Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5](/[C:6](=[N:9]/[H])/[NH:7][OH:8])=[CH:4][CH:3]=1.[O:13]=[C:14]1[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][CH2:16][N:15]1[CH2:32][C:33](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]2[N:9]=[C:33]([CH2:32][N:15]3[CH2:16][CH2:17][CH2:18][C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:14]3=[O:13])[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: [H]/N=C(\NO)c1ccc(Cl)cc1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C1N(Cc2nc(-c3ccc(Cl)cc3)no2)CCCC1(c1ccccc1)c1ccccc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A solution of (Z)-4-chloro-N-hydroxybenzimidamide (0.121 g, 0.711 mmol), 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (0.200 g, 0.646 mmol; Example 68E) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.161 g, 0.840 mmol) were stirred together in dichloroethane (0.5 mL) at room temperature for 2 hours. The reaction was then heated to 85° C. and stirred overnight. The reaction was cooled, loaded onto a SF15-12 column (Analogix®) and the product eluted using a gradient of 5% ethyl acetate/hexanes to 50% ethyl acetate over 20 minutes (Flow=30 mL/minute) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 8.09-8.02 (m, 2H), 7.52-7.45 (m, 2H), 7.33-7.25 (m, 10H), 4.91 (s, 2H), 3.62 (t, J=6.5, 2H), 2.73-2.67 (m, 2H), 1.98-1.85 (m, 2H); MS (ESI+) m/z 444.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=4)[C:11]=3[N:10]=[C:9]2[C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.I[C:45]1[CH:50]=[N:49][CH:48]=[CH:47][N:46]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=4)[C:11]=3[N:10]=[C:9]2[C:29]2[CH:30]=[CH:31][C:32]([C:45]3[CH:50]=[N:49][CH:48]=[CH:47][N:46]=3)=[CH:33][CH:34]=2)=[CH:6][CH:7]=1
Reactant: Ic1cnccn1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cnn4-c4cccc(NS(C)(=O)=O)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5cnccn5)cc4)nc32)c1
Temperature: 100 °C

Procedure:
A solution of N-(3-{5-(4-chloro-phenyl)-4-oxo-6-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)phenyl]-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl}-phenyl)-methane sulfonamide (prepared as described in example 35, 0.50 g, 0.81 mmol) in N,N-dimethylformamide (20 mL) is degassed with argon for 0.5 h. Then 2-iodopyrazine (0.25 g, 1.21 mmol), cesium carbonate (0.527 g, 1.61 mmol), Pd(dppf)2Cl2 (0.06 g, 0.082 mmol) are added and the resulting solution is degassed with argon for 0.5 h. The reaction mixture is then heated at 100° C. for 3 h. The reaction mixture is cooled to rt and diluted with water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography to afford N-{3-[5-(4-chloro-phenyl)-4-oxo-6-(4-pyrazin-2-yl-phenyl)-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-phenyl}-methane sulfonamide. 1H NMR (DMSO-d6, 400 MHz) δ 10.15 (br, 1H), 9.26 (d, 1H), 8.71 (d, 1H), 8.62 (d, 1H), 8.52 (s, 1H), 8.06 (m, 3H), 7.82 (m, 1H), 7.60 (m, 2H), 7.52 (m, 1H), 7.40 (m, 4H), 7.18 (m, 1H), 3.02 (s, 3H); LC-MS calculated for C28H20ClN7O3S (M+H+) 570.1, found 570.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N+:8]([O-])=[CH:7][CH:6]=[CH:5]2.P(Cl)(Cl)([Cl:18])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:18][C:7]1[CH:6]=[CH:5][C:4]2[C:3]([NH2:13])=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: O=[N+]([O-])c1c(Cl)ccc2c1ccc[n+]2[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1c(Cl)ccc2nc(Cl)ccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
6-Chloro-5-nitroquinoline 1-oxide (4 g) was added to phosphorus oxychloride (15 mL) at 0° C. The solution was allowed to warm to room temperature and stirred for 12 hours. The excess phosphorus oxychloride was evaporated in vacuo and the residue dissolved in water (100 mL)/dichloromethane (100 mL). The layers were separated and the aqueous layer extracted with dichloromethane (2×50 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil. The residue was dissolved in ethanol/water (1:1, 80 mL), ammonium chloride (2.8 g) and iron (2.8 g) added. The mixture was stirred at 65° C. for 4 hours, cooled to room temperature and filtered. The resulting solid was suspended in dimethylsulfoxide (50 mL), methanol (50 mL) and aqueous hydrochloric acid added (2M, 100 mL). The resulting solid was removed by filtration and then treated with ether (50 mL) and isohexane (50 mL). Evaporation of the mixture afforded the sub-title compound as a solid (1 g).
Reaction SMILES: O=[C:2]([CH:9]1[CH2:18][CH2:17][C:12]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:11][CH2:10]1)[CH2:3][C:4]([O:6]CC)=O.[NH2:19][C:20]1[CH:24]=[CH:23][NH:22][N:21]=1>CCO>[O:13]1[C:12]2([CH2:11][CH2:10][CH:9]([C:2]3[CH:3]=[C:4]([OH:6])[N:21]4[N:22]=[CH:23][CH:24]=[C:20]4[N:19]=3)[CH2:18][CH2:17]2)[O:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)CC(=O)C1CCC2(CC1)OCCO2
Reactant: Nc1cc[nH]n1
Solvent: CCO
Product: Oc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Temperature: 100 °C

