Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Ca+2:5].[NH2:6][C@H:7]([C:12]([OH:14])=[O:13])[CH2:8][C:9]([OH:11])=[O:10]>O>[Ca:5].[NH2:6][C@H:7]([C:12]([OH:14])=[O:13])[CH2:8][C:9]([OH:11])=[O:10]
Reactant: [Ca+2]
Agent: N[C@@H](CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Product: [Ca]

Procedure:
20 g of calcium carbonate (calcium content: 38%) was dispersed in 500 ml of water and dissolved therein by stirring, and 60 g of aspartic acid was added thereto to perform a reaction, then the solution was continually stirred until the calcium carbonate and aspartic acid were entirely dissolved. Bubbles were generated in the initial stage of reaction but they disappeared after a certain time. The resulting reaction solution was centrifuged to remove insoluble materials, and the clear supernatant was separated. The supernatant was freeze-dried to obtain about 78 g of calcium-aspartic acid chelate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:50]([O:52]CC(=O)C1C=CC=CC=1)=[O:51])[CH2:13][O:14][C:15]([C@@H:17]1[CH2:21][C@@H:20]([CH3:22])[CH2:19][N:18]1[C:23](=[O:49])[C@@H:24]([NH:26][C:27]([C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[C:35]([C@@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:36])=[O:28])[CH3:25])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Zn].C(O)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:50]([OH:52])=[O:51])[CH2:13][O:14][C:15]([C@@H:17]1[CH2:21][C@@H:20]([CH3:22])[CH2:19][N:18]1[C:23](=[O:49])[C@@H:24]([NH:26][C:27]([C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[C:35]([C@@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])=[O:36])=[O:28])[CH3:25])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1C[C@@H](C(=O)OC[C@H](NC(=O)OCc2ccccc2)C(=O)OCC(=O)c2ccccc2)N(C(=O)[C@H](C)NC(=O)[C@@H]2CCCCN2C(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)C1
Agent: [Zn]
Solvent: CC(=O)O
Product: C[C@@H]1C[C@@H](C(=O)OC[C@H](NC(=O)OCc2ccccc2)C(=O)O)N(C(=O)[C@H](C)NC(=O)[C@@H]2CCCCN2C(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.17 g (6.1 mmol) of the phenacyl ester from example 24A are dissolved in 90 pc. aqueous acetic acid (60 ml) and treated with 2.99 g (45.8 mmol) of zinc powder. The reaction mixture is stirred at RT for 2 h. The reaction solution is filtered off through kieselguhr and washed with ethyl acetate. The organic phase is concentrated in vacuo (not to dryness), the residue is extracted by shaking with ethyl acetate and 1N hydrochloric acid, and the phases are separated. The aqueous phase is extracted with ethyl acetate, and the combined organic phases are dried over sodium sulfate, filtered and concentrated to dryness. The residue is taken up twice in toluene and evaporated in vacuo. The residue is taken up in diethyl ether, extracted by shaking with saturated aqueous sodium hydrogencarbonate solution and the aqueous phase is washed again with diethyl ether. The aqueous phase is subsequently adjusted to pH 2.7 using 5N hydrochloric acid and extracted twice with ethyl acetate. The combined organic extracts are dried over sodium sulfate, filtered and the solvent is removed in vacuo. 4.01 g (91% of th.) of the product are obtained as a hard foam.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([NH:16][CH:17]([CH3:19])[CH3:18])[C:8]3[N:9]2[C:12](=[O:15])[NH:13][N:14]=3)=[CH:4][CH:3]=1.CO.CCO.C1CCCCC=1>C(Cl)(Cl)Cl.[Pd]>[CH:17]([NH:16][C:7]1[C:8]2[N:9]([C:12](=[O:15])[NH:13][N:14]=2)[C:10]2[C:5]([N:6]=1)=[CH:4][CH:3]=[CH:2][CH:11]=2)([CH3:19])[CH3:18]
Reactant: CC(C)Nc1nc2ccc(Br)cc2n2c(=O)[nH]nc12
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Solvent: CO
Product: CC(C)Nc1nc2ccccc2n2c(=O)[nH]nc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 40 mg of 8-bromo-4-isopropylamino-2H-[1,2,4]triazolo[4,3-a]quinoxalin-1-one and 40 mg of 10% Pd/C in a 1:1 mixture of MeOH/EtOH was added 81 mg of cyclohexene. This mixture was heated at reflux for 3.5 hrs. and then stirred at room temperature for 18 hrs. The reaction mixture was diluted with chloroform, filtered through a pad of diatomaceous earth, and concentrated. The residue was triturated with IPE to provide an orange solid. MS (M+H)+=244.0.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CN(C)C=O.O.C(OCC)(=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Fc1cccnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cccnc1-c1ccc(Cl)cc1
Yield: 65.7 %

