2/[C:30]([NH:29][C@@H:26]([CH2:25][OH:24])[C:27]#[CH:28])=[N:31][C:32](=[O:35])[S:33]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: C#C[C@H](CO)NC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C#C[C@H](CO)NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Yield: 41.3 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (135 mg) in 2-propanol (5 mL) were added (R)-4-[(1-hydroxybut-3-yn-2-yl)amino]thiazol-2(5H)-one (110 mg) and piperidinium acetate (59 mg). The reaction mixture was heated under reflux overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (83 mg).
Reaction SMILES: [NH2:1][C:2]1[C:12]2[CH2:11][N:10]([C:13](=[O:15])[CH3:14])[CH2:9][CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:34])=[CH:19][N:18]=1.Cl.O1CCOCC1>COCCO>[C:13]([N:10]1[CH2:11][C:12]2[C:2]([NH:1][C:17]3[N:22]=[C:21]([NH:23][C:24]4[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=4[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:34])=[CH:19][N:18]=3)=[CH:3][CH:4]=[CH:5][C:6]=2[NH:7][CH2:8][CH2:9]1)(=[O:15])[CH3:14]
Reactant: CC(=O)N1CCNc2cccc(N)c2C1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cccc3c2CN(C(C)=O)CCN3)ncc1Cl
Yield: 3.8 %

Procedure:
1-(6-Amino-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-ethanone (35 mg, 0.17 mmol) was dissolved in 2-methoxyethanol (3 mL) and the mixture was treated with 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (25 mg, 0.084 mmol) and 4N HCl/dioxane (0.05 mL, 0.17 mmol). The reaction was then irradiated at 140° C. for 20 minutes. The mixture was then reduced en vacuo and the crude mixture was purified by prep HPLC to afford 1.47 mg of 2-[2-(4-Acetyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzamide as a light brown foam. LC/MS (ESI)=466.37 (M+H). 1H NMR (400 MHz, MeOD, d4) δ 8.80 (m, 1H), 8.29 (s, 1H), 8.04 (s, 1H), 7.79 (m, 3H), 7.64 (m, 3H), 7.35 (m, 1H), 6.97 (m, 1H), 6.49 (m, 1H), 3.64 (m, 2H), 3.35 (m, 2H), 3.21 (m, 2H), 2.98 (s, 3H), 1.94 (d, 3H, J=7.07 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1B(O)O>>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:21]2[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:28])[F:27])=[CH:25][C:20]=2[Cl:19])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1OCc1ccccc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Product: O=[N+]([O-])c1c(-c2ccc(C(F)(F)F)cc2Cl)ccnc1OCc1ccccc1
Yield: 79 %

Procedure:
2-Benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et al. WO 99/01454, which is incorporated herein by reference in its entirety) (2.0 g, 7.56 mmol) and 2-chloro-4-trifluoromethylphenylboronic acid (2.31 g, 11.3 mmol) were treated as in Part A of Example 19a to give 2.44 g (79%) of 2-benzyloxy-4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridine: MS (AP) m/z 408.8 [(M+H)+, 72].
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](OC)=[O:5].[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][NH2:15]>>[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][NH:15][C:4](=[O:5])[CH:3]([O:8][CH3:9])[O:2][CH3:1]
Reactant: NCc1cccc(F)c1
Reactant: COC(=O)C(OC)OC
Product: COC(OC)C(=O)NCc1cccc(F)c1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
Into a sealable tube were added methyl dimethoxyacetate (0.98 g, 7.3 mmol) and 3-fluorobenzylamine (0.91 g, 7.3 mmol); this mixture was stirred at 60° C. for 2 days. The compound was purified by chromatography on silica gel (10 g/70 mL prepacked column, eluting with 5% EtOAc in hexanes→5% MeOH in hexanes), affording the title compound. HPLC: tR=2.59 min. (ZQ2, polar—5 min.). MS (ES+): m/z=249.92 (29) [MNa+], 227.91 (100) [MH+].
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[CH2:11][N:12]1[CH:16]=[CH:15][CH:14]=[N:13]1)[CH2:8]2.[C:17]1(C)C=CC=CC=1.C([Li])CCC.CI>O1CCCC1>[CH3:17][C:16]1[N:12]([CH2:11][CH:2]2[CH:1]3[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]2[CH2:4]4)[CH2:8]3)[N:13]=[CH:14][CH:15]=1
Reactant: Cc1ccccc1
Reactant: c1cnn(CC2C3CC4CC(C3)CC2C4)c1
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccnn1CC1C2CC3CC(C2)CC1C3
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 62A (0.192 g, 0.888 mmol) in tetrahydrofuran (1 mL)/toluene (1 mL) was added n-butyllithium (1.6 M, 0.721 mL) at 0° C. The reaction mixture was stirred for 60 minutes. Then CH3I (0.166 mL) was added and stirring continued for 3 hours at 0° C. The reaction mixture was quenched with water, extracted with diethyl ether, dried over Na2SO4, filtered, and concentrated.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].CCOCC.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=1.C(=O)([O-])[O-].[Ca+2]>O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]=[C:1]=[S:2])=[N:15][CH:16]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CCOCC
Product: S=C=Nc1ccc(Cl)cn1

