Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([C@H:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1)[C:4]1[C:5]2[CH:12]=[CH:11][N:10]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:6]=2[N:7]=[CH:8][N:9]=1)[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:50][C:51]1[CH:52]=[C:53]([NH:58][CH2:59][C:60](O)=[O:61])[CH:54]=[C:55]([Cl:57])[CH:56]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:50][C:51]1[CH:52]=[C:53]([NH:58][CH2:59][C:60]([N:25]2[CH2:26][CH2:27][CH2:28][C@H:23]([N:3]([CH2:1][CH3:2])[C:4]3[C:5]4[CH:12]=[CH:11][N:10]([S:13]([C:16]5[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=5)(=[O:14])=[O:15])[C:6]=4[N:7]=[CH:8][N:9]=3)[CH2:24]2)=[O:61])[CH:54]=[C:55]([Cl:57])[CH:56]=1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Reactant: CCN(c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1)[C@H]1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1)[C@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of (S)—N-ethyl-N-(piperidin-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (60 mg, 0.15 mmol), in DMF (5 mL), was added EDCI (34 mg, 0.18 mmol), HOBt (24 mg, 0.18 mmol), 2-(3,5-dichlorophenylamino)acetic acid (33 mg, 0.15 mmol) and DIEA (0.06 mL, 0.36 mmol) at 0° C. The reaction mixture was stirred overnight at rt. After completion of the reaction, the reaction mixture was diluted with EtOAc (25 mL) and the organic phase was washed with water (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give the crude compound that was purified by column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford the titled compound (75 mg, 82%). LC-MS: m/z [M+1]=601.
Reaction SMILES: C(SCCC([N:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20](F)(F)F)=[CH:16][CH:15]=2)[S:11]C1C(OCC1C=CC=CC=1)=O)=O)(=O)C.S[CH2:35][CH2:36][C:37](N1N=C(C2C=CC(C(F)(F)F)=CC=2)SC1C(O)=O)=O>>[CH:19]1[C:18]2[C:17](=[CH:20][CH:35]=[CH:36][CH:37]=2)[CH:16]=[CH:15][C:14]=1[C:12]([NH:13][NH2:9])=[S:11]
Reactant: CC(=O)SCCC(=O)N1N=C(c2ccc(C(F)(F)F)cc2)SC1C(=O)OCc1ccccc1
Reactant: O=C(O)C1SC(c2ccc(C(F)(F)F)cc2)=NN1C(=O)CCS
Product: NNC(=S)c1ccc2ccccc2c1

Procedure:
The sub-title product was prepared from appropriate starting materials by the processes of Example 7, steps (a), (b), (c) and (d). mp 166°-167°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][NH2:12].[Br:13][C:14]1[CH:15]=[C:16]([C:22](OC)=[O:23])[N:17]([CH2:19][CH2:20]Br)[CH:18]=1>CS(C)=O>[Br:13][C:14]1[CH:15]=[C:16]2[C:22](=[O:23])[N:12]([CH2:11][C:4]3[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=3[O:2][CH3:1])[CH2:20][CH2:19][N:17]2[CH:18]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COC(=O)c1cc(Br)cn1CCBr
Solvent: CS(C)=O
Product: COc1ccc(CN2CCn3cc(Br)cc3C2=O)c(OC)c1
Temperature: 150 °C
Yield: 85.3 %

Procedure:
(2,4-Dimethoxyphenyl)methanamine (Aldrich; 4.36 mL, 28.9 mmol) was added to a stirred solution of methyl 4-bromo-1-(2-bromoethyl)-1H-pyrrole-2-carboxylate (Example 165a; 3.60 g, 11.58 mmol) in DMSO (15 mL) at RT. The reaction was heated at 150° C. in an oil bath for 5 h. After it was cooled to RT, the brown mixture was partitioned between 10 mL of 2.0 N aq. HCl and 200 mL of EtOAc. The layers were separated; the organic solution was washed with 2.0 N aq. HCl (5 mL) followed by brine (5 mL), dried (Na2SO4), and concentrated. Purification on a silica gel column (25-75% EtOAc in Hexanes) gave 7-bromo-2-(2,4-dimethoxybenzyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (3.61 g, 9.88 mmol, 85% yield) as an off-white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.15 (1H, d, J=1.8 Hz), 7.11 (1H, d, J=8.2 Hz), 6.68 (1H, d, J=1.8 Hz), 6.59 (1H, d, J=2.3 Hz), 6.50 (1H, dd, J=8.3, 2.4 Hz), 4.53 (2H, s), 4.12 (2H, dd, J=6.7, 5.2 Hz), 3.81 (3H, s), 3.76 (3H, s), 3.57 (2H, dd, J=6.7, 5.0 Hz). m/z (ESI, +ve) 365/367 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]=[S:8]1(=[O:33])[C:13]2[CH:14]=[C:15]([O:18][C:19]3[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=3)[C:22]([N:24]([CH3:26])[CH3:25])=O)[CH:16]=[CH:17][C:12]=2[N:11]2[CH2:30][CH2:31][CH2:32][C:10]2=[N:9]1.[H-].O>C1COCC1>[O:33]=[S:8]1(=[O:7])[C:13]2[CH:14]=[C:15]([O:18][C:19]3[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=3)[CH2:22][N:24]([CH3:26])[CH3:25])[CH:16]=[CH:17][C:12]=2[N:11]2[CH2:30][CH2:31][CH2:32][CH:10]2[NH:9]1
Reactant: CN(C)C(=O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1cccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)c1
Reaction time: 3 h

