Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]=1.[H-].[Li+].IC.[CH3:24][N:25]([CH:27]=O)[CH3:26]>>[CH3:26][N:25]([CH3:24])[C:27]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]=1
Reactant: CCOC(=O)c1cc(N)n(Cc2ccccc2F)n1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Li+]
Solvent: CI
Product: CCOC(=O)c1cc(N(C)C)n(Cc2ccccc2F)n1
Reaction time: 1 h

Procedure:
1.96 g of ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate 1-8-1 (7.46 mmol, 1.0 eq.) were dissolved in 9.8 mL of dry DMF. Under nitrogen atmosphere 237 mg of lithium hydride (29.8 mmol, 4.0 eq.) were added at 0° C. bath temperature. The mixture was stirred for one hour at this temperature. Then 3.7 mL of iodomethane (59.6 mmol, 8.0 eq.) were added at 0° C. bath temperature. The reaction mixture was stirred then for three days at rt. After the addition of ice it was stirred for 30 minutes and then extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography to provided 1.35 g (4.49 mmol, 60%) of analytically pure target compound.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][NH:48][CH2:49][CH2:50][CH3:51]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:48]([CH3:47])[CH2:49][CH2:50][CH3:51])=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CCCNC
Product: CCCN(C)C(=O)CC1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with n-methyl-1-propylamine (Aldrich) to give the title product. LC-MS (ES+) 720 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:26][CH:27]1[CH2:31][CH2:30][O:29][CH2:28]1>>[O:29]1[CH2:30][CH2:31][CH:27]([NH:26][C:21]([C:17]2[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH2:24][OH:25])[CH:16]=2)=[O:23])[CH2:28]1
Reactant: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)O
Reactant: NC1CCOC1
Product: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)NC1CCOC1
Yield: 61 %

Procedure:
As described for example 107, 5-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.28 mmol) was converted, using rac-3-aminotetrahydrofuran instead of 2-amino-2-methyl-1-propanol, to the title compound (73 mg, 61%) which was obtained as a colorless gum. MS: m/e=433.3 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH:4]([CH3:9])[C:5]([O:7]C)=O.[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[O:25][C:24]=2[CH:23]=[CH:22][C:21]=1[CH:33]=O>>[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[O:25][C:24]=2[CH:23]=[CH:22][C:21]=1[CH2:33][N:1]1[CH:2]([C:10]2[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:3][CH:4]([CH3:9])[C:5]1=[O:7]
Reactant: COC(=O)C(C)CC(N)c1c(OC)ccnc1OC
Reactant: O=Cc1ccc2oc3ccccc3c2c1
Product: COc1ccnc(OC)c1C1CC(C)C(=O)N1Cc1ccc2oc3ccccc3c2c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,4-dimethoxypyridin-3-yl)-2-methylbutanoate with commercially available dibenzo[b,d]furan-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.85 min.; [M+H]+: 416.90 g/mol.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[C:21]1([CH3:29])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27]N.Cl>>[C:14]1([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[CH3:29])[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccccc1NN
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Agent: Cl
Product: Cc1ccccc1-n1nccc1-c1nn(-c2ccccc2)ccc1=O
Yield: 55 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and o-tolylhydrazine×HCl according to the method described for Example 1 in 55% yield. MS: M=329.1 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[C:12]1[S:16][C:15](=[S:17])[NH:14][C:13]1=[O:18])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:19]CN(C(C)C)C(C)C.IC>CO>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[C:12]1[S:16][C:15]([S:17][CH3:19])=[N:14][C:13]1=[O:18])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1[nH]c2ccccc2c1C=C1SC(=S)NC1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CI
Product: CSC1=NC(=O)C(=Cc2c(C)[nH]c3ccccc23)S1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a room temperature suspension of (Z) 5-[(2-methyl-1H-indol-3-yl)methylene]-2-thioxo-4-thiazolidinone (1.502 g, 5.48 mmols) in 50 mL of methanol is added Hunig's base (1.15 mL, 6.61 mmols) followed by iodomethane (0.500 mL, 8.03 mmols). The thick suspension is stirred for 2 hours at room temperature. Filtration washing with 1:1 hexane:ether provides 1.201 g of an orange solid. This material is suspended in 100 mL of hot ethyl acetate and filtered to provide 943 mg (60%) of (Z)-5-[(2-methyl-1H-indol-3-yl)methylene]-2-(methylthio)-4(5H)-thiazolone; mp 253-255° C. dec.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=2[CH3:33])[C:5]([CH3:23])=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.[CH3:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:33][C:32]1[CH:31]=[C:30]([CH3:34])[NH:29][C:28](=[O:35])[C:27]=1[CH2:26][NH:25][C:24]([C:4]1[C:5]([CH3:23])=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:13][CH2:14]2)[CH:7]=[C:2]([C:41]2[CH:40]=[N:39][N:38]([CH3:37])[CH:42]=2)[CH:3]=1)=[O:36]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnn(C)c3)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Temperature: 100 °C

