Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[CH:15][CH:14]=2)[C:9](O)=[O:10])=[CH:4][CH:3]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH:25]1([NH:28][C:9](=[O:10])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:12][C:13]2[CH:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:18]=2)[CH2:27][CH2:26]1
Reactant: COC(=O)/C=C/c1ccc(C=C(C(=O)O)c2ccc(F)cc2)cc1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(C=C(C(=O)NC2CC2)c2ccc(F)cc2)cc1
Yield: 114 %

Procedure:
A mixture of 2-(4-fluorophenyl)-3-(4-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenyl)acrylic acid (0.23 g, 0.71 mmol) and cyclopropylamine (0.03 g, 0.60 mmol), EDCI (0.27 g, 1.4 mmol), HOBt (0.10 g, 0.71 mmol) was dissolved in N,N-dimethylformamide (DMF) (6 mL) under stirring. Triethylamine (TEA) (0.75 mL, 36 mmol) was added dropwise with constant stirring to the above reaction mixture and it was stirred at 30° C. for 2 hours. Subsequently the reaction mixture was diluted with ethyl acetate and washed successively with water (3×50 mL) and brine (3×50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to afford the pure compound (0.25 g, 96% yield).
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C@H:18]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:21][CH2:20][S:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[CH3:38][NH:39][CH3:40]>>[C:29]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:30]=[CH:31][C:26]([S:23]([N:22]2[CH2:21][CH2:20][S:19][CH:18]2[C:16]([NH:15][CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][N:39]([CH3:40])[CH3:38])=[O:17])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: CNC
Reactant: CS(=O)(=O)OCC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Product: CN(C)CCC(NC(=O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1

Procedure:
Following the general method A as outlined in Example 16, starting from 3-({[3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and N,N-dimethylamine, the title compound was obtained in 99.6% purity by HPLC.
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)(=[O:3])[CH3:2].[H-].[Na+].CI.[C:26](O)(=O)C>CS(C)=O.O.C(O)C>[C:1]([NH:4][C:5]1([CH3:26])[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Solvent: CI
Product: CC(=O)NC1(C)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 3.54 g of 10-acetamido-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one in 80 ml of anhydrous dimethyl sulphoxide, maintained at 20° C. under a nitrogen atmosphere, is added 0.86 g of 80% sodium hydride and the mixture is stirred for 20 minutes. A solution of 1.7 g of methyl iodide in 8 ml of anhydrous dimethyl sulphoxide is then added dropwise over 5 minutes at the same temperature, the mixture is stirred for 1 hour and 40 ml of distilled water are added slowly. After stirring for 16 hours, the mixture is poured onto a mixture of 200 g of ice and 560 ml of distilled water, then the pH is adjusted to 4 by addition of 4 ml of acetic acid. The mixture is centrifuged so as to remove the tarry part and to recover the supernatant suspension, which is concentrated to dryness under reduced pressure (1 mmHg; 0.13 kPa) at 60° C. The product obtained (10 g) is suspended in 200 ml of distilled water, isolated by filtration, washed twice with 80 ml in total of distilled water and dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. The product obtained (1.6 g) is suspended for 10 minutes in 20 ml of boiling ethanol and, after storing for 1 hour at 5° C., is then isolated by filtration, washed twice with 4 ml in total of chilled ethanol and dried under reduced pressure (15 mmHg; 2 kPa) at 20° C. The product obtained (1.4 g) is suspended for 10 minutes in 20 ml of boiling ethanol and, after storing for 1 hour at 5° C., is then isolated by filtration, washed twice with 4 ml in total of chilled ethanol and dried under reduced pressure (1 mmHg; 0.13 kPa) at 40° C. 1.28 g of 10-acetamido-10-methyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are thus obtained, decomposing without melting above 260° C. (NMR spectrum: [200 MHz; (CD3)2SO-d6 ; δ in ppm]: 1.61 and 1.79 (2s, 3H each: --CH3 at 10 and --NHCOCH3 at 10); 7.28 and 7.36 (2t, J=7.5 Hz, 1H each: --H 7 and --H 8); 7.43 and 7.80 (2d, J=7.5 Hz, 1H each: --H 6 and --H 9); 7.63 and 7.91 (2s, 1H each: --H of the imidazole); 8.63 (s, 1H: --NHCO-- at 10); 12.41 (s, 1H: --NHCO-- of the ring)).
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:27][C:28]2[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=[C:30](F)[C:29]=2[F:38])[CH:26]=1)[C:22]#[N:23].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOC(C)=O.C1COCC1>[Cl:18][C:19]1[CH:26]=[C:25]([O:27][C:28]2[C:29]([F:38])=[C:30]([CH:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:31]=[CH:32][C:33]=2[N+:34]([O-:36])=[O:35])[CH:24]=[C:21]([C:22]#[N:23])[CH:20]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c([N+](=O)[O-])ccc(F)c2F)c1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(Oc2cc(Cl)cc(C#N)c2)c1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% dispersion in oil, 2.16 g, 54.1 mmol) was added to anhydrous THF (50 mL) and cooled to 0° C. under nitrogen. Di-tert-butyl malonate (4.65 g, 24.8 mmol) was added dropwise and the reaction mixture was stirred 15 min and allowed to warm to RT. The reaction was cooled to 0° C. and 3-chloro-5-[(2,3-difluoro-6-nitrophenyl)oxy]benzonitrile (7.0 g, 22.5 mmol) was added dropwise in a minimal amount of THF. The reaction was allowed to warm to RT and stirred for 3 h then 10% aqueous citric acid (50 ml) and EtOAc (50 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The organic extracts were combined, washed with brine, dried over Na2SO4, filtered and evaporated to afford the title compound as an oil. 1H NMR (400 MHz, DMSO-d6): 6 ppm 8.13 (dd, 1H), 7.84 (d, 1H), 7.65 (dd, 1H), 7.59-7.61 (m, 1H), 7.56-7.59 (m, 1H), 5.10 (s, 1H), 1.40 (s, 18H). MS: m/z 507.2 (M+1).
Reaction SMILES: O[C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2sccc12
Product: Clc1ncnc2sccc12