Procedure:
A solution of 16.3 ml. of thiophosgene in 600 ml. of ether is added with rapid stirring to a suspension of 25.6 g. of 5-chloro-2-aminopyridine and 42 g. of calcium carbonate in 600 ml. of water. The reaction mixture is stirred for 11/2 hours and the ether layer separated and the water layer extracted with a 400 ml. portion of ether. The combined ether extracts are washed with water, dried over magnesium sulfate and evaporated to dryness in vacuo affording 29.9 g. of a dark red oil. The oil is distilled at 0.75 mm. of Hg. at a temperature 96° C. affording 5-chloro-2-pyridylisothiocyanate.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:7][F:8])([OH:6])[C:4]#[CH:5].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[H-].[Na+].CCCCCC.CC>O1CCCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:6][C:3]([CH2:7][F:8])([C:4]#[CH:5])[CH2:2][F:1])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: C#CC(O)(CF)CF
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: CC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#CC(CF)(CF)OS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
An amount (1.2 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-ol and p-chlorobenzenesulfonyl chloride (2.1 g) were dissolved in tetrahydrofuran (10 ml); to the solution under cooling with ice, 60% oily sodium hydride (0.48 g) was added under a nitrogen atmosphere. After the end of the addition, the mixture was stirred for 4 hours while its temperature was raised to room temperature. A hexane/ethane mixed solvent (1/1) was added to the reaction mixture, which was then washed with water and a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane/methylene chloride=1/1) and then recrystallized from methylene chloride/hexane to give the titled compound (2.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[CH:7]=[C:6]2[CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C[O:26][C:27](=[O:38])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[CH2:36]Br>>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([C:27]([OH:38])=[O:26])=[C:29]([CH2:36][N:22]2[CH2:23][CH2:24][CH:19]([C:6]3[C:5]4[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=4)[N:8]([CH2:12][CH2:13][C:14]4[CH:18]=[CH:17][S:16][CH:15]=4)[CH:7]=3)[CH2:20][CH2:21]2)[CH:30]=1
Reactant: COc1ccc2c(c1)c(C1CCNCC1)cn2CCc1ccsc1
Reactant: COC(=O)c1ccc(OC)cc1CBr
Product: COc1ccc(C(=O)O)c(CN2CCC(c3cn(CCc4ccsc4)c4ccc(OC)cc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 0.05 g (0.16 mmol) of 5-methoxy-3-piperidin-4-yl-1-(2-thiophen-3-yl-ethyl)-1H-indole (example 87, part D) and 0.054 g (0.21 mmol) of 2-bromomethyl-4-methoxy-benzoic acid methyl ester. After standard work-up and purification by chromatography using a C18 column, 0.019 g (24% of yield) of the expected acid were obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[OH:13][C:14]1[CH:26]=[CH:25][C:17]([O:18][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([O:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:25][CH:26]=1)[CH:11]=[N:10]2
Reactant: COC(=O)C(C)Oc1ccc(O)cc1
Reactant: Clc1ccc2nc(Cl)cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1