Procedure:
To a 20 mL scintillation vial containing ethyl 3-oxo-3-(1,4-dioxaspiro[4.5]decan-8-yl)propanoate (Int-5d, 11.7 mmol, 3.00 g) was added 3-amino-1H-pyrazole (11.7 mmol, 973 mg). The mixture was mixed and heated neat at 100° C. for 3 hours. The resulting off-white solid was taken up in EtOH (100 mL) and reduced in vacuo to remove water formed during cyclization. This solid was taken forward without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[Cl:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1>>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:9])[CH:15]=2)[CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Brc1cncc(Br)c1
Product: Clc1cccc(-c2cncc(Br)c2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 3,5-dibromo-pyridine and 3-chlorophenylboronic acid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([NH:15][C:16]2[C:21]([CH:22]=[O:23])=[CH:20][N:19]=[C:18]3[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=[CH:26][C:17]=23)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].CCCCCC.C(OCC)(=O)C>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([NH:15][C:16]2[C:21]([CH2:22][OH:23])=[CH:20][N:19]=[C:18]3[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[CH:25]=[CH:26][C:17]=23)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CCN(Cc2ccccc2)C[C@@H]1Nc1c(C=O)cnc2c1ccn2COCC[Si](C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@@H]1CCN(Cc2ccccc2)C[C@@H]1Nc1c(CO)cnc2c1ccn2COCC[Si](C)(C)C
Yield: 48.9 %

