Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=CC=1[N+]([O-])=O)C[P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].Cl[CH2:21][C:22]1[CH:23]=[C:24]([O:32][CH3:33])[C:25]([N+:29]([O-:31])=[O:30])=[C:26]([F:28])[CH:27]=1>>[F:28][C:26]1[CH:27]=[C:22]([CH:23]=[C:24]([O:32][CH3:33])[C:25]=1[N+:29]([O-:31])=[O:30])[CH2:21][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(Cl)c1)OCC
Reactant: COc1cc(CCl)cc(F)c1[N+](=O)[O-]
Product: CCOP(=O)(Cc1cc(F)c([N+](=O)[O-])c(OC)c1)OCC

Procedure:
The title compound was prepared using the procedure from Compound 104C (Diethyl (3-chloro-4-nitrobenzyl)phosphonate) with 5-(chloromethyl)-1-fluoro-3-methoxy-2-nitrobenzene (Compound 146C). 1H NMR (CDCl3, 400 MHz): δ=1.31 (t, J=7.07 Hz, 6H), 3.11-3.18 (m, 2H), 3.94 (s, 3H), 4.07-4.13 (m, 4H), 6.77 (dt, J=9.79, 1.93 Hz, 1H), 6.82 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:15][C:16]1[N:17]=[C:18]([SH:22])[S:19][C:20]=1[CH3:21]>>[N:5]1([C:3](=[O:4])[CH2:2][S:22][C:18]2[S:19][C:20]([CH3:21])=[C:16]([CH3:15])[N:17]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: Cc1nc(S)sc1C
Reactant: O=C(CCl)N1CCCc2ccccc21
Product: Cc1nc(SCC(=O)N2CCCc3ccccc32)sc1C
Yield: 74 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 4,5-dimethylthiazole-2-thiol as the nucleophile to yield 33 as a cream solid (690 mg, 74%). MS (APCI): m/z 319 [M+H]+. Anal. Calcd. for C16H18N2OS2: C, 60.34; H, 5.70; N, 8.80. Found: C, 60.51; H, 5.71; N, 8.72.
Reaction SMILES: I[C:2]1C=C[C:5]([N:8]2C[C@H](CNC(=O)OC(C)(C)C)O[C:9]2=[O:22])=[CH:4][CH:3]=1.F[C:24]1[CH:25]=[C:26]([N:31]2[CH2:35][C@H:34]([CH2:36][NH:37][C:38](=[O:40])[CH3:39])[O:33][C:32]2=[O:41])[CH:27]=[CH:28][C:29]=1I>>[O:41]=[C:32]1[N:31]([C:26]2[CH:27]=[CH:28][C:29]([CH:4]3[CH2:3][CH2:2][C:9](=[O:22])[NH:8][CH2:5]3)=[CH:24][CH:25]=2)[CH2:35][C@H:34]([CH2:36][NH:37][C:38](=[O:40])[CH3:39])[O:33]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCC(=O)NC3)cc2)C(=O)O1

Procedure:
N-({(5S)-2-oxo-3-[4-(6-oxopiperidin-3-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)acetamide is prepared by the route described in Example 1 substituting tert-butyl [(5S)-3-(4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methylcarbamate for N-{[(5S)-(3-fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide. 1H-NMR (DMSO) δ: 8.24, 7.51, 7.47, 7.33, 4.71, 4.10, 3.72, 3.40, 3.18, 3.14, 2.97, 2.28, 1.94, 1.83
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[C:30]#[N:31]>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=5[C:30]#[N:31])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: N#Cc1ccccc1F
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccccc5C#N)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-fluoro-benzonitrile following a procedure analogous to that described for Intermediate 12. LC (method 2): tR=1.11 min; Mass spectrum (ESI+): m/z=460 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[C:8]([C:9]([NH:11][CH:12]([CH2:15]O)CO)=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1.[CH3:19][O:20][C:21]([O:24]C)([CH3:23])[CH3:22].CO>C1(C)C=CC=CC=1>[CH3:22][C:21]1([CH3:23])[O:24][CH:12]([NH:11][C:9](=[O:10])[C:8]2[C:3]([C:2]([F:1])([F:17])[F:18])=[CH:4][CH:5]=[N:6][CH:7]=2)[CH2:15][CH2:19][O:20]1
Reactant: O=C(NC(CO)CO)c1cnccc1C(F)(F)F
Reactant: COC(C)(C)OC
Solvent: CO
Solvent: Cc1ccccc1
Product: CC1(C)OCCC(NC(=O)c2cnccc2C(F)(F)F)O1