Procedure:
3.72 ml (3.72 mmol) of a 1M solution of LiAlH4 in THF are added dropwise to a suspension of 577 mg (1.49 mmol) of the product obtained in Step D in 20 ml of THF. The reaction mixture is observed passing into solution and stirring is carried out at ambient temperature for 3 hours. The excess of hydride is hydrolysed by the dropwise addition of water until the evolution of gas ceases. The suspension is stirred for 10 minutes, 20 ml of water are added, and extraction is carried out with AcOEt. The organic phases are combined, washed (saturated NaCl), dried (MgSO4) and evaporated, and the residue is chromatographed on a silica column (CH2Cl2/MeOH 95/5) to yield the title product.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([NH:41][C:42](=[O:46])[CH2:43][CH2:44][CH3:45])=[N:29][N:30]3COCC[Si](C)(C)C)=[CH:26][CH:25]=2)=[CH:20]1.C(OCC)(=O)C>O1CCCC1>[O:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([NH:41][C:42](=[O:46])[CH2:43][CH2:44][CH3:45])=[N:29][NH:30]3)=[CH:26][CH:25]=2)=[CH:20]1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccoc3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccoc3)ccc12
Temperature: 66 °C

Procedure:
1.95 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 120 mg of N-[6-(furan-3-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 5 cm3 of tetrahydrofuran. The reaction medium is heated at about 66° C. for 17 hours. The heating is then stopped and 50 cm3 of ethyl acetate are added. This mixture is washed with 50 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2 cm), eluting with ethyl acetate/cyclohexane (30/70 by volume) and collecting 15 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 10 cm3 of diisopropyl ether. This solution is filtered through a sinter funnel to give, after drying (90 Pa; 50° C.), 35 mg of N-[6-(furan-3-yl)-1H-indazol-3-yl]butanamide in the form of a white solid melting at 195° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[N:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([NH2:36])[C:30]=3[CH:29]=[N:28]2)=[CH:23][CH:22]=1>>[F:14][C:13]([F:16])([F:15])[C:10]([CH2:12][NH:36][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:30]=1[CH:29]=[N:28][N:27]2[C:24]1[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=1)([OH:11])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:19][CH3:20])([CH3:18])[CH3:17]
Reactant: Nc1cccc2c1cnn2-c1ccncc1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2c1cnn2-c1ccncc1)C(F)(F)F