Procedure:
rac-4-{[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (112 mg, 0.234 mmol) in methanol was stirred with sodium borohydride (13.3 mg, 0.351 mmol) at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and, after addition of water, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hi Flash column amino type manufactured by Yamazen Corporation: hexane/ethyl acetate=1/1 (v/v)) to give the title compound as a colorless oil (55 mg, yield 49%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][CH:11]([CH3:26])[CH2:12][CH:13]1[CH2:15][N@@:14]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(O)C>[CH3:26][CH:11]([CH3:10])[CH2:12][CH:13]([NH:14][C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[CH2:15][N:8]([CH2:15][CH:13]([NH:14][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:12][CH:11]([CH3:10])[CH3:26])[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC(C)CC1CN1C(=O)OCc1ccccc1
Solvent: CCO
Product: CC(C)CC(CN(CC(=O)OC(C)(C)C)CC(CC(C)C)NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
A refluxing solution of 15.1 g (a 10% excess) of glycine t-butyl ester in 200 ml of absolute ethanol is treated dropwise over one hour with a solution of 24.2 g of (S)-2-(2-methylpropyl)-1-aziridinecarboxylic acid, phenylmethyl ester in 50 ml of absolute ethanol. The refluxing is continued over two nights. The solvent is removed under reduced pressure and the residue chromatographed on 1.5 kg of silica gel, eluting with chloroform/ethylacetate (3:1). Combining the fractions containing the faster eluting compound gives 14.3 g of an oil which crystallizes on standing. A small example, recrystallized from hexane has mp 107°-108°, [α]D23 -16.3° (c 1.03, methanol). Spectral and elemental analysis shows this to be [S-(R*,R*)]-N,N-bis[4-methyl-2-[[(phenylmethoxy)carbonyl]amino]pentyl]glycine, 1,1-dimethylethyl ester.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:15][C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:3]=1.[F:36][C:37]1[N:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[CH:39][CH:38]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:36][C:37]1[N:42]=[C:41]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[S:15][C:14]([NH:16][CH2:17][C:18]5[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=5)=[N:13][N:12]=4)[CH:9]=3)[N:4]([S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=3)(=[O:28])=[O:27])[CH:3]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: CC1(C)OB(c2cccc(F)n2)OC1(C)C
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cccc(F)n3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Temperature: 105 °C
Yield: 88 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (500 mg, 0.811 mmol) and 6-fluoropyridine-2-boronic acid pinacol ester (226 mg, 1.014 mmol) in p-dioxane/H2O (4:1, 7.5 mL) followed by potassium phosphate (430 mg, 2.028 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (28.7 mg, 0.041 mmol). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 105° C. for 30 min. The mixture was diluted with DCM and washed with H2O. The organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 5-15% EtOAc in DCM with 1% MeOH) to give 5-(3-(6-fluoropyridin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (418 mg, 0.714 mmol, 88%) as a yellow solid. MS (ESI, pos. ion) m/z: 378 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH:6]=[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:16])[CH3:5].C[CH2:18][O:19][CH2:20][CH3:21]>CCCCCC.CN(C)C=O>[CH3:18][O:19][C:20]1[CH:21]=[C:6]([N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7](=[CH:6][N:4]([CH3:3])[CH3:5])[C:8]2=[O:16])[CH:7]=[CH:15][CH:14]=1
Reactant: CCOCC
Reactant: CN(C)C=C1C(=O)Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1cccc(N2C(=O)C(=CN(C)C)c3ccccc32)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried flask under nitrogen, sodium hydride (50% dispersion in oil, 0.96 g, 20 mmoles) was washed free of oil with hexane. Dry dimethylformamide (DMF, 50 ml) and 3-(dimethylaminomethylene)-2(1H,3H)-indolone [Chem. Ber. 85:774 (1952); 3.77 g, 20 mmoles] were added, and the mixture stirred for 30 minutes (until gas evolution ceased). m-Indoanisole (9.36 g, 40 mmoles) in 20 ml DMF was added, followed by Cu2Br2 (5.74 g, 20 mmoles). The reaction mixture was heated at 120°-130° for 40 hours, poured over 300 g of ice, stirred with 300 ml ether, filtered and the ether layer separated, dried over MgSO4, filtered and concentrated to an oil. The oil was chromatographed on silica gel, using ethyl acetate as eluant and title product initially isolated as an oil, crystallized from ether, 2.46 g (42%), m.p. 106°-108.5° (dec.).
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][CH:5]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]2[C@:22]3([C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:31])[CH2:21]2)=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C@H:20]2[C@@:22]3([C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH2:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:12])=[CH:5][CH:6]=4)[C:23]3=[O:31])[CH2:21]2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(F)cc1
Product: O=C(O)c1ccc(CN2C(=O)[C@@]3(C[C@H]3c3ccc(F)cc3)c3ccccc32)cc1