Procedure:
4-hydroxythieno[2,3-d]pyrimidine (300 mg, 2.0 mmol) in phosphorous oxychloride (1.5 ml) was heated to reflux for 1 hour. 4-chlorothieno[2,3-d]pyrimidine obtained by distilling off the solvent under reduced pressure. Without further purification of 4-chlorothieno[2,3-d]pyrinidine the resultant mixture was heated to reflux with 2-aminoindane (1.1 g, 8.0 mmol) in dry ethanol (6 ml) under an argon atmosphere for 2 hours. The residue obtained by distilling off the solvent was purified by silica gel chromatography (hexane:ethyl acetate=5:2) to obtain the title compound (150 mg, 0.56 mmol) having the following physical properties:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH:15]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)=O>C(O)C>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([N:1]=[CH:15][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccncc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CCO
Product: C(=NC1CCN(Cc2ccccc2)CC1)c1ccncc1
Yield: 100.4 %

Procedure:
8.57 ml (42.01 mmol) of 4-amino-1-benzylpiperidine were added to a solution of 3.95 ml (42.01 mmol) of 4-formylpyridine in 5 ml of ethanol, and the resulting mixture was then heated under reflux for 1 hour. At the end of this time, the solvent was distilled off from the reaction mixture by evaporation under reduced pressure to afford 11.78 g (quantitative yield) of the title compound as a pale brown powder.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH:8]=1)(=O)=O.[CH3:19][C:20]1([CH3:34])[CH2:24][O:23][C:22]([C:25]2[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=2)=[N:21]1.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[C:7]1([C:27]2[CH:26]=[C:25]([C:22]3[O:23][CH2:24][C:20]([CH3:34])([CH3:19])[N:21]=3)[CH:30]=[CH:29][CH:28]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH:8]=1
Reactant: CC1(C)COC(c2cccc(B(O)O)c2)=N1
Reactant: O=S(=O)(OC1=CCCc2ccccc21)C(F)(F)F
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: [Cl-]
Solvent: COCCOC
Product: CC1(C)COC(c2cccc(C3=CCCc4ccccc43)c2)=N1
Temperature: 85 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
A mixture of 3,4-dihydro-1-(trifluoromethylsulfonyloxy)naphthalene (1.0 g), 3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)phenyl-dihydroxyborane (1.1 g), tetrakis(triphenylphosphine)palladium(0) (0.21 g), lithium chloride (0.46 g), 2M sodium carbonate aqueous solution (5.1 ml) in 1,2-dimethoxyethane (12 ml) was heated at 85° C. and stirred vigorously for 3 hours under nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane (35 ml) and 2N sodium carbonate aqueous solution (35 ml) and conc. ammonia solution (2.0 ml). The aqueous layer was extracted again with dichloromethane (35 ml) and the combined organic extracts are dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (30:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give 2-[3-(3,4-dihydro-1-naphthyl)phenyl]-4,4-dimethyl-4,5-dihydrooxazole (1.05 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21](C(OCC2C=CC=CC=2)=O)[CH2:20][C:19]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)=O.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[O:34])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1c(CN2CCN(C(=O)OCc3ccccc3)CC2=O)cc2cnccc21
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CC(C)(C)OC(=O)n1c(CN2CCNCC2=O)cc2cnccc21
Yield: 67.6 %