Procedure:
In the presence of 0.50 g of p-toluolsulfonic acid hydrate, 2.64 g (10 mmol) of N-(4-trifluoromethylnicotinoyl)serinol and 4.20 g (40 mmol) of acetone dimethyl acetal in 50 ml of toluene were stirred at 80° C. for 12 hours, with distillative removal of the methanol that was formed. After cooling, the mixture was extracted with dilute sodium hydroxide solution and water and the organic phase was dried and concentrated. This gave 1.5 g of product (49.3% of theory) as a colorless solid of melting point 155-156° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.CN1CCOCC1.[NH2:33][C@@H:34]([CH:38]([CH3:40])[CH3:39])[C:35]([NH2:37])=[O:36]>CN(C=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:33][C@@H:34]([CH:38]([CH3:40])[CH3:39])[C:35]([NH2:37])=[O:36])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)[C@H](N)C(N)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(CCCCN2C(=O)c3ccccc3C2=O)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 66 h
Yield: 75.3 %

Procedure:
4-[4-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)butyl]benzenesulfonyl chloride 13 (0.45 g, 1.19 mmol) was dissolved in dry DMF (5 mL), and added to a solution of N-methylmorpholine (3 mL) and (2S)-amino-3-methylbutyramide (0.18 g, 1.19 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 66 h. Solvent was removed by rotary evaporation and the residue was purified by flash silica gel chromatography eluting with chloroform/methanol/concentrated ammonium hydroxide (15:1:0.1, v/v) to give the desired product 14 as a white powder (0.41 g, 73% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.72 (d, 3H), 0.76 (d, 3H), 1.77 (m, 4H), 1.79 (m, 1H), 2.68 (m, 2H), 3.40 (m, 1H), 3.60 (m, 2H), 6.92 (s, 1H), 7.21 (s, 1H), 7.34 (d, 2H) 7.50 (d, 1H), 7.65 (d, 2H), 7.82 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[CH:33]=2)[CH:27]=1)=[O:25])(C)(C)C>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:22](=[O:21])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[C:34]([CH3:39])[N:35]=[C:36]([CH3:38])[CH:37]=2)[CH:27]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)ccc3NC(=O)OC(C)(C)C)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-amino-4-chloro-phenyl)-carbamic acid tert-butyl ester (Example J4) (243 mg, 1.0 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (325 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (240 mg, 49%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16])(=[O:3])[CH3:2].[O-:18][O-:19].[Na+].[Na+]>>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:18][O:19][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCCCCCCCC(=O)Cl
Reactant: [O-][O-]
Agent: [Na+]
Product: CC(=O)OCCCCCCCCCCC(=O)OOC(=O)CCCCCCCCCCOC(C)=O
Temperature: 0 °C

Procedure:
In 50 ml of petroleum ether was dissolved 10.5 g of 11-acetoxyundecanoylchloride. To the solution was added 20 ml of ice-water. To the mixture was further added, while stirring, 4 g of sodium peroxide little by little. The organic layer was separated, and the aqueous layer was subjected to extraction with ether. The organic layer and the ether extracts were combined, washed with water and dried, followed by evaporation of the solvent to yield 8.6 g of white wax-like bis(11-acetoxyundecanoyl)peroxide.
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH2:7][O:8][C:9]2[C:17]3[N:16]([CH2:18][CH2:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:15](=[O:26])[N:14]([CH3:27])[C:13]=3[CH:12]=[CH:11][C:10]=2[C:28]2[C:29]3[CH:38]=[CH:37][N:36](S(C4C=CC(C)=CC=4)(=O)=O)[C:30]=3[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=2)[CH2:6][CH2:5][CH2:4]1>O.CO>[CH:3]1([CH2:7][O:8][C:9]2[C:17]3[N:16]([CH2:18][CH2:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:15](=[O:26])[N:14]([CH3:27])[C:13]=3[CH:12]=[CH:11][C:10]=2[C:28]2[C:29]3[CH:38]=[CH:37][NH:36][C:30]=3[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5c(c4OCC4CCC4)n(CCC4CCNCC4)c(=O)n5C)cn(C)c(=O)c32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1cc(-c2ccc3c(c2OCC2CCC2)n(CCC2CCNCC2)c(=O)n3C)c2cc[nH]c2c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 7.2 %