Procedure:
To a stirred solution of tert-butyl 4-((5-bromo-3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenyl)(methyl)amino)piperidin-1-carboxylate (1 equiv.) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.1 equiv.) was added and argon was purged again for 10 min. The reaction was heated at 100° C. for 5 h. After cooling, the reaction mixture was diluted with water, and the product was extracted with 10% MeOH/DCM. The combined organic layers were dried over Na2SO4 and the solvent removed under reduced pressure to afford crude product which was purified by column chromatography over silica gel to afford tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)phenyl)(methyl)amino)piperidine-1-carboxylate. A stirred solution of this compound (1 mmol) in DCM (5 mL) was cooled to 0° C. and TFA (2 mL) was added to it. The reaction was stirred at room temperature for 1 h. On completion, the solution was concentrated to dryness. The residue was purified by solvent washings to afford the title compound (0.07 g, 87%). LCMS: 463.30 (M+1)+; HPLC: 98.02% (@ 254 nm) (Rt; 4.145; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.47 (bs, 1H), 8.12 (s, 2H), 8.05 (s, 1H), 7.83 (s, 1H), 7.32 (s, 1H), 7.14 (s, 1H), 5.86 (s, 1H), 4.28 (m, 2H), 3.84 (s, 3H), 3.24-3.27 (m, 2H), 3.11 (bs, 1H), 2.87-2.89 (m, 2H), 2.59 (s, 3H), 2.20 (s, 3H), 2.18 (s, 3H), 2.10 (s, 3H), 1.77-1.80 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C[O:20][C:21](=O)[C:22]1[C:27]([NH:28][C:29]([CH:31]2[CH2:33][CH2:32]2)=[O:30])=[CH:26][CH:25]=[C:24]([Cl:34])[C:23]=1[CH2:35]Br.C(N(CC)CC)C>CN(C=O)C>[Cl:34][C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:29]([CH:31]2[CH2:32][CH2:33]2)=[O:30])=[C:22]2[C:23]=1[CH2:35][N:18]([C@@H:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:21]2=[O:20]
Reactant: COC(=O)c1c(NC(=O)C2CC2)ccc(Cl)c1CBr
Reactant: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 90 °C
Yield: 27.9 %

Procedure:
To a solution of (1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (1.4 g, 5.1 mmol) in DMF (20 ml) was added 2-bromomethyl-3-chloro-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (1.6 g, 4.6 mmol) and triethyl amine (2.0 ml, 14 mmol). The mixture was heated at 90° C. overnight. The solvent was removed in vacuo. The resulted oil was extracted with ethyl acetate (50 ml) and water (30 ml). The organic layer was washed with water (30 ml×2), brine (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulted oil was purified by silica gel column to give (1S)-cyclopropanecarboxylic acid {7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (650 mg, 30%): mp, 197–199° C.; 1H NMR (CDCl3) δ 0.89–0.93 (m, 2H, c-CH2), 1.08–1.12 (m, 2H, c-CH2), 1.44 (t, J=7.0 Hz, 3H, OCH2CH3), 1.65–1.69 (m, 1H, c-CH), 2.97 (s, 3H, CH3SO2), 3.70 (dd, J=5, 15 Hz, 1H, CHH), 3.87(s, 3H, OCH3), 4.05–4.23 (m, 4H, NCH+CH+OCH2CH3), 4.41 (d, J=17 Hz, 1H, CHH), 5.75–5.81 (m, 1H, CHN), 6.86–6.96 (m, 3H, Ar), 7.39 (d, J=9.0 Hz, 1H, Ar), 8.45(d, J=9.0 Hz, 1H, Ar), 10.36 (s, 1H, NHCO). 13CNMR (CDCl3): δ 8.5, 14.7, 16.2, 41.6, 46.9, 51.3, 55.5, 56.0, 64.7, 111.7, 112.3, 118.6, 119.3, 119.7, 121.8, 129.1, 133.2, 136.8, 139.0, 149.0, 149.9, 169.2, 172.6; Anal Calcd for C24H27ClN2O6S: C, 56.86; H, 5.37; N, 5.53. Found: C, 56.81; H, 5.26; N, 5.56.
Reaction SMILES: [NH2:1][C:2]1([C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.N1C=CC=CC=1.[Cl:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>C(Cl)Cl>[CH3:18][O:17][C:15]([C:2]1([NH:1][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][Cl:25])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7]1)=[O:16]
Reactant: O=C(Cl)CCCCl
Reactant: COC(=O)C1(N)CCN(C(=O)OC(C)(C)C)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)CCCCl)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 4-amino-1-BOC-piperidine-4-carboxylate (2.0 g, 6.78 mmol) in DCM (15 mL) and pyridine (2.10 mL, 20.35 mmol), 4-chlorobutyryl chloride (0.84 mL, 7.5 mmol) in DCM (5 mL) was added slowly at 0° C. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with DCM (40 mL), and quenched with saturated NaHCO3 (30 mL). The organic layer was separated and the aqueous layer was extracted twice with DCM. The combined organic layers were then washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated to give 4-(4-chloro-butyrylamino)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester which was used further without purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[S:10].[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13]>C(N(CC)CC)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[S:10][CH2:13][CH2:12][C:11]([OH:15])=[O:14]
Reactant: S=C1Cc2ccccc2N1
Reactant: C=CC(=O)O
Solvent: CCN(CC)CC
Product: O=C(O)CCSc1cc2ccccc2[nH]1