Procedure:
The title compound was prepared in analogy to Example 1 starting from 4-bromomethyl-benzoic acid methyl ester (commercially available), (1R,2S) and (1S,2R)-2-(4-fluorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C24H18FlNO3: 387, observed (M+H)+: 388.1 1H NMR (400 MHz, DMSO-d6) δppm 2.05-2.14 (m, 1 H) 2.30-2.40 (m, 1 H) 3.21 (t, 2 H) 5.09 (s, 2 H) 6.10 (d, 1 H) 6.70 (t, 1 H) 6.92 (d, 1 H) 7.07 (t, 1 H) 7.11-7.20 (m, 2 H) 7.31-7.38 (m, 2 H) 7.44 (d, 2 H) 7.93 (d, 2 H).
Reaction SMILES: [F:1][C:2]1[C:12]([F:13])=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[CH2:8][O:7]1.[C:16]1([C:22]2[C:30]3[C:29]([N:31]4[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]4)=[N:28][CH:27]=[N:26][C:25]=3[S:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[F:1][C:2]1[C:12]([F:13])=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]([OH:7])[CH2:8][NH:37][CH:34]1[CH2:35][CH2:36][N:31]([C:29]2[C:30]3[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:23][S:24][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:32][CH2:33]1
Reactant: NC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Reactant: COc1ccc(OCC2CO2)c(F)c1F
Product: COc1ccc(OCC(O)CNC2CCN(c3ncnc4scc(-c5ccccc5)c34)CC2)c(F)c1F
Yield: 49 %

Procedure:
Synthesis followed SP6 (3 h), using 430 μmol 2-((2,3-difluoro-4-methoxyphenoxy)methyl)oxirane and 1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give O-methylated intermediate 1-(2,3-difluoro-4-methoxyphenoxy)-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propan-2-ol upon purification by prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 4:6:1) with 49% yield. Product was obtained by O-demethylation according to SP12 (3 h) with 58% yield (LCMS: detected [M+1]=513.2).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][C:5]2=[C:4]([C:13]([NH:15][C@@H:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]([NH:19]C)=[O:18])=[O:14])[N:3]=1.N[C@H](C(N)=O)CC(C)C>>[NH2:19][C:17](=[O:18])[C@@H:16]([NH:15][C:13]([C:4]1[N:3]=[C:2]([Br:1])[N:6]2[CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][C:5]=12)=[O:14])[CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)c1nc(Br)n2c1CN(C)CCC2
Agent: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)c1nc(Br)n2c1CN(C)CCC2)C(N)=O