Procedure:
A 3.0 M solution of sodium hydroxide in water (0.40 L) was added to the solution of 4-(cyclobutylmethoxy)-1-methyl-5-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one (20.0 mg, 0.031 mmol) in methanol (1.0 mL), and the resultant reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (1.1 mg, 7%). LCMS calculated for C28H36N5O3 (M+H)+: m/z=490.3. found: 490.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:15][C:14]([NH:13][C:4]1[N:3]=[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(C)Nc1nc(Cl)cc(N2CCCC2)n1
Reactant: C1CNCCN1
Product: CC(C)(C)Nc1nc(N2CCCC2)cc(N2CCNCC2)n1
Yield: 78.1 %

Procedure:
4-Chloro-2-(1,1-dimethylethylamino)-6-pyrrolidinopyrimidine is reacted with piperazine as described in Example 17 to obtain the title compound in a yield of 78.1%, m.p.: 162°-165° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.Br[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18].Cl>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.C1COCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18]
Reactant: Brc1ccccn1
Reactant: O=Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(-c2ccccn2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 38.2 %

Procedure:
Ex-587A) To a THF solution (8 mL) of 2-bromopyridine (1.30 g, 8.23 mmol) at −78° C. was added 1.6 M n-BuLi in hexanes (5.3 mL, 8.48 mmol). The resulting dark red solution was stirred at −78° C. for 10 min, and a solution of 0.5 M ZnCI2 in THF (18 mL, 9.0 mmol) was added giving a light brown slurry. After warming to room temperature, 3-bromobenzaldehyde (0.816 mL, 7.0 mmol) and Pd(PPh3)4 (0.242 g, 0.21 mmol) were added, and the mixture was stirred for 18 h at room temperature under argon. The reaction mixture was poured into 1 N HCl (30 mL) and washed with diethyl ether. The aqueous layer was neutralized with NaHCO3 and extracted with diethyl ether. The solvent was removed in vacuo to give the crude product as an oil. Purification by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane gave 0.49 g (38%) of the desired 3-(2-pyridinyl)benzaldehyde product as a colorless oil. GCMS: m/z=183 [M+].
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:7]=[C:8]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([NH2:21])=[CH:20][C:14]=3[CH:13]=2)[CH:9]=[N:10][CH:11]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33]>O1CCCC1.C(OCC)(=O)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:21][C:19]2[CH:18]=[CH:17][C:15]3[S:16][C:12]([C:8]4[CH:9]=[N:10][CH:11]=[C:6]([C:5]5[N:1]=[N:2][NH:3][N:4]=5)[CH:7]=4)=[CH:13][C:14]=3[CH:20]=2)=[O:31])=[CH:25][C:24]=1[C:32]([F:33])([F:34])[F:35]
Reactant: Nc1ccc2sc(-c3cncc(-c4nn[nH]n4)c3)cc2c1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc2sc(-c3cncc(-c4nn[nH]n4)c3)cc2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The reaction mixture of 2-(5-(2H-tetrazol-5-yl)pyridin-3-yl)benzo[b]thiophen-5-amine (44.1 mg, 0.15 mmol, 1 eq) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (33.2 mg, 1 eq) in anhydrous tetrahydrofuran (1.5 mL) under nitrogen atmosphere was stirred at room temperature for 45 minutes. The reaction was then diluted with ethyl acetate, washed with aqueous ammonium chloride, brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted and concentrated. The soft solid was wrapped with silica gel and chromatographed (EtOAc to MeOH-EtOAc 1:4) to give 1-[4-chloro-3-(trifluoromethyl)phenyl]-3-{2-[5-(2H-tetrazol-5-yl)pyridin-3-yl]-1-benzothien-5-yl}urea as a yellow powder in the amount of 26 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.Cl.Cl[CH2:21][C:22]1[C:23]([NH:36][CH2:37][CH3:38])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH2:33][CH3:34])=[C:27]([F:35])[CH:26]=2.[Li+].[OH-]>C1COCC1.CO>[CH2:33]([O:32][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[F:35])[N:24]=[C:23]([NH:36][CH2:37][CH3:38])[C:22]([CH2:21][C:6]1[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=1[OH:18])=[CH:31]2)[CH3:34]
Reactant: CCNc1nc2cc(F)c(OCC)cc2cc1CCl
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1nc(O)c(Cc2cc3cc(OCC)c(F)cc3nc2NCC)c2cc(OC)c(OC)cc12