Procedure:
Prepared similarly to Example 1 from racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane and 1-(4-pyridinyl)-1H-indazol-4-amine (Intermediate 5).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:34]([O:38][C:39](=[O:51])[NH:40][CH2:41][CH:42]([NH2:50])[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[CH:44]=1)([CH3:37])([CH3:36])[CH3:35]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:50][CH:42]([C:43]5[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[CH:44]=5)[CH2:41][NH:40][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:51])[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1
Reactant: CC(C)(C)OC(=O)NCC(N)c1cccc(Cl)c1
Product: CC(C)(C)OC(=O)NCC(Nc1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1)c1cccc(Cl)c1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 9 supra) (300 mg, 0.64 mmol) and [2-amino-2-(3-chloro-phenyl)-ethyl]-carbamic acid tert-butyl ester (from Example 4 supra) (686 mg, 2.5 mmol) was heated at 130° C. with stirring for 2 hours. The resulting oil was purified by chromatography (silica gel, 8 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) to afford crude [4-(3-{2-[2-tert-butoxycarbonylamino-1-(3-chloro-phenyl)-ethylamino]-pyrimidin-4-yl}-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester. (Yield 140 mg, 32.5%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.[Cl-].[C:11]1([P+:17]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)CC2C=NC=CC=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl-:1].[C:31]1([P+:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:2][C:3]2[CH:8]=[N:7][C:6]([CH3:9])=[CH:5][CH:4]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: c1ccc([P+](Cc2cccnc2)(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccc(CCl)cn1
Agent: [Cl-]
Product: Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
Prepared from 5-chlormethyl-2-methyl-pyridine (Arch. Pharm. 1975, 308, 359) as described in expl. 1a): 1H-NMR (DMSO-d6) inter alia 5.24 (d, J=15.6 Hz, H2C), 2.38 (s H3C).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[Br:12]Br>[Fe]>[Br:12][C:7]1[CH:6]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:4]=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: BrBr
Agent: [Fe]
Product: Cc1ccc(S(N)(=O)=O)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of p-toluenesulfonamide (2 g, 1.16 mmol) and iron (0.41 g, 7.36 mmol) was slowly added bromine (6 mL, 116 mmol). The resulting reddish brown solution was stirred at RT for 1 h. The reaction was carefully poured into ice-cold 1 M Na2S2O3 aqueous solution and extracted with CH2Cl2 (2×). The organic extracts were combined and washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. CombiFlash purification (1% to 10% MeOH/CH2Cl2) afforded the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz): □ 7.98 (s, 1H), 7.71 (d, J=8 Hz, 1H), 7.55 (d, J=8 Hz, 1H), 7.54 (br s, 2H), 2.41 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][N:12]1[C:17]([CH3:18])=[C:16]([Cl:19])[N:15]=[C:14](Cl)[C:13]1=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28][NH2:29])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:23]1([CH3:22])[CH:31]=[CH:30][C:26]([CH2:27][CH2:28][NH:29][C:14]2[C:13](=[O:21])[N:12]([CH2:11][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[C:17]([CH3:18])=[C:16]([Cl:19])[N:15]=2)=[CH:25][CH:24]=1
Reactant: Cc1ccc(CCN)cc1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(CCNc2nc(Cl)c(C)n(CC(=O)OCc3ccccc3)c2=O)cc1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A solution of 1-benzyloxycarbonylmethyl-3,5-dichloro-6-methylpyrazinone (656 mg, 2.00 mmol), as prepared in the preceding step, 4-methylphenethylamine (380 mg, 2.81 mmol), triethylamine (405 mg, 4.01 mmol), and ethyl acetate (20 mL) was refluxed overnight. After cooling to room temperature, the solution was washed with 10% citric acid (×2). The aqueous solutions were back extracted with dichloromethane. The combined organic layers were dried (Na2SO4) and contracted to give the title compound as a yellow solid (854 mg, 100%). 1H NMR (CDCl3) δ 7.38-7.32 (m, 5H), 7.12 (s, 4H), 6.09 (s, 1H), 5.21 (s, 2H), 4.79 (s, 2H), 3.65 (dd, 2H, J=7.0, 13.0 Hz), 2.88 (t, 2H, J=7.1 Hz), 2.32 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].[CH3:31][Sn](C)(C)C>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:31])=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(C)sc1C(=O)OCC