Procedure:
This intermediate was prepared following the synthesis of (S)-3-bromo-8-methyl-N-(4-methyl-1-(methylamino)-1-oxopentan-2-yl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepine-1-carboxamide (intermediate 55B) by replacing H-Leu-NHMe with Leucine amide 59A (Chem-Impex). LCMS (+ESI) m/z 386.1 [M+H]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:24])[CH2:7][CH:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:21]([O-])=O)=[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)[CH:13]=2)[CH2:4][CH2:3]1>CO.[Pd]>[O:24]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:21])=[C:12]([N:14]3[CH2:15][CH2:16][CH:17]([CH3:20])[CH2:18][CH2:19]3)[CH:13]=2)[CH2:4][CH2:3]1
Reactant: CC1CCN(c2cc(C3=CCS(=O)(=O)CC3)ccc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: CC1CCN(c2cc(C3CCS(=O)(=O)CC3)ccc2N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A mixture of 1-[5-(1,1-dioxo-1,2,3,6-tetrahydro-1λ6-thiopyran-4-yl)-2-nitro-phenyl]-4-methyl-piperidine (as prepared in the previous step, 65 mg, 0.19 mmol) and 10% Pd/C (40 mg) in 3 mL of MeOH was stirred at RT under H2 (balloon pressure) for 1 h. The Pd catalyst was removed by filtration on Celite and the filtrate was concentrated to give a white solid. Flash chromatography of the compound on silica gel (5% EtOAc/DCM) gave 42 mg (70%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 6.82 (s, 1H), 6.76 (d, 1H, J=8.2 Hz), 6.68 (d, 1H, J=8.2 Hz), 3.91 (s, 2H), 3.05-3.16 (m, 6H), 2.67 (dddd, 2H, J=12.0, 12.0, 3.2, 3.2 Hz), 2.57 (dd, 2H, J=11.6, 11.6 Hz), 2.36 (m, 2H), 2.14-2.23 (m, 2H), 1.71-1.79 (m, 2H), 1.51 (m, 1H), 1.24-1.40 (m, 2H), 0.99 (d, 3H, J=6.6 Hz). Mass spectrum (ESI, m/z): Calcd. for C17H26N2O2S, 323.2 (M+H), found 323.2.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C@@H:11]3[CH2:15][CH2:14][CH2:13][O:12]3)[NH:7][C:6]=2[CH:5]=[C:4]([OH:16])[CH:3]=1.[Cl:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:17][C:18]1[N:19]=[CH:20][N:21]=[C:22]([O:16][C:4]2[CH:3]=[C:2]([CH3:1])[C:10]3[N:9]=[C:8]([C@@H:11]4[CH2:15][CH2:14][CH2:13][O:12]4)[NH:7][C:6]=3[CH:5]=2)[CH:23]=1
Reactant: Cc1cc(O)cc2[nH]c([C@@H]3CCCO3)nc12
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]c([C@@H]3CCCO3)nc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
135 mg (0.62 mmol) (S)-4-methyl-2-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-6-ol and 97 mg (0.63 mmol) 4,6-dichloropyrimidine in 2.0 mL DMF were combined with 97 mg (0.70 mmol) potassium carbonate and stirred overnight at 50° C. Then ice water was added and the mixture was extracted with ethyl acetate. The organic phase was concentrated by rotary evaporation i.vac.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[NH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=O)=[CH:12][CH:11]=1>C(=O)(O)[O-].[Na+]>[NH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]2[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccccc1S
Reactant: Nc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ccc(-c2nc3ccccc3s2)cc1
Temperature: 230 °C
Yield: 56.9 %

Procedure:
A stirrable paste prepared by mixing 2-aminothiophenol (9.39 g, 0.075 mol) and 4-aminobenzoic acid (10.29 g, 0.075 mol) with PPA (120 g) was heated to 230° C. for 4 hours, cooled and poured into a large volume of 10% sodium bicarbonate solution (about 1000 ml). The solid was collected by filtration, washed with water and dried. Recrystallisation from methanol gave pale yellow needed crystals (9.65 g, 57%), m.p. 155-157° C.
Reaction SMILES: O=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[NH:3]1.O.[NH2:14][NH2:15]>C(O)CCC>[NH:14]([CH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[NH:3]1)[NH2:15]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: NNC1NS(=O)(=O)c2ccccc21
Yield: 91.1 %

Procedure:
36.6 g (0.2 mol) of 3-keto-2H,3H-1,2-benzisothiazole 1,1-dioxide and 20 g of hydrazine hydrate in 200 ml of n-butanol are boiled under reflux for about 35 hours. The yellow solution is then evaporated down in vacuo, and the residue is stirred with 50 ml of acetic acid. The crystal slurry is filtered under suction, and the crude product which is obtained in this manner and has a melting point of 249° C. can be recrystallized from water. 36.3 g (91% of theory) of 3-hydrazino-2H,3H-1,2-benzisothiazole 1,1-dioxide of melting point 263° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[NH:5][C:6]2=[O:11].[CH2:13]([O:15][C:16](=[O:22])[CH:17](Cl)[O:18][CH2:19][CH3:20])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:22])[CH:17]([O:18][CH2:19][CH3:20])[N:5]1[C:4](=[O:12])[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])[C:6]1=[O:11])[CH3:14]
Reactant: O=C1NC(=O)c2c(F)cccc21
Reactant: CCOC(=O)C(Cl)OCC
Product: CCOC(=O)C(OCC)N1C(=O)c2cccc(F)c2C1=O