Temperature: 155 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (55 mg, 222 μmol) in THF (5 mL) in a 10 mL microwave vial equipped with a magnetic stirrer was added a solution of 3-(chloromethyl)-6-ethoxy-N-ethyl-7-fluoroquinolin-2-amine hydrochloride SMA 44106 (76 mg, 238 μmol) in MeOH (0.5 mL) at RT followed by a 2 N aq. LiOH solution (240 μL, 480 μmol) and the mixture was stirred at 155° C. for 1.5 h under microwave irradiation. After cooling to RT, THF and MeOH were removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (50 mL). The organic solution was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 96:4) gave 4-((6-ethoxy-2-(ethylamino)-7-fluoroquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.5 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((6-ethoxy-2-(ethylamino)-7-fluoroquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol 86 as a brown solid (15 mg, 12% yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][O:16][S:27]([CH3:26])(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CCO)CCOCOCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CCOCOCc1ccccc1)CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.99 g (3.92 mmol) of 1-benzyloxymethoxy-3,3-dimethyl-5-pentanol and 0.60 ml (4.3 mmol) of triethylamine in 15 ml of dichloromethane, 0.33 ml (4.3 mmol) of methanesulfonyl chloride was added at 0° C., followed by stirring at room temperature for 30 minutes, after which saturated aqueous sodium hydrogen carbonate was added. The mixture was extracted with dichloromethane and dried, after which the solvent was distilled off to yield 1-benzyloxymethoxy-3,3-dimethyl-5-methanesulfonyloxypentane.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.F[C:17]1[C:18]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:19]([CH3:35])[C:20]([C:33]#[N:34])=[C:21]2[C:25]=1[O:24][C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32])=[N:22]2>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:17]2[C:18]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[C:19]([CH3:35])[C:20]([C:33]#[N:34])=[C:21]3[C:25]=2[O:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])=[N:22]3)[CH2:4]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(-c3ccccc3O)nc2c1C#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(-c3ccccc3O)nc2c1C#N
Temperature: 120 °C
Yield: 24.7 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (100 μl, 0.79 mmol) and triethylamine (220 μl) were added to a dimethyl sulfoxide (5 ml) solution of 7-fluoro-2-(2-hydroxyphenyl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-212) (204 mg, 0.59 mmol). The system was purged with nitrogen, then sealed up, and heated at 120° C. for 30 minutes. After cooling, the solvent was evaporated away under reduced pressure, then the resulting residue was dissolved in chloroform, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated away under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. Elution with a mixed solvent of chloroform/methanol (97:3, v/v) gave a main product. This was washed with a mixed solvent of isopropyl ether and ethanol, and the solid was collected by filtration to obtain the entitled compound (64 mg, 24%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH2:33][CH2:34][O:35][CH2:36][CH:37]=2)O1>>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C@H:12]([O:11][C:10]1[C:5]2[O:4][CH:3]=[C:2]([C:32]3[CH2:37][CH2:36][O:35][CH2:34][CH:33]=3)[C:6]=2[CH:7]=[N:8][C:9]=1[NH2:23])[CH3:13]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCOCC3)coc12)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared according to General procedure A with starting materials 3-Bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-furo[3,2-c]pyridin-6-ylamine and 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran. 1H-NMR (CDCl3, 400 MHz): δ=1.86 (d, 3H), 2.40-2.52 (m, 2H), 3.94 (t, J=5.6 Hz, 2H), 4.36 (q, J=2.5 Hz, 2H), 4.77 (br. s., 2H), 6.24 (br. s., 1H), 6.52 (q, J=6.6 Hz, 1H), 7.01-7.10 (m, 1H), 7.29 (t, 1H), 7.37 (s, 1H), 8.24 (s, 1H). MS (ES+): m/z 423.02 (MH+, 35Cl, 37Cl), 424.94 (MH+, 37Cl, 37Cl). HPLC: tR=3.34 min (polar—5 min, ZQ3).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:4]=1[CH3:12]>CO.[H][H].[Ni]>[CH3:1][N:2]([CH3:13])[C:3]1[C:4]([CH3:12])=[C:5]([CH:6]=[CH:7][CH:8]=1)[NH2:9]
Reactant: [H][H]
Reactant: Cc1c(N(C)C)cccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: Cc1c(N)cccc1N(C)C
Yield: 93.7 %

