Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:48]=[CH:49][C:50]=1[Cl:51])[CH2:8][O:9][CH:10]1[O:15][CH:14]([CH2:16][O:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH:13]([O:27][CH:28]2[O:37][CH:36]3[CH:31]([O:32][CH:33]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[O:34][CH2:35]3)[CH:30]([OH:44])[CH:29]2[OH:45])[CH:12]([OH:46])[CH:11]1[OH:47])(=[O:3])[CH3:2].[K+].[Br-]>O>[C:14]([O:46][CH:12]1[CH:11]([O:47][C:18](=[O:17])[CH3:19])[CH:10]([O:9][CH2:8][C:7]2[CH:48]=[CH:49][C:50]([Cl:51])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=2)[O:15][CH:14]([CH2:16][O:17][C:18](=[O:26])[C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[CH:13]1[O:27][CH:28]1[O:37][CH:36]2[CH:31]([O:32][CH:33]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[O:34][CH2:35]2)[CH:30]([O:44][C:8](=[O:9])[CH3:7])[CH:29]1[O:45][C:1](=[O:3])[CH3:2])(=[O:15])[CH3:13]
Reactant: CC(=O)Nc1cc(COC2OC(COC(=O)c3ccc(Cl)cc3)C(OC3OC4COC(c5ccccc5)OC4C(O)C3O)C(O)C2O)ccc1Cl
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: CC(=O)Nc1cc(COC2OC(COC(=O)c3ccc(Cl)cc3)C(OC3OC4COC(c5ccccc5)OC4C(OC(C)=O)C3OC(C)=O)C(OC(C)=O)C2OC(C)=O)ccc1Cl

Procedure:
The title compound was prepared as a white foam (0.225 g, 72%) from 4-chloro-benzoic acid 6-(3-acetylamino-4-chloro-benzyloxy)-3-(7,8-dihydroxy-2-phenyl-hexahydro-pyrano[3,2-d][1,3]dioxin-6-yloxy)-4,5-dihydroxy-tetrahydro-pyran-2-ylmethyl ester using a procedure similar to Example 25, mp 114-115° C.; 1H NMR (DMSO-d6) δ1.94 (s, 3H), 1.95 (s, 3H), 1.98 (s, 3H), 1.99 (s, 3H), 2.05 (s, 3H), 3.62 (t, J=9.2 Hz, 1H), 3.68-3.74 (m, 1H), 3.79 (dd, J=4.2, 9.2 Hz, 1H), 3.86 (t, J=9.4 Hz, 1H), 4.13-4.19 (m, 1H), 4.18 (q, J=9.4, 1H), 4.47 (dd, J=3.5, 12.3 Hz, 1H), 4.63 (ABq, J=12.7 Hz, Δδ=0.14, 2H), 4.66 (d, J=10.8 Hz, 1H), 4.79 (dd, J=8.1, 9.2 Hz, 1H), 4.86-4.91 (m, 2H), 5.26 (t, J=9.9 Hz, 1H), 5.32-5.38 (m, 2H), 5.54 (s, 1H), 7.05 (dd, J=1.8, 8.3 Hz, 1H), 7.27-7.31 (m, 2H), 7.32-7.36 (m, 3H), 7.42 (d, J=8.3 Hz, 1H), 7.58-7.63 (m, 3H), 8.02-8.06 (m, 2H), 9.49 (s, 1H); IR (KBr) 3410, 2950, 2860, 1755, 1690, 1600, 1530, 1450, 1420, 1375, 1260, 1140, 1070, 1055, and 1030 cm−1; mass spectrum [(+) FAB], m/z 918/920/922 (M+H)+, 940/942/944 (M+Na)+; Anal. Calcd. for C43H45Cl2NO17.1.0 H2O: C, 55.13; H, 5.06; N, 1.50, Found: C, 54.77; H, 4.73; N, 1.45.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6]CC.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(#N)C1C=CC=CC=1>>[C:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[C:16][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C#CCCCCCC
Reactant: C#Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: CCCCCCC#Cc1ccccc1
Reaction time: 18 h
Yield: 80 %