Procedure:
Palladium black (1.1 g, 10.3 mmol) is added to a solution of 2-(4-benzyloxycarbonyl-2-oxo-piperazin-1-ylmethyl)pyrrolo[3,2-c]pyridin-1-carboxylic acid tert-butyl ester (1.7 g, 3.7 mmol) in HCO2H/MeOH (45 mL, 4.4% solution). After 40 minutes the catalyst is filtered through Celite and washed with MeOH. The filtrate is concentrated in vacuo to remove methanol then the resulting solution is diluted with methylene chloride and washed with saturated sodium bicarbonate, and brine. The organic layer is dried over MgSO4, filtered and concentrated to dryness. The resulting solid is purified by column chromatography eluting with a gradient of 5% MeOH/CH2Cl2 to 10% MeOH/CH2Cl2 to give the product (0.8 g, 2.5 mmol) as a pale yellow foamy solid. 1H NMR (CDCl3, 300 MHz) δ8.78 (s, 1H), 8.40 (d, 1H), 7.9 (d, 1H), 6.48 (s, 1H), 4.98 (s, 2H), 3.7 (s, 2H), 3.51 (t, 2H), 3.40 (t, 2H), 1.91 (bs, 1H), 1.70 (s, 9H).
Reaction SMILES: [F:1][CH2:2][C:3]1[C@H:7]2[CH2:8][O:9][CH2:10][C@H:6]2[O:5][N:4]=1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18]>>[F:1][CH2:2][C@@:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C@H:7]2[CH2:8][O:9][CH2:10][C@H:6]2[O:5][NH:4]1
Reactant: Fc1ccccc1Br
Reactant: FCC1=NO[C@@H]2COC[C@H]12
Product: FC[C@]1(c2ccccc2F)NO[C@@H]2COC[C@@H]21