Procedure:
A solution of 18.60 g 2-chloro-3-fluoropyridine, 23.25 g 4-chlorophenylboronic acid and 2.30 g 1,1′bis(diphenylphosphino)ferrocenedichloropalladium(II), 22.50 g sodium carbonate in toluol:dimethylformamide:water 190:20:40 and the mixture was stirred at 90° C. over 5 hours. The reaction mixture was diluted with ethyl acetate and water. The phases were separated and the organic phase was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with a gradient of heptane to heptane:ethyl acetate 1:1. The product fractions were collected and evaporated. The residue was crystallized in ether to yield 19.30 g (65.73%) of the title compound as off-white solid, MS 208.1 (M+H)+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C:27]1[CH:28]=[C:29]([C:35]([C:39]2[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[C:41]([O:47][CH3:48])[CH:40]=2)=[CH:36][C:37]#[N:38])[CH:30]=[CH:31][C:32]=1[O:33][CH3:34])(C(C)(C)C)(C)C.CCOCC>C1COCC1>[CH3:48][O:47][C:41]1[CH:40]=[C:39]([C:35]([C:29]2[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:27]([OH:26])[CH:28]=2)=[CH:36][C:37]#[N:38])[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=1
Reactant: COc1cc(OC)cc(C(=CC#N)c2ccc(OC)c(O[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2ccc(OC)c(O)c2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
Tetrabutylammonium fluoride (1.0 M solution in THF, 1.49 ml, 1.49 mmol) was added at rt to a stirred solution of 3-[3-(tert-butyldimethylsilanyloxy)-4-methoxyphenyl]-3-(3,5-dimethoxyphenyl)acrylonitrile (0.53 g, 1.25 mmol) in THF (15 ml). The colorless clear solution immediately turned into brown/red wine color. The reaction should be done within one hour. Ice water (10 ml) was poured into the reddish solution, followed by addition of ether (50 ml). The mixture was washed with water (2×80 ml), dried over MgSO4, filtered and concentrated to a yellow oil, which was lyophilized to give 3-(3,5-dimethoxy-phenyl)-3-(3-hydroxy-4-methoxy-phenyl)-acrylonitrile as a foamy solid (0.35 g, 90%): mp, 43-45° C.; 1HNMR (DMSO-d6) δ 9.36 (s, 1H, OH group of one isomer), 9.28 (s, 1H, OH group of the other isomer), 7.07 (d, J=8 Hz, 1H, Ar), 7.00 (d, J=8 Hz, 1H, Ar), 6.91-6.82 (m, 4H, Ar), 6.69-6.65 (m, 2H, Ar), 6.49 (t, J=2 Hz, 4H, Ar), 6.19 (s, 1H, double bond proton of one isomer), 6.17 (s, 1H, double bond proton of the other isomer), 3.87 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 3.81 (s, 6H, 2OCH3), 3.78 (s, 6H, 2OCH3), isomer ratio based on 1HNMR was 45%:55%; 13C NMR (CDCl3) δ 162.8, 162.6, 160.8, 160.8, 148.7, 148.2, 145.7, 145.5, 141.4, 139.1, 131.9, 130.2, 122.3, 121.3, 118.2, 118.1, 116.0, 114.4, 110.4, 110.4, 107.8, 107.1, 102.2, 94.2, 93.5, 56.2, 56.1, 55.6; Anal. Calcd. For C18H17NO4: C, 69.12; H, 5.53; N, 4.48. Found: C, 68.76; H, 5.69; N, 4.22.
Reaction SMILES: Br.Br[CH2:3][C:4]1[S:8][CH:7]=[N:6][C:5]=1[CH3:9].[SH:10][C:11]1[N:16]=[C:15]([OH:17])[CH:14]=[C:13]([C:18]([F:21])([F:20])[F:19])[N:12]=1.C(N(CC)CC)C>C(O)C>[CH3:9][C:5]1[N:6]=[CH:7][S:8][C:4]=1[CH2:3][S:10][C:11]1[N:16]=[C:15]([OH:17])[CH:14]=[C:13]([C:18]([F:21])([F:19])[F:20])[N:12]=1
Reactant: Cc1ncsc1CBr
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ncsc1CSc1nc(O)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.5 %