Procedure:
73 g of N,N-dimethyl-2-methyl-3-nitroaniline are dissolved in 800 ml of methanol and hydrogenated at 20° C under 5 bar of hydrogen using Raney nickel as catalyst. 57 g of 3-dimethylamino-2-methylaniline are obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1.Br[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH:19][C:22]3[CH:29]=[CH:28][CH:27]=[C:24]([C:25]#[N:26])[CH:23]=3)=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1
Reactant: COCCn1ccc(NC(=O)c2nc(C)ccc2N)n1
Reactant: N#Cc1cccc(Br)c1
Product: COCCn1ccc(NC(=O)c2nc(C)ccc2Nc2cccc(C#N)c2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid [1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-amide in accordance with the general method of example, step using 3-Bromobenzonitrile instead of 3-bromopyridineto yield the final compound as a light yellow solid, MS (ISP): m/e=377.5 (M+H+).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.C(N1[CH:52]=[C:51]([CH2:53][CH2:54][NH2:55])[N:50]=[CH:49]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[C@H:54]12[CH2:53][C@H:51]([NH:50][CH2:49]1)[CH2:52][N:55]2[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Product: Cn1cc(-c2cc3c(-c4cccc(N5C[C@@H]6C[C@H]5CN6)n4)n[nH]c3cn2)cn1
Yield: 69.7 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and 2-(1-trityl-1H-imidazol-4-yl)-ethylamine were reacted. The product was deprotected to give 216 as a white solid (69.7% over two steps). 1H NMR (400 MHz, DMSO) δ 9.02 (s, 1H), 8.59 (s, 1H), 8.11 (s, 1H), 7.84 (s, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.36 (d, J=7.4 Hz, 1H), 6.64 (broad s, 1H), 6.50 (d, J=8.2 Hz, 1H), 4.76 (s, 1H), 3.91 (s, 3H), 3.75 (s, 1H), 3.69 (d, J=8.5 Hz, 1H), 3.49-3.32 (m, 2H), 3.00 (s, 2H), 1.89 (d, J=8.5 Hz, 1H), 1.78 (d, J=9.1 Hz, 1H). LC/MS: m/z 373.1 [M+1]
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]([F:11])([F:10])[C:7](Cl)=[O:8].[C:12]([Cl:15])([Cl:14])=[CH2:13]>ClCCl.O>[Cl:14][C:12]([Cl:15])=[CH:13][C:7](=[O:8])[C:6]([F:11])([F:10])[F:5]
Reactant: O=C(Cl)C(F)(F)F
Reactant: C=C(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(C=C(Cl)Cl)C(F)(F)F
Temperature: -50 °C
Reaction time: 0.25 h

Procedure:
To a solution of aluminum chloride (3.0 g, 22.5 mmol) in dichloromethane (100 mL) was added dropwise a solution of trifluoroacetyl chloride (3 g, 22.6 mmol) in dichloro-methane (5 mL) while keeping the temperature of the reaction mixture below −30° C. The reaction mixture was stirred for 15 minutes at −50° C. Then a solution of vinylidene chloride (2.2 g, 22.7 mmol) in dichloromethane (10 mL) was added dropwise over 2 h to the reaction mixture. The reaction mixture was stirred an additional 2 h at −50° C. and then warmed gradually to room temperature. The reaction mixture was diluted with water, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried (MgSO4), and concentrated under reduced pressure to give 4,4-dichloro-1,1,1-trifluoro-3-buten-2-one as an oil which was used for the next step without further purification.