Procedure:
One liter of triethylamine is added slowly in the course of 2 hours 30 minutes to a vigorously stirred suspension of 194 g (1.3 mol) of 2-indolinethione (prepared according to Y. Nakisumi and Coll. Chem. Pharm. Bull. 1984, 32, (3), 877) in 108 g (1.5 mol) of acrylic acid. The mixture is brought to reflux for 12 hours while stirring is maintained, and then cooled and concentrated under vacuum. The residue is taken up with 10% strength aqueous sodium bicarbonate solution and the mixture is filtered. The filtrate is acidified with aqueous hydrochloric acid solution. The precipitate formed is drained, washed with water and dried. It is recrystallized in toluene.
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].Cl[S:21]([C:24]1[CH:39]=[CH:38][C:27]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[CH:26][C:25]=1[O:40][CH3:41])(=[O:23])=[O:22]>C(Cl)Cl.CCOC(C)=O>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:21]([C:24]2[CH:39]=[CH:38][C:27]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])=[CH:26][C:25]=2[O:40][CH3:41])(=[O:23])=[O:22])[C:3]1=[O:12]
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1S(=O)(=O)Cl
Reactant: NC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(C(=O)OCc2ccccc2)ccc1S(=O)(=O)N1C(=O)C(N)(c2ccccc2Cl)c2cc(Cl)ccc21
Yield: 78.7 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 0.860 g of 3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one and 1 g of benzyl 4-chlorosulfonyl-3-methoxybenzoate. Chromatography on silica using a DCM/AcOEt mixture (99/1; v/v) as the eluent gives 1.38 g of the expected product, which is used as such in the next step.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=3)[CH:15]=[CH:16][C:17]=1[C:18]#[N:19])[N:5]=2.[Cl:34][CH2:35][C:36](Cl)=[O:37]>CN(C)C=O.C(OCC)(=O)C>[Cl:34][CH2:35][C:36]([NH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:29])[CH3:30])[CH:23]=3)[CH:15]=[CH:16][C:17]=1[C:18]#[N:19])[N:5]=2)=[O:37]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C#N)c(Oc3ccc4nc(N)sc4n3)c2)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C#N)c(Oc3ccc4nc(NC(=O)CCl)sc4n3)c2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-cyanophenyl}-3-(1-cyano-1-methylethyl)benzamide (150 mg, 0.330 mmol) produced in Example C43(vi) in N,N-dimethylformamide (3.0 mL) was added chloroacetyl chloride (42 μL, 0.528 mmol), and the mixture was stirred at room temperature for 4 hr. Chloroacetyl chloride (21 μL, 0.264 mmol) was further added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give N-[3-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-4-cyanophenyl]-3-(1-cyano-1-methylethyl)benzamide as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([N:22]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][C:25]=3[F:33])[CH3:23])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]>C(OCC)(=O)C.[Pd]>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([N:22]([CH3:23])[CH:19]2[CH2:20][CH2:21][N:16]([CH2:15][C:12]3[CH:11]=[CH:10][C:9]([C:3]([OH:8])([C:2]([F:35])([F:1])[F:34])[C:4]([F:5])([F:6])[F:7])=[CH:14][CH:13]=3)[CH2:17][CH2:18]2)=[C:25]([F:33])[CH:26]=1
Reactant: CN(c1ccc([N+](=O)[O-])cc1F)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(c1ccc(N)cc1F)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Yield: 42.5 %