Procedure:
The procedure was identical to Example 1, with the exception that 1-octyne (0.590 ml; 0.441 g; 4.00 mmol) was used as a substrate instead of phenylacetylene. GC analysis of the organic phase of the hydrolyzed reaction sample after 18 h at 65° C. showed the presence of 1.59 mmol (80% yield) of 1-octynylbenzene, and 0.03 mmol of benzonitrile remaining in the reaction mixture.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([C:8]([OH:10])=[O:9])[CH:6]([NH:11]CC2C=CC=CC=2)[CH:5]([CH3:19])[C:4](=[O:20])[O:3]1.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][CH:2]1[CH:7]([C:8]([OH:10])=[O:9])[CH:6]([NH2:11])[CH:5]([CH3:19])[C:4](=[O:20])[O:3]1
Reactant: CC1OC(=O)C(C)C(NCc2ccccc2)C1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1OC(=O)C(C)C(N)C1C(=O)O

Procedure:
(2SR,3SR,4RS,5RS)-Tetrahydro-2,5-dimethyl-6-oxo-4-benzylamino-2H-pyrane-3-carboxylic acid (100 mg) was dissolved in acetic acid (20 ml), and palladium hydroxidecarbon (prepared by the method as described in J.Am.Chem. Soc., 83, p.4798 (1961)) (20 mg) was added thereto. The resultant mixture was stirred at room temperature under hydrogen pressure of 3-4 kg/cm2 until the designed amount of hydrogen was consumed. The catalyst was collected by filtration and washed with water. The washing and the filtrate were combined together and concentrated at 40° C. under reduced pressure to give (2SR,3SR,4RS,5RS)-tetrahydro2,5-dimethyl-6-oxo-4-amino-2H-pyrane-3-carboxylic acid.
Reaction SMILES: O=C1[C@@H](NC(=O)OC(C)(C)C)COC2C=CC=CC=2N1.[NH2:21][C:22]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([O:44][CH3:45])=[O:43])[C:23]=1[O:24][CH2:25][C@H:26]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:27](O)=[O:28]>>[C:34]([O:33][C:31]([NH:30][C@H:26]1[CH2:25][O:24][C:23]2[C:38]([C:42]([O:44][CH3:45])=[O:43])=[CH:39][CH:40]=[CH:41][C:22]=2[NH:21][C:27]1=[O:28])=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: COC(=O)c1cccc(N)c1OC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)OC(=O)N[C@H]1COc2ccccc2NC1=O
Product: COC(=O)c1cccc2c1OC[C@H](NC(=O)OC(C)(C)C)C(=O)N2
Yield: 65.8 %

Procedure:
In a similar manner to that described for the preparation of (S)-tert-butyl 4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate except the crude product was purified by silica gel chromatography, (S)-3-(2-amino-6-(methoxycarbonyl)phenoxy)-2-(tert-butoxycarbonylamino)propanoic acid (3.9 g, 6.6 mmol) was converted to the title compound (1.46 g, 65%) as a white foam.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH3:26][CH:27]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[N:29]1[CH2:30][CH2:31][CH2:32][CH:27]([CH3:26])[CH2:28]1)=[O:13])[CH2:8]2
Reactant: CC1CCCNC1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Product: CC1CCCN(c2c(C(=O)NC3C4CC5CC(C4)CC3C5)cnn2-c2ccccc2)C1

Procedure:
5-(3-Methyl-piperidin-1-y1)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and 3-methylpiperidine. Mass spectrum (ES) MH+=419.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=1)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2.C(=[NH:54])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:54][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)C(O)(c1ccc2cc(Br)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)C(O)(c1ccc2cc(N)ccc2c1)c1c[nH]cn1
Temperature: 80 °C
Reaction time: 18 h
Yield: 213.3 %