Procedure:
Intermediate VI-2: Starting from (3aS,6aS)-rel-3-fluoromethyl-3a,4,6,6a-tetrahydro-furo[3,4-d]isoxazole and 1-bromo-2-fluorobenzene, the product (3S,3aS,6aS)-rel-3-fluoromethyl-3-(2-fluoro-phenyl)-hexahydro-furo[3,4-d]isoxazole was obtained as a light yellow oil. MS: m/z=242.1 [M+H]+.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23]([NH:26][CH:27]1[CH2:30][N:29]([C:31]2[N:36]=[CH:35][C:34]([C:37](O)=[O:38])=[CH:33][N:32]=2)[CH2:28]1)(=[O:25])=[O:24].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.[O:57]1[CH2:62][CH2:61][CH2:60][CH2:59][CH:58]1[O:63][NH2:64]>C(Cl)Cl.C1COCC1>[O:57]1[CH2:62][CH2:61][CH2:60][CH2:59][CH:58]1[O:63][NH:64][C:37]([C:34]1[CH:33]=[N:32][C:31]([N:29]2[CH2:28][CH:27]([NH:26][S:23]([C:14]3[CH:15]=[CH:16][C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:13]=3)(=[O:25])=[O:24])[CH2:30]2)=[N:36][CH:35]=1)=[O:38]
Reactant: NOC1CCCCO1
Reactant: O=C(O)c1cnc(N2CC(NS(=O)(=O)c3ccc4ccccc4c3)C2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(NOC1CCCCO1)c1cnc(N2CC(NS(=O)(=O)c3ccc4ccccc4c3)C2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
EDCl (90 mg, 0.47 mmol) was added to a solution of 2-{3-[(2-naphthylsulfonyl)amino]azetidin-1-yl}pyrimidine-5-carboxylic acid (150 mg, 0.39 mmol) in DCM (10 ml) and THF (10 ml) at r.t. under N2. Et3N (0.14 ml, 1.02 mmol), HOBt (63 mg, 0.47 mmol) and O-(tetrahydro-pyran-2-yl)-hydroxylamine (55 mg, 0.47 mmol) were added and the reaction stirred at r.t. overnight. The reaction mixture was concentrated in vacuo giving a colourless oil which was dissolved in DCM (20 ml), washed with water (3×20 ml), dried (Na2SO4) and concentrated in vacuo to give the title compound as a white solid (162 mg, 86%). LCMS purity 93%, m/z 484 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:6].[H-].[Na+]>C1COCC1>[O:11]1[CH2:12][CH2:13][CH:8]([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])[CH2:9][CH2:10]1
Reactant: O=C(NCCCl)NC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NCCN1C1CCOCC1
Temperature: -20 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A dry RB flask charged with 1-(2-chloroethyl)-3-(tetrahydro-2H-pyran-4-yl)urea (19.96 g, 97 mmol) in THF (480 mL), placed under Ar and stirred for 20 minutes at −20° C. after which 60% Sodium Hydride in mineral oil (9.66 g, 241 mmol) was added portion wise. The reaction was allowed to stir at −20° C. for 1 h and was then allowed to warm to ambient temp overnight. The reaction was cooled in an ice bath and quenched via slow addition of saturated NH4Cl (50 mL). Brine (30 mL) was added and the reaction was allowed to stir for 20 minutes. The organic layer was separated and aqueous layer extracted with EtOAc (2×) and THF (2×). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated to dryness to afford a white gummy solid. The crude product was purified by silica gel chromatography (5% MeOH in CH2Cl2) to afford 1-(tetrahydro-2H-pyran-4-yl)imidazolidin-2-one as a white solid (10.54 g, 64% yield, 2 steps). 1H NMR (DMSO-d6): δ 6.24 (s, 1 H), 3.91-3.81 (m, 2 H), 3.73-3.61 (m, 1 H), 3.29-3.23 (m, 2 H), 3.22-3.21 (m, 2 H), 3.19-3.14 (m, 2 H), 1.67-1.53 (m, 2 H), 1.45-1.44 (m, 2 H); MS (ESI) m/z: 171.1 (M+H+).
Reaction SMILES: Cl.C[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[NH:7].[OH-].[Na+]>C(Cl)(Cl)Cl>[C:6]([NH2:8])(=[NH:7])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:3][CH:4]=1
Reactant: Cc1cccc(C(=N)N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: N=C(N)c1ccccc1

Procedure:
A 92.3 g portion of 3-methylbenzamidine, hydrochloride [J. B. Ekeley, et al., J. Am. Chem. Soc., 57, 381 (1935)] was stirred with 200 ml of 5N sodium hydroxide and 400 ml of chloroform for 1/2 hour. When solution was complete the chloroform layer was separated and the aqueous layer extracted twice with 50 ml portions of chloroform. The chloroform solutions were combined, dried over sodium sulfate and evaporated, giving 69.3 g of free benzamidine. This benzamidine was taken up in one liter of absolute ethanol, 71.6 g of ethyl formylacetate sodium salt was added and the mixture was refluxed for 3 days. After cooling, the ethanol was evaporated and the residue dissolved in one liter of water and filtered. The pH of the filtrate was adjusted to 6 with 1N hydrochloric acid and the solid was collected and dried, giving 59.1 g of the desired intermediate as a white solid, mp 148°-149.5° C.
Reaction SMILES: I[C:2]1C=CC(O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:23]=2[CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:36]([CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]4)[C:35]4[CH:43]=[CH:44][C:45]([C:47]([O:49][CH3:50])=[O:48])=[CH:46][C:34]=4N=3)=[CH:28][CH:27]=2)=[CH:18][CH:17]=1>CC(C)=O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:23]=2[CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]3[N:36]([CH:37]4[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]4)[C:35]4[C:34]([CH:2]=3)=[CH:46][C:45]([C:47]([O:49][CH3:50])=[O:48])=[CH:44][CH:43]=4)=[CH:30][CH:31]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(OC)ccc3-c3ccc(Cl)cc3)cc1)n2C1CCCCC1
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc2c(c1)cc(-c1ccc(OCc3cc(OC)ccc3-c3ccc(Cl)cc3)cc1)n2C1CCCCC1
Yield: 167 %