Procedure:
To a 0° C. mixture of 5-(bromomethyl)-4-methyl-1,3-thiazole hydrobromide (19.4 mmol) and 2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (2.47 g, 12.6 mmol) in absolute ethanol (100 mL) was added triethylamine (8.00 mL, 57.4 mmol). The mixture was stirred at room temperature for 2 days. The solid material was removed by filtration and washed with diethyl ether (100 mL). The filtrate was evaporated to dryness and then co-evaporated with ethyl acetate (1×50 mL). The solid residue was treated with water (100 mL), and the mixture was stirred for 30 minutes. The solid product was recovered by filtration, washed with water (2×25 mL), diethyl ether (2×25 mL), and hexanes (2×25 mL), and then dried in vacuo to afford 2-{[(4-methyl-1,3-thiazol-5-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (1.76 g, 45%); 1H NMR (500 MHz, DMSO-d6): δ 2.39 (s, 3H), 4.61 (s, 2H), 6.65 (s, 1H), 8.86 (s, 1H); M+ 308.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:27][C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/B(O)O)=[CH:30][CH:29]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[K+]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:27][C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:2]2[CH:3]=[CH:4][C:5]([C:8]3([C:11]([N:13]4[CH2:17][CH2:16][C@@:15]5([C:21]6[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=6[C:19](=[O:26])[O:18]5)[CH2:14]4)=[O:12])[CH2:10][CH2:9]3)=[CH:6][CH:7]=2)=[CH:30][CH:29]=1
Reactant: Cc1ccc(/C=C/B(O)O)cc1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(Br)cc4)CC3)C2)c2ccccc21
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(/C=C/c2ccc(C3(C(=O)N4CC[C@@]5(C4)OC(=O)c4ccccc45)CC3)cc2)cc1
Yield: 50 %

Procedure:
A mixture of (1R)-1′-{[1-(4-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (25 mg, 0.061 mmol), [(E)-2-(4-methylphenyl)vinyl]boronic acid (11 mg, 0.067 mmol), tri-tert-butylphosphine (1.5 mg, 0.007 mmol), tris(dibenzylideneacetone)dipalladium(0) (3 mg, 0.003 mmol), potassium fluoride (12 mg, 0.2 mmol) in tetrahydrofuran (0.4 ml) was microwave irradiated at 90° C. for 20 minutes. The desired product was obtained from the mixture by prep-HPLC (13.7 mg, yield: 50%). LCMS: m/z 450.2 (M+H)+; 472.2 (M+Na)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][OH:28])=[N:24][CH:25]=1>>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][OH:28])=[N:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(CCO)nc1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Product: OCCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cn1
Yield: 22.9 %