Procedure:
1-(6-Bromonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (14.0 g), benzophenonimine (5.18 g), tris(dibenzylideneacetone)dipalladium (440 mg), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (872 mg) and sodium t-butoxide (5.72 g) were dissolved in toluene (140 ml). The solution was stirred at 80° C. for 18 h under argon atmosphere. The solution was cooled, and diluted with ethyl acetate. The mixture was filtered with celite, the residue was washed with ethyl acetate. The filtrate was concentrated and the residue was purified by silica gel chromatography (eluent, hexane:THF=1:1), then recrystallized from hexane-THF (4:1) to give the titled compound (14.3 g) as a yellow powder.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1)=O.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:1][C:3]2[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=2)[CH2:15][CH2:14]1
Reactant: CN1CCNCC1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCN(Cc2cccc(B(O)O)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-Formylphenylboronic acid (1 eq, 2 mmol, 0.3 g) in dry DCM (7 ml) under an inert atmosphere of argon is treated with 1-methyl-piperazine (1.2 eq, 2.4 mmol, 0.266 ml) followed by acetic acid (1.2 eq, 2.4 mmol, 0.14 ml) and NaBH(OAc)3 (1.6 eq, 3.2 mmol, 0.678 mg) and the resulting mixture is stirred at room temperature for 3 hours. The reaction is quenched by addition of water and is then extracted with DCM. The organic extracts are concentrated in vacuo and the crude residue is purified by flash chromatography on silica eluting with MeOH/DCM (0 to 100% MeOH in DCM) followed by 2M NH3 in MeOH. The appropriate fractions are combined and concentrated in vacuo to afford the title compound; [M+H]+=235.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:13]([Cl:20])=[N:14][CH:15]=[C:16]([CH2:18][CH3:19])[CH:17]=2)[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].C(O)C.Cl>O>[Cl:20][C:13]1[C:12]([N:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)=[CH:17][C:16]([CH2:18][CH3:19])=[CH:15][N:14]=1
Reactant: CCOC(=O)c1cnn(-c2cc(CC)cnc2Cl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1cnc(Cl)c(-n2ncc(C(=O)O)c2C)c1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
1-(2-Chloro-5-ethylpyridin-3-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.639 g) and 4N aqueous solution of sodium hydroxide (5 ml) were added to a mixed solvent of ethanol (10 ml) and water (5 ml) and stirred at room temperature for an hour. The reaction solution was cooled to 0° C., 1N hydrochloric acid aqueous solution (30 ml) was added dropwise and the precipitated solid was filtered to give the titled compound (0.488 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16](=O)[NH2:17])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][C:9]1[C:10]([CH3:19])=[CH:11][C:12]([C:16]#[N:17])=[CH:13][C:14]=1[CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(N)=O)cc(C)c1CCC(=O)OC(C)(C)C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C#N)cc(C)c1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To an ice-cooled solution of 3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionic acid tert-butyl ester (7.00 g, 25.2 mmol) and triethylamine (7.66 g, 75.7 mmol) in DCM (100 mL), trifluoroacetic anhydride (6.06 g, 28.8 mmol) is added slowly so that the reaction temperature stays below 15° C. The clear yellow solution is stirred at rt for 1 h before it is washed twice with water (100 mL) and concentrated. The crude product is purified by recrystallisation from methanol to give 3-(4-cyano-2,6-dimethyl-phenyl)-propionic acid tert-butyl ester (4.2 g) as a white solid, 1H NMR (CDCl3): δ 1.48 (s, 9H), 2.33-2.37 (m, 2H), 2.38 (s, 6H), 2.94-3.01 (m, 2H), 7.31 (s, 2H).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:30]=[O:31])[CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][N:10]=[C:9]2[NH:14][CH2:15][C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][CH:21]=1)=[O:3].[Na].[BH4-].[Na+]>O1CCCC1>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH2:30][OH:31])[CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][N:10]=[C:9]2[NH:14][CH2:15][C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])[CH:19]=[CH:20][CH:21]=1)=[O:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CNc2ncnc3c(C(N)=O)cc(C=O)cc23)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(CNc2ncnc3c(C(N)=O)cc(CO)cc23)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
To a solution of tert-butyl [3-({[8-(aminocarbonyl)-6-formylquinazolin-4-yl]amino}methyl)phenyl]carbamate (90.00 mg; 0.21 mmol; 1.00 eq.) in tetrahydrofuran (2.00 ml) added sodium added sodium borohydride (4.04 mg; 0.11 mmol; 0.50 eq.). The reaction mixture was stirred at 0° C. for 1 h. After workup, the product was purified by HPLC to get tert-butyl [3-({[8-(aminocarbonyl)-6-(hydroxymethyl)quinazolin-4-yl]amino}methyl)phenyl]carbamate (60 mg, 66%) MS (M+1) 424.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:21])[NH:9][C@@H:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@@H:13]([OH:20])[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].[Cl:22][C:23]1[CH:28]=[C:27]([N+]([O-])=O)[CH:26]=[CH:25][N:24]=1>CN(C=O)C.O>[C:3]([O:7][C:8](=[O:21])[NH:9][C@@H:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@@H:13]([O:20][C:27]2[CH:26]=[CH:25][N:24]=[C:23]([Cl:22])[CH:28]=2)[CH2:12][CH2:11]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)c2ccccc21
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2ccnc(Cl)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Sodium hydride (60% in mineral oil, 0.32 g, 8.00 mmol) was suspended in dry DMF (15 mL) under argon. To this was added Intermediate 10a (1.05 g, 4.00 mmol) followed by 2-chloro-4-nitropyridine (0.64 g, 4.02 mmol). The dark coloured mixture was stirred at RT under argon for 30 min. The reaction mixture was diluted with water and extracted with DCM (3×30 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, concentrated in vacuo. Purification by FCC, eluting with 0-70% ethyl acetate in cyclohexane, gave the title compound as a white foam (1.43 g, 95%). LCMS (Method 3): Rt 4.22 min, m/z 373.1 [MH−].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:30][CH2:29][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([OH:28])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:31][C@H:32]([C:37]2[CH:42]=[CH:41][C:40](Br)=[CH:39][C:38]=2[N:44]2[CH:48]=[CH:47][C:46]([CH3:49])=[N:45]2)[C:33]([F:36])([F:35])[F:34])[N:3]=1.[CH3:50][O:51][C:52]1[CH:53]=[C:54](B(O)O)[CH:55]=[CH:56][C:57]=1[C:58]([O:60][CH3:61])=[O:59].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:30][CH2:29][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([OH:28])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:31][C@H:32]([C:37]2[CH:42]=[CH:41][C:40]([C:54]3[CH:55]=[CH:56][C:57]([C:58]([O:60][CH3:61])=[O:59])=[C:52]([O:51][CH3:50])[CH:53]=3)=[CH:39][C:38]=2[N:44]2[CH:48]=[CH:47][C:46]([CH3:49])=[N:45]2)[C:33]([F:36])([F:35])[F:34])[N:3]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1OC
Reactant: Cc1ccn(-c2cc(Br)ccc2[C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)O)N(C(=O)OCc3ccccc3)C4)nc(N)n2)C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc([C@@H](Oc3cc(N4CCC5(CC4)C[C@@H](C(=O)O)N(C(=O)OCc4ccccc4)C5)nc(N)n3)C(F)(F)F)c(-n3ccc(C)n3)c2)cc1OC
Temperature: 80 °C