Procedure:
In 150 ml of acetonitrile, 2.0 g (0.01 mole) of 2,6-dichloroquinoxaline, 2.0 g (0.01 mole) of methyl 2-(4'-hydroxyphenoxy)propionate and 2.0 g (0.014 mole) of potassium carbonate were added and the mixture was refluxed for 24 hours.
Reaction SMILES: C(=O)([O-])[O-].[Sr+2:5].[C:6]([OH:14])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O>[C:6]([O-:14])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Sr+2:5].[C:6]([O-:14])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Sr+2]
Solvent: O
Product: O=C([O-])c1ccccc1

Procedure:
Strontium carbonate (1.0 g, 6.77 mmol) and benzoic acid (1.65 g, 13.5 mmol) in water (30 ml) were stirred for 4 hours at 70.degree. C. The mixture was filtered and the filtrate was evaporated to dryness and dried in vaccuo at ambient temperature. The title compound was isolated. Yield 1.8 g (81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:15])[CH:13]=[CH2:14])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[NH:16]1[CH:20]=[C:19]([CH:21]=[O:22])[N:18]=[CH:17]1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.O1CCOCC1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:11][C:12](=[O:15])[CH2:13][CH2:14][N:16]2[CH:20]=[C:19]([CH:21]=[O:22])[N:18]=[CH:17]2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: O=Cc1c[nH]cn1
Reactant: C=CC(=O)NC(C)(C)c1ccc(Cl)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(NC(=O)CCn1cnc(C=O)c1)c1ccc(Cl)cc1
Temperature: 95 °C

Procedure:
A mixture of N-[1-(4-chlorophenyl)-1-methylethyl]-acrylamide (22.35 g), imidazole-4-carboxaldehyde (9.6 g), benzyltrimethylammonium hydroxide (2.24 ml of a 40% solution in methanol, Triton®B) and 1,4-dioxane (112 ml) was stirred and heated at 95° C. for 6 hours and then worked up as described in Example 19a to give N-[1-(4-chlorophenyl)-1-methylethyl]-3-(4-formylimidazol-1-yl) propionamide, m.p. 151°-153° C.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:18](O)=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([N:23](CC)[CH2:24]C)C>>[C:1]([NH:9][CH:10]([CH2:18][N:23]([CH3:24])[CH3:21])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Product: CN(C)CC(Cc1ccccc1)NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of 26.5 g of N-benzoyl phenylalanine (XIII) in 200 ml of T.H.F. are added 11 g of triethylamine, it is cooled to 0° C. and 11 g of ethyl chloroformiate are added. After 30 mn at 0° C., a solution of 4.5 g of diethyllamine in 50 ml of T.H.F. is added, then it is left for 2 hours at ambient temperature. Then the solvent is evaporated, the residue taken up in water, extracted with chloroform, dried on sodium sulfate, filtered and the filtrate evaporated. Thus, the expected product was obtained with a yield of 81%.
Reaction SMILES: CC1(C)[NH:6][CH:5]([PH:7](=[O:9])[OH:8])[C:4]([CH3:11])([CH3:10])[S:3]1>O.C(O)(C)C>[NH2:6][CH:5]([PH:7](=[O:8])[OH:9])[C:4]([SH:3])([CH3:11])[CH3:10]
Reactant: CC1(C)NC([PH](=O)O)C(C)(C)S1
Solvent: O
Solvent: CC(C)O
Product: CC(C)(S)C(N)[PH](=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.5 g of DL-(2,2,5,5-tetramethyl-4-thiazolidinyl)-phosphinic acid were dissolved in 10 ml of boiling water and the volume was reduced by boiling for 0.25 hour. The mixture was cooled to room temperature and diluted with 25 ml of isopropanol. The resulting mixture was cooled at 0° C. overnight. The resulting solid was collected, washed with isopropanol and dried to give 0.85 g of DL-(1-amino-2-mercapto-2-methylpropyl)phosphinic acid of melting point 211° C. (decomposition).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:15])[C:12](O)=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.[NH2:17][NH2:18]>CO>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:15])[C:12]([NH:17][NH2:18])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C(=O)O)c1ccc2ncccc2c1
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C(=O)NN)c1ccc2ncccc2c1
Yield: 82 %