Procedure:
1,1,1,3,3,3-Hexafluoro-2-(4-((4-((2-fluoro-4-nitrophenyl)(methyl)amino)-piperidin-1-yl)methyl)phenyl)propan-2-ol (1.472 mmol, 750 mg) and palladium (10% on carbon, Degussa) (0.015 mmol, 31.3 mg) were hydrogenated in ethyl acetate (10 mL) at 5 bar for 1 hour at room temperature. The reaction mixture was filtered and concentrated under vacuum to give the intermediate 2-(4-((4-((4-amino-2-fluorophenyl)-(methyl)amino)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (300 mg).
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14]3[NH:15][C:16]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)=[CH:17][N:18]=3)=[C:7]2[N:6]=[N:5]1)[C:2]#[CH:3].[H-].[Na+].[CH3:26]I>CN(C=O)C>[CH3:26][N:18]1[CH:17]=[C:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[N:15]=[C:14]1[C:13]1[N:12]=[CH:11][N:8]2[C:9](=[O:10])[N:4]([CH2:1][C:2]#[CH:3])[N:5]=[N:6][C:7]=12
Reactant: C#CCn1nnc2c(-c3ncc(-c4cccs4)[nH]3)ncn2c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCn1nnc2c(-c3nc(-c4cccs4)cn3C)ncn2c1=O
Reaction time: 0.17 h
Yield: 90 %

Procedure:
3-(Prop-2-ynyl)-8-(5-(thiophen-2-yl)-1H-imidazol-2-yl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one (0.15 mmol) was dissolved in dry DMF (1 mL) and cooled in ice under a nitrogen atmosphere. A 60% suspension of sodium hydride in mineral oil (0.17 mmol) was added in one portion and the reaction stirred on ice for 10 minutes. Methyl iodide (0.30 mmol) was then added dropwise to the reaction and the mixture stirred at room temperature for 24 hours. Solvent was then removed under vacuum and product isolated by preparative thin layer chromatography eluting with 2.5% MeOH/DCM. Yield 90%. δH (DMSO-d6) 8.97 (1H, s), 7.78 (1H, s), 7.40 (1H, dd, J=5.2, 1.2), 7.33 (1H, dd, J=3.6, 1.2), 7.08 (1H, m), 5.13 (2H, d, J=2.4), 3.96 (3H, s), 3.52 (1H, t, J=2.4).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:11]=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([O:19][C:12]2[CH:13]=[CH:14][C:15]([N+:16]([O-:18])=[O:17])=[C:10]([CH3:9])[CH:11]=2)[N:3]=[CH:4][N:5]=1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(Cl)ncn2)ccc1[N+](=O)[O-]

Procedure:
0.40 g (2.68 mmol) 4,6-dichloropyrimidine, 0.42 g (2.74 mmol) 3-methyl-4-nitrophenol and 0.40 g (2.89 mmol) potassium carbonate in 2.0 mL DMF were stirred for 2 h at RT. The reaction mixture was mixed with water and the precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:19])=[C:14]([CH:18]=2)[C:15](O)=[O:16])[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C([Cl:23])=O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:19])=[C:14]([CH:18]=2)[C:15]([Cl:23])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCc2cccc(Cl)c2)cc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2cccc(Cl)c2)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DMF (1 drop) was added to a suspension of 5-{[(3-chlorophenyl)methyl]oxy}-2-methylbenzoic acid from the preparation of Intermediate 85 as described above (200 mg, 0.72 mmol) and oxalyl chloride (95 ul, 1.08 mmol, 1.5 eq) in DCM (5 ml). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then evaporated to dryness and azeotroped with toluene (2×50 ml). The organic layer was separated, dried and evaporated in vacuo to afford the title compound as a yellow solid, 213 mgs. No further purification carried out. LCMS sample dissolved in methanol, MS (ES+) m/z 291 [M+H]+ (C16H1535ClO3), corresponding to methyl ester generated from acid chloride.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.[OH:18][C:19]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[OH:18][C:19]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:24][CH2:23][N:22]([C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]2[CH:7]=[C:6]3[C:11](=[N:10][CH:9]=2)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]3)[CH2:21][CH2:20]1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: OC1(c2ccccc2)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CCc2cc(/C=C/C(=O)N3CCC(O)(c4ccccc4)CC3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 4-hydroxy-4-phenylpiperidine (25 mg, 0.14 mmol), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on preparative TLC (eluent: dichloromethane/MeOH, 95/5) to give a white solid. This solid was triturated in acetone and diethyl ether, filtered, washed with diethyl ether and then dried to give the title compound (18.5 mg, 41%) as a white solid.