Procedure:
Following general procedure B2, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.075 g, 0.25 mmol) was reacted with 2-(5-aminopyridin-2-yl)ethanol (0.045 g, 0.33 mmol), followed by formation of the hydrochloride salt to afford the desired product (0.023 g, 21%) as a white solid. MW=438.78. 1H NMR (DMSO-d6, 500 MHz) δ 14.38 (s, 1H), 10.12 (s, 1H), 8.72 (s, 1H), 8.10 (s, 1H), 7.98-7.95 (m, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.71-7.58 (m, 3H), 7.21 (s, 1H), 3.80 (t, J=8.0 Hz, 2H), 3.20 (t, J=8.0 Hz, 2H), 3.03 (t, J=7.5 Hz, 2H), 2.98 (t, J=7.5 Hz, 2H), 2.26 (quin, J=7.5 Hz, 2H); APCI MS m/z 366 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][CH2:9][C:10]2[S:11][C:12]3[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([F:21])[C:13]=3[N:14]=2)=[O:7])=[C:4]([OH:24])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].Cl>CC(C)=O.C(OCC)(=O)C>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][O:24][C:4]1[CH:3]=[C:2]([F:1])[CH:23]=[CH:22][C:5]=1[C:6](=[O:7])[NH:8][CH2:9][C:10]1[S:11][C:12]2[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([F:21])[C:13]=2[N:14]=1)[CH3:37]
Reactant: CCOC(=O)CBr
Reactant: O=C(NCc1nc2c(F)c(F)cc(F)c2s1)c1ccc(F)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(F)ccc1C(=O)NCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 45 °C
Yield: 80.7 %

Procedure:
A solution of 4-fluoro-2-hydroxy-N-(4,5,7,-trifluoro-benzothiazol-2-ylmethyl)-benzamide (1.0 g, 2.8 mmol) in acetone (14 mL) was treated with aq 2 N K2CO3 (2.1 mL, 4.2 mmol) and ethyl bromoacetate (2 mL, 19 mmol) and heated to 45° C. for 5 h. After cooling to room temperature, the solution was acidified to a pH 1 with aq 2 N HCl. The resulting solution was diluted with ethyl acetate and washed with saturated NaCl. The organic layer was dried over MgSO4, filtered and concentrated. Purification by MPLC (10-100% ethyl acetate in heptane 23 mL/min, 75 min) provided {5-fluoro-2[(4,5,7-trifluoro-benzothiazol-2-ylmethyl)carbamoyl]-phenoxy}-acetic acid ethyl ester (1.0 g, 81%) as a white crystalline solid: 1H NMR (DMSO-d6 300 MHz) δ 9.32 (t, J=5.9 Hz, 1H), 7.94 (dd, J1=9.0 Hz, J2=7.2 Hz, 1H), 7.80-7.70 (m, 1H), 7.13 (dd, J1=11.1 Hz, J2=2.4 Hz, 1H), 6.95 (dt, J1=8.4 Hz, J2=2.5 Hz, 1H), 5.02 (s, 2H), 4.94 (d, J=6 Hz, 2H), 4.17 (q, J=7.2 Hz, 2H), 1.18 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][CH2:16]1)[C:6]([O:8]C)=[O:7])#[N:2].[OH-].[Li+]>O1CCCC1.CO.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:16][CH2:17]1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(OCC2CC2)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cc(C(=O)O)ccc1OCC1CC1
Yield: 73.4 %

Procedure:
Methyl 3-cyano-4-[(cyclopropylmethyl)oxy]benzoate (D23; 74 mg, 0.320 mmol) was stirred at room temperature under nitrogen with lithium hydroxide (15.33 mg, 0.640 mmol) in tetrahydrofuran (THF) (2 ml), methanol (2 ml) and water (1 ml) for 20 h. The mixture was partitioned between water (20 ml), 2N hydrochloric acid (5 ml) and ethyl acetate (3×20 ml), and the organic layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and evaporated in vacuo to give the title compound as a white solid (51 mg)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][CH:21]=[CH:20]4)[CH:16]=[C:4]2[N:3]=1.O.[NH2:28][NH2:29]>O1CCOCC1.O>[CH3:15][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[CH:20]=[N:28][NH:29][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][CH:21]=[CH:20]4)[CH:16]=[C:4]2[N:3]=1
Reactant: NN
Reactant: Clc1cc(N2CCOCC2)n2nc(-c3ccc4ncccc4c3)cc2n1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccc5ncccc5c4)cc3n2)c1
Reaction time: 8 h