Procedure:
To a solution of (S)-8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10m) (135 mg, 0.18 mmol) in dioxane (2 mL) was added (3-methoxy-4-(methoxycarbonyl)phenyl)boronic acid (84 mg, 0.4 mmol) and Cs2CO3 (48 mg, 0.16 mmol). The reaction was heated to 80° C. for 16 h, cooled to RT, and filtered. The solvent was removed in vacuo. Purification via normal phase silica gel chromatography (CH2Cl2/Heptane) provided (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-4′-(methoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+:16].[K+].[C:18]([OH:22])(=[O:21])[CH:19]=O>CO>[C:10]([C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[CH:19][C:18]([O-:22])=[O:21])#[N:11].[K+:16]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: O=CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#CC(=CC(=O)[O-])c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
18.6g (0.1 mol) of (3,4-dichlorophenyl)acetonitrile and 35 g (0.25 mol) of potassium carbonate were initially charged in 200 ml of methanol and admixed with 22.2 g (0.15 mol) of 50% strength agueous glyoxylic acid, and the mixture was stirred at room temperature for 5 h. The residue was filtered off, washed with methylene chloride, stirred with 1 l of water at room temperature overnight and filtered off, and the precipitated product was washed with water and dried. Yield 26.2 g, m.p. 235-238° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15](=[O:21])[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[CH2:32](Br)[CH:33]=[CH2:34]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:10]([CH2:34][CH:33]=[CH2:32])[C:11]([O:13][CH3:14])=[O:12])[C:15](=[O:21])[N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: COC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC[C@H](C(=O)OC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of the product from Step A (2.05 g, 6.83 mmol) in THF (30 mL) was added potassium hexamethyldisilazide (30.0 mL, 0.5M in toluene, 15.0 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 30 min. Allyl bromide (3.0 mL, 34.7 mmol) was then added. After stirring at −78° C. for 2 h, the reaction was quenched with saturated aqueous ammonium chloride solution. The organic phase was separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic layers were washed with brine and concentrated in vacuo. Purification by flash chromatography (30:70 hexanes/ethyl acetate) afforded the desired product (major diastereoisomer from the reaction).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].[CH2:22]([S:29][CH2:30][C@@H:31]([C:33]([NH:35][CH2:36][CH2:37][CH3:38])=[O:34])[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O>[CH2:22]([S:29][CH2:30][C@H:31]([NH:32][C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])=[O:21])[C:33](=[O:34])[NH:35][CH2:36][CH2:37][CH3:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: CCCNC(=O)[C@@H](N)CSCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCNC(=O)[C@H](CSCc1ccccc1)NC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.5 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.34 g), S-benzyl-N-propyl-L-cysteinamide (0.27 g), 1H-1,2,3-benzotriazol-1-ol (0.22 g) and N,N-dimethylformamide (15 ml) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.27 g) at 4° C., and the mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-1:1), and the obtained crystals were washed with ethyl acetate-hexane to give the title compound (285 mg, yield 49%) as colorless crystals. melting point 124-125° C.
Reaction SMILES: Cl.Cl.[S:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[C:4]1[NH2:12].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[S:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[C:4]1[NH:12][S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20]
Reactant: Nc1cc2cccnc2s1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(Nc1cc2cccnc2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound 147-E (0.22 g, 1.00 mmol) in pyridine (5.0 mL) was stirred at rt for 30 min, to which was added benzenesulfonyl chloride (0.135 mL, 1.05 mmol) and the reaction mixture was stirred at rt for 4 h. Another portion of benzenesulfonyl chloride (0.030 mL, 0.235 mmol) was added and the reaction mixture stirred at rt for 72 h. Water and saturated sodium bicarbonate solution were added and the mixture was extracted with dichloromethane, dried over sodium sulfate and evaporated in vacuo to afford a residue. Flash column chromatography (SiO2) eluting with dichloromethane afforded compound 147-F as a yellow solid (0.24 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2N(C)C(=O)[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[H-].[Na+].C(O[C:26](=[O:30])[O:27][CH2:28][CH3:29])C.[Cl-].[Na+]>CN(C)C=O>[CH2:28]([O:27][C:26]([C:9]1[NH:8][C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:6]2[C:5]=1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20]2)=[O:30])[CH3:29]
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: CCOC(=O)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Reaction time: 0.25 h