Procedure:
2-Quinolin-6-yl-propionic acid (5.6 g, 26.1 mmol), hydrazine hydrate (1.6 mL) and methanol (150 mL) were combined and heated to reflux for 72 hours. After such time the mixture was concentrated in vacuo and portioned between NaHCO3 (200 mL) and dichloromethane (150 mL). The aqueous phase was extracted with dichloromethane (2×150 mL) and the combined organic extracts dried (Na2SO4) and concentrated in vacuo to return the title compound as a white solid (4.6 g, 21.4 mmol, 82%). 1H-NMR (DMSO-d6, 500 MHz): 9.30 (1H, bs), 8.85 (1H, dd), 8.33 (1H, dd), 7.95 (1H, d), 7.86 (1H, d), 7.74 (1H, dd), 7.51 (1H, dd), 4.22 (3H, s), 3.74 (1H, q), 1.44 (3H; MS: m/z 216 [M+H+]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:10]=1[C:35]([O-:37])=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH+](CC)CC)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:52]([CH3:54])[CH3:53]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:10]=1[C:35]([O:37][CH:52]([CH3:54])[CH3:53])=[O:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-n2c(C(=O)[O-])c(OCc3ccccc3)c(OCc3ccccc3)c2C(=O)N(C)C)cc1
Reactant: CC(C)Br
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2c(C(=O)OC(C)C)c(OCc3ccccc3)c(OCc3ccccc3)c2C(=O)N(C)C)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
To a stirred suspension of triethylammonium 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (7) [prepared as example B-step (iv) using ethyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (6) as starting material] (360 mg, 0.60 mmol) and Cs2CO3 (429 mg, 1.32 mmol) in DMF (3 mL) was added 2-bromopropane (197 μL, 2.10 mmol) and the reaction stirred at 40° C. for 2 h then partitioned between EtOAc (50 mL) and water (20 mL). The organic was separated and washed with water (2×50 mL), brine (2×50 mL), dried (MgSO4), filtered and concentrated in vacuo to afford a yellow oil. The residue was purified by silica gel chromatography (40 g, 20-60% EtOAc in isohexane) to afford isopropyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (8) (108 mg, 33%) as a yellow oil: 1H NMR (400 MHz, DMSO-d6) δ: 7.51-7.43 (m, 2H), 7.43-7.28 (m, 8H), 7.19-7.05 (m, 2 H), 6.96-6.84 (m, 2H), 5.13 (s, 2H), 4.96 (s, 2H), 4.85 (sept., J=6.2 Hz, 1H), 3.78 (s, 3H), 2.72 (s, 3H), 2.71 (s, 3H), 1.10 (d, J=6.2 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH:6]=[CH:5]2.[OH:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:28][C:27]3[CH:26]=[C:25]([CH2:24][CH2:23][OH:22])[CH:31]=[CH:30][CH:29]=3)[CH:3]=2)[N:8]=1
Reactant: Nc1cccc(CCO)c1
Reactant: COc1ccccc1CNc1ccc2cc(Br)ccc2n1
Product: COc1ccccc1CNc1ccc2cc(Nc3cccc(CCO)c3)ccc2n1

Procedure:
The title compound, yellow oil, MS: m/e=400.3 (M+H+), was prepared in accordance with the general method of example 84 from (6-bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) and commercially available 3-(2-hydroxyethyl)-aniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH2:9])=[C:4]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH:3]=1.[CH2:19]([O:21][C:22](=[O:27])[CH2:23][C:24](Cl)=[O:25])[CH3:20]>>[CH2:19]([O:21][C:22](=[O:27])[CH2:23][C:24]([NH:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:10]#[C:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:25])[CH3:20]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: Nc1c(F)cc(Cl)cc1C#Cc1ccccc1Cl
Product: CCOC(=O)CC(=O)Nc1c(F)cc(Cl)cc1C#Cc1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 29 step A from 4-chloro-2-(2-chloro-phenylethynyl)-6-fluoro-phenylamine (570 mg, 2.03 mmol) and chlorocarbonyl-acetic acid ethyl ester (460 mg, 3.05 mmol). White solid (440 mg, 55%) MS (ESI): 394 (M+H)+.