Procedure:
There was suspended, in 1,4-dioxane (2.0 mL), 6-(5-chloro-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidin-2-yl)-quinoline (83 mg, 0.23 mM) prepared in the preceding step 1, then hydrazine monohydrate (110 μL, 2.3 mM) was added to the suspension and the mixture was stirred for 8 hours while refluxing the same with heating. After the stirring operation, the reaction liquid was concentrated, the concentrate thus obtained was diluted with water and then the mixture was extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate and the solvent was distilled off. The resulting solid was dried in vacuo, suspended in ethanol (2.0 mL), then acetic acid (6.5 μL, 0.11 mM) and metatolualdehyde (30 μL, 0.25 mM) were added to the suspension and the mixture was stirred at room temperature for 2 hours. The precipitated solid was recovered through filtration and then washed with diethyl ether to thus give the title compound (60 mg, overall yield of these two steps: 56%).
Reaction SMILES: O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)C(C)C)(C)C.[CH:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1.[C:39]([O:43][C:44]([NH:46][CH2:47][C:48](O)=[O:49])=[O:45])([CH3:42])([CH3:41])[CH3:40]>ClCCl>[CH2:31]([C:32]1[CH:33]=[CH:34][C:35]([NH:38][C:48](=[O:49])[CH2:47][NH:46][C:44]([O:43][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:45])=[CH:36][CH:37]=1)[C:28]1[CH:27]=[CH:26][CH:25]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1ccc(Cc2ccccc2)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(Cc2ccccc2)cc1
Reaction time: 17.5 h
Yield: 83.9 %

Procedure:
Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (1.90 g) and N,N-diisopropylethyl-amine (1.5 mL) were added to a solution of 4-aminodiphenylmethane (0.52 g) and N-tert-butoxycarbonylglycine (0.50 g) in dichloromethane (30 mL) at 0° C. After stiriing at 0° C. for 10 min and at room temperature for 17.5 hr, the solvent was removed in vacuo. The residue was diluted with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium hydrogen carbonate, and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1, v/v) to afford the title compound (0.81 g) as a colorless powder: 1H NMR (400 MHz, CDCl3) δ 1.47 (s, 9H), 3.90 (d, 2H), 3.94 (s, 2H), 7.12-7.21 (m, 5H), 7.28 (d, 2H), 7.41 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][C:11]1=[O:16].C(=O)([O-])[O-].[K+].[K+].C(#N)C>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:13]2[CH2:14][CH2:15][NH:10][C:11](=[O:16])[CH2:12]2)=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C1CN(Cc2ccc(Cl)nc2)CCN1
Temperature: 25 °C
Reaction time: 84 h
Yield: 34.3 %

Procedure:
A mixture of 2-chloro-5-(chloromethyl)pyridine (1.4 g, 8.4 mmol), piperazinone (0.84 g, 8.4 mmol), and potassium carbonate (1.0 mL, 17 mmol) in a mixed solvent consisting of acetonitrile (40 mL) and THF (20 mL) was stirred at room temperature for 3.5 days. Upon workup, the mixture was filtered through a layer of celite and the cake was washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was subjected to combi-flash column chromatography (methanol/DCM) to give compound 356 (0.65 g, 34% yield) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.35 (1 H, d, J=2.0 Hz), 7.81 (1 H, dd, J=8.1, 2.4 Hz), 7.76 (1 H, br. s.), 7.49 (1 H, d, J=8.3 Hz), 3.57 (2 H, s), 3.10-3.16 (2 H, m), 2.93 (2 H, s), 2.52-2.56 (2H, m). LCMS-ESI (POS), M/Z, M+1: Found 226.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:15]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11].ClCl.O.NC1C=CC=CC=1>C(OCC)(=O)C.C(O)(=O)C.C(Cl)(Cl)Cl.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:13])([F:14])[CH:10]([F:11])[F:12])[NH2:15]
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)C(F)F)c(Cl)c1
Agent: [Fe]
Agent: ClCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: Nc1ccccc1
Product: Nc1ccc(OC(F)(F)C(F)F)c(Cl)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
12.5 Grams of 3-chloro-4-(1',1',2',2'-tetrafluoroethoxy)nitrobenzene [i.e. the nitro compound (X) containing chlorine as the substituted X] was dissolved in a mixed solvent of 50 ml of ethyl acetate and 50 ml of acetic acid. The resulting solution was slowly added dropwise to a suspension of 12.2 g of iron powders in a mixed solution of 13 ml of acetic acid and 130 ml of water while maintaining the temperature at 40° C. Thereafter, stirring was continued for 30 minutes at 40° C. to 60° C. The reaction solution was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and then with water, dried over anhydrous magnesium sulfate and concentrated. The residue obtained was subjected to column chromatography on silica gel with chloroform as an eluent to obtain 9.41 g of 3-chloro-4-(1',1',2',2'-tetrafluoroethoxy)aniline [i.e. the aniline compound (IX) containing chlorine as the substituted X]. 1H-NMR (CDCl3): δ(ppm) 7.10(1H, d, J=9 Hz , 6.70(1H, d, J=3 Hz), 6.48(1H, dd, J=9, 3 Hz), 5.95(1H, tt, J=53, 3 Hz), 3.65(2H, broad)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:11](=[O:22])[N:12]([CH2:15][C:16]3O[CH:19]=[N:18][C:17]=3[CH3:21])[CH2:13][CH2:14][C:3]1=2.C([NH2:25])=O>O>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:11](=[O:22])[N:12]([CH2:15][C:16]3[N:25]=[CH:19][NH:18][C:17]=3[CH3:21])[CH2:13][CH2:14][C:3]1=2
Reactant: NC=O
Reactant: Cc1ncoc1CN1CCc2c(c3ccccc3n2C)C1=O
Solvent: O
Product: Cc1[nH]cnc1CN1CCc2c(c3ccccc3n2C)C1=O