Procedure:
4-Iodophenol (5.0 g) was dissolved in acetone (50 ml), and potassium carbonate (4.7 g) and 4′-chloro-2-chloromethyl-4-methoxybiphenyl (6.0 g) obtained in Example 241, Step 4 were added. The mixture was refluxed for 10 hr. The reaction mixture was concentrated and 4N aqueous sodium hydroxide solution (50 ml) was added. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to give the title compound (10.0 g, yield 98%).
Reaction SMILES: C(O)(=O)C.CN(C)[CH:7]=[CH:8][CH:9]=O.[CH:12]([C:15]1[C:16]([NH2:21])=[N:17][NH:18][C:19]=1[NH2:20])([CH3:14])[CH3:13]>C(O)C>[CH:12]([C:15]1[C:16]([NH2:21])=[N:17][N:18]2[CH:9]=[CH:8][CH:7]=[N:20][C:19]=12)([CH3:14])[CH3:13]
Reactant: CC(C)c1c(N)n[nH]c1N
Reactant: CN(C)C=CC=O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)c1c(N)nn2cccnc12

Procedure:
Acetic acid (0.038 mL, 0.67 mmol) was added to a solution of 3-dimethylaminoacrylaldehyde (624 mg, 4.43 mmol) and the product from Example 112B (414 mg, 2.95 mmol) in ethanol (9 mL), and the reaction mixture was heated at 80° C. for 4 hours, then concentrated under vacuum to a dark oil. The residue was purified by flash chromatography (silica gel eluted with hexanes-EtOAc 50:50-0:100) to provide the title compound as a yellow solid. MS (ESI) m/z 177 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:36])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3C[CH2:20][N:19]([C:22]([O:24][C:25](C)(C)[CH3:26])=[O:23])[CH2:18][C:16]=3[N:17]=2)=[CH:8][CH:7]=1)[CH3:2].ClC1N=C(N2CCOC[C@@H]2C)C2CN(C(OCC)=O)CC=2N=1.[F:59]CCNC(NC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)=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]>[F:59][CH2:2][CH2:1][NH:3][C:4](=[O:36])[NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][C:16]=3[N:17]=2)=[CH:10][CH:11]=1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCF)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Product: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NCCF)cc3)nc(N3CCOC[C@@H]3C)c2C1
Yield: 13 %

Procedure:
Method as described for intermediate 5 using (S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11) and 1-(2-fluoroethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea as starting materials and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) as catalyst. The mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and solvent removed in vacuo. The residue was purified first by flash chromatography using a gradient of 0-20% MeOH/DCM as eluent, then prep HPLC (low pH) yielding the title compound (9.2 mg, 0.02 mmol, 13%).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:17]([C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:20])[CH:18]=[CH2:19]
Reactant: c1ccc(-c2cccc3ccccc23)cc1
Reactant: C=CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccc2ccccc2c1-c1ccccc1
Yield: 125.2 %

Procedure:
1-phenylnaphthalene (204 mg), acryloyl chloride (200 mg), and aluminium chloride (290 mg) were reacted in dichloromethane (1.5 mL) at from −40° C. to room temperature for 2 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (323 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@@H:38]1[C:42](O)=[O:43])=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:42]([C@H:38]4[CH2:39][CH2:40][CH2:41][N:37]4[C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:36])=[O:43])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)[C@H]2CCCN2C(=O)OC(C)(C)C)c1

Procedure:
Prepared as described in Example 83 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (37 mg, 0.17 mmol). Yield 31 mg (41%).