Procedure:
A solution of 28.5 g. of 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one in 400 ml. of dimethylformamide is treated under an atmosphere of argon at -10° C. with 0.25 mol. of sodium hydride (11.0 g. of a 55% dispersion in mineral oil) and the mixture is stirred at the same temperature for 15 minutes. The suspension is then treated at -10° C. to -5° C. with a solution of 35.5 g. of diethylcarbonate in 50 ml. of dimethylformamide. The mixture is stirred at 20° C. for 1 hour and at 60° C. for an additional 4 hours. Then, the mixture is poured on to a mixture of 100 g. of sodium chloride and 2.5 kg. of ice. The precipitate is removed by filtration, washed with water and dissolved in methylene chloride. The organic solution is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated to dryness. The crystalline residue is heated to reflux with 500 ml. of ethanol for 10 minutes and then cooled in an ice-bath. After filtration and washing with ethanol and diethyl ether, there is obtained 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester in the form of greenish crystals having a melting point of 208°-210° C. (decomposition). Recrystallization from acetonitrile does not increase the melting point.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([CH:32]=O)[NH:24][C:23]=1[CH3:34])=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([CH:32]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[NH:11][C:10]2=[O:16])[NH:24][C:23]=1[CH3:34])=[O:21])[CH3:18]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCC(=O)O
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)c1CCC(=O)O

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 4-(2-carboxyethyl)-5-formyl-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester to give the title compound.