Procedure:
A mixture of 2,3,4,5-tetrahydro-5-methyl-2-[(4-methyloxazol-5-yl)methyl]-1H-pyrido[4,3-b]indol-1-one (100 mg) in formamide (20 ml) was heated at 180° for 24 h. The mixture was then cooled, diluted with water (100 ml) and extracted with dichloromethane (3×100 ml). The combined organic extracts were concentrated in vacuo and the residue was purified by FCC eluting with System A (100:8:1) to give the title compound (40 mg) as a solid. The 1H-n.m.r. and t.l.c. data for this material were consistent with those obtained for the product of Example 20.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][NH:19][CH2:18][C:17]4[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][N:32]1[CH2:39][CH2:38][CH2:37][C@@H:33]1[C:34](O)=[O:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([C:34](=[O:35])[C@H:33]4[CH2:37][CH2:38][CH2:39][N:32]4[CH3:31])[CH2:18][C:17]4[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN1CCC[C@@H]1C(=O)O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNCc1cc(F)ccc1-3
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(C(=O)[C@H]1CCCN1C)Cc1cc(F)ccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1 eq of methyl-14-cyclohexyl-3-fluoro-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocin-11-carboxylate (prepared as described in Example 18, Step 5) in DCM (0.06 M), 1.5 eq of 1-methyl-D-proline (prepared according to literature precedent J. Org. Chem. 2003, 68, 2652) in DCM (0.2 M), 1.5 eq of DIPEA and 1.5 eq of TBTU were added and the mixture stirred at RT overnight. Volatiles were removed in vacuo and the crude was used in the next step without further purification; MS (ES+) m/z 518 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:11]1[C:16](=O)[CH2:15][O:14][CH:13]([CH2:18][O:19][C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:28]=2[CH2:27][CH:26]=[CH:25]3)[CH2:12]1)[CH2:8][CH2:9][CH3:10]>O1CCCC1>[CH2:7]([N:11]1[CH2:16][CH2:15][O:14][CH:13]([CH2:18][O:19][C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:28]=2[CH2:27][CH:26]=[CH:25]3)[CH2:12]1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCN1CC(COc2cccc3c2CC=C3)OCC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCN1CCOC(COc2cccc3c2CC=C3)C1

Procedure:
In 250 ml. of anhydrous tetrahydrofuran was suspended 2.0 g. of lithium aluminum hydride and then a solution prepared by dissolving 8.0 g. of 4-butyl-2-(7-indenyloxymethyl)morpholin-5-one in 50 ml. of anhydrous tetrahydrofuran was added slowly to the suspension with stirring. Then, by treating the mixture in a similar manner as in Example 1, 6.4 g. (yield) of oily 4-butyl-2-(7-indenyloxymethyl)-morpholine was obtained.