Procedure:
According to general procedure H, 4-fluoro-1H-isoindole-1,3(2H)-dione (CAS51108-29-3) was reacted with 2-chloro-2-ethoxyacetic acid ethyl ester to give (RS)-ethoxy-(4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetic acid ethyl ester, MS 296.3 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=3)=[CH:11][C:10]([C:20]([F:23])([F:22])[F:21])=[N:9]2)=[CH:4][CH:3]=1.[C:24]([N:32]=C=O)(=[O:31])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:24]([NH2:32])=[O:31])[CH:14]=3)=[CH:11][C:10]([C:20]([F:21])([F:22])[F:23])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(F)cc2)ccn1
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: NC(=O)Nc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(F)cc2)ccn1
Temperature: 50 °C
Yield: 14 %

Procedure:
4-[2-(4-Fluoro-phenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-pyridin-2-ylamine (132 mg, 0.41 mmol) and benzoyl isocyanate (120 mg, 0.82 mmol) are mixed in DCM (4.0 mL) and the reaction mixture is heated at 50° C. for 16 hrs. After it is cooled down, the solvent is removed and the residue is dissolved in ethanol (2.5 mL). Potassium carbonate (70 mg, 0.49 mmol) is added and the reaction mixture is heated at 85° C. for 2 hrs before it is cooled down to room temperature. The solvent is removed and the residue is partitioned between water (30 mL) and EtOAc (50 mL). The organic layer is separated and concentrated to give the crude product. Purification by flash column chromatography using MeOH in DCM (gradient from 0% to 10%) affords 21 mg of the titled product.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:12](Br)=[CH:11][C:10]([O:14][CH3:15])=[C:9]([O:16][CH3:17])[N:8]=2)[CH:2]=1.C1(C2C=CC=CC=2)C=CC=C(C2[C:31](Br)=[N:32]C(OC)=C(OC)C=2)C=1>[C-]#N.[C-]#N.[Zn+2].[Zn].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=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].CC(N(C)C)=O>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:12]([C:31]#[N:32])=[CH:11][C:10]([O:14][CH3:15])=[C:9]([O:16][CH3:17])[N:8]=2)[CH:2]=1
Reactant: COc1cc(Br)c(-c2cccc(-c3ccccc3)c2)nc1OC
Reactant: COc1cc(-c2cccc(-c3ccccc3)c2)c(Br)nc1OC
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: COc1cc(C#N)c(-c2cccc(-c3ccccc3)c2)nc1OC
Temperature: 25 °C
Yield: 39 %

Procedure:
To the above mixture of 2-(biphenyl-3-yl)-3-bromo-5,6-dimethoxypyridine and 3-(biphenyl-3-yl)-2-bromo-5,6-dimethoxypyridine (50 mg, 0.135 mmol) were added, under argon, Zn(CN)2 (32 mg, 0.27 mmol), Zn powder (0.9 mg, 0.014 mmol), Pd2(dba)3 (12.4 mg, 0.014 mmol), DPPF (15 mg, 0.027 mmol), DMA (2 mL) and stirred at 120° C. for 3.5 h. Cooled to room temperature and filtered. Purification by preparative HPLC (10->85% CH3CN/H2O over 20 min, 0.05% added TFA) afforded 17 mg (39%) of 2-(biphenyl-3-yl)-5,6-dimethoxypyridine-3-carbonitrile as a tan solid. LC/MS (M+H)+ 317.2.