Procedure:
A solution of 2-Bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethyl ester (4 g, 8 mmol, example 81(b), tetramethyl tin (3.3 mL, 24 mmol), dichlorobis(triphenylphosphine)palladium II (460 mg, 0.66 mmol) in 50 mL anhydrous DMF was heated to 130° C. for 1 h. The reaction mixture was cooled, diluted with ethyl acetate, and washed successively with water, saturated sodium bicarbonate, and brine. The organic fraction was dried over anhydrous sodium sulfate, concentrated to a crude residue and purified by column chromatography (eluting from silica gel with a gradient of 15-60% ethyl acetate in hexanes) to give 3.13 mg of the title compound. MS (ESI+): m/z 436.8 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]#[N:12])=[CH:10][C:4]=2[N:3]1[CH:13]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:14](=[O:29])[N:15]1[CH2:19][CH2:18][C@H:17]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]2)[CH2:16]1.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[S:44](Cl)(=[O:46])=[O:45].C(Cl)Cl>CN(C1C=CN=CC=1)C>[CH3:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[S:44]([N:6]1[C:5]2[CH:7]=[CH:8][C:9]([C:11]#[N:12])=[CH:10][C:4]=2[N:3]([CH:13]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:14](=[O:29])[N:15]2[CH2:19][CH2:18][C@H:17]([N:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:25]3)[CH2:16]2)[C:2]1=[O:1])(=[O:46])=[O:45]
Reactant: COc1ccccc1S(=O)(=O)Cl
Reactant: CCCN1CCN([C@H]2CCN(C(=O)C(c3ccccc3)n3c(=O)[nH]c4ccc(C#N)cc43)C2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCN1CCN([C@H]2CCN(C(=O)C(c3ccccc3)n3c(=O)n(S(=O)(=O)c4ccccc4OC)c4ccc(C#N)cc43)C2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
To a solution of 2-oxo-3-{2-oxo-1-phenyl-2-[(S)-3-(4-propyl-piperazin-1-yl)-pyrrolidin-1-yl]-ethyl}-2,3-dihydro-1H-benzoimidazole-5-carbonitrile (70 mg, 0.15 mmol), DMAP (catalytic amount) and 2-methoxybenzenesulfonyl chloride (37 mg, 0.18 mmol) in CH2Cl2 (3 mL) SilicaBond-diethylamine resin (Silicycle; 1.04 mmol/g; 570 mg, 0.59 mmol) was added. The reaction mixture was agitated at room temperature for 24 hours, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 4% methanol in CH2Cl2 as eluent to afford 1-(2-methoxy-benzenesulfonyl)-2-oxo-3-{2-oxo-1-phenyl-2-[(S)-3-(4-propyl-piperazin-1-yl)-pyrrolidin-1-yl]ethyl}-2,3-dihydro-1H-benzoimidazole-5-carbonitrile (55 mg, 57%) as a white solid.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.[CH2:12]([Zn]CC)C.IC(I)C.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[CH2:12]1[C:2]2([CH2:11][CH2:10][C:5]3([O:6][CH2:7][CH2:8][O:9]3)[CH2:4][CH2:3]2)[CH2:1]1
Reactant: C=C1CCC2(CC1)OCCO2
Reactant: CC[Zn]CC
Agent: CC(I)I
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: C1COC2(CCC3(CC3)CC2)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 8-methylene-1,4-dioxa-spiro[4.5]decane (6.0 g, 39 mmol, prepared according to a literature procedure (K. C. Nicolaou, R. L. Magolda, D. A. Claremon, J. Am. Chem. Soc. 102 (1980) 1404-1409)) in toluene (10 mL), a solution of diethyl zinc (100 mL, 1 M in hexane) is added at −40 to −20° C. The mixture is stirred for 10 min before diiodoethane (53.6 g, 200 mmol) is added dropwise over a period of 20 min. The reaction is warmed to rt and stirring is continued for 18 h. The reaction mixture is poured onto ice-cooled sat. aq. NH4Cl solution and extracted twice with diethyl ether. The combined organic extracts are washed with sat. aq. Na2S2O3 and water, dried over Na2SO4, filtered and the solvent of the filtrate is evaporated to give 7,10-dioxa-dispiro[2.2.4.2]dodecane (12.35 g) as a colourless liquid containing approx. 20% of toluene (product volatile).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH3:10][C:11]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1.O>C(Cl)Cl>[Si:14]([O:9][C:6]1[CH:7]=[CH:8][C:3]([NH:2][CH3:1])=[CH:4][CH:5]=1)([C:11]([CH3:13])([CH3:12])[CH3:10])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CNc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CNc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Yield: 43.6 %

Procedure:
A solution of 4-(methylamino)phenol (5.0 g, 29 mmol), TBDMSCl (4.8 g, 32 mmol) and imidazole (9.9 g, 0.15 mol) in DCM was stirred at r.t. for 1 h. Water was added, and the mixture was extracted with EtOAc. The organic layer was dried (Na2SO4), concentrated and purified by silica gel chromatography (PE:EtOAc=10:1) to give 3.0 g (43%) of the title compound as a dark green oil. [M+H] Calc'd for C13H23NOSi, 238. Found, 238.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>CC(CC)=O>[OH:2][C:1]1[C:3]2[O:4][C:1]([CH2:3][CH3:5])([CH3:9])[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Oc1cccc(O)c1O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCC(C)=O
Solvent: O
Product: CCC1(C)Oc2cccc(O)c2O1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of pyrogallol (50 parts) in ethyl methyl ketone (200 parts) was stirred and heated to 50° C, then phosphorus pentoxide was added portionwise at such a rate that the temperature remained about 80° C. After stirring for a further 30 minutes at about 50° C the liquid layer was poured into cold water (1,000 parts) and the crude product isolated by extracting with benzene and evaporating the extracts. Distillation of the crude product gave pure 4-hydroxy-2-ethyl-2-methyl-1,3-benzodioxole (39.5 parts), boiling point 84°-85° C/0.4 mm., melting point 48°-50° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.Cl[C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C.ClCCl>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:20](=[O:22])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(N)c(C(=O)O)c1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2[nH]c(=O)oc(=O)c2c1
Temperature: 52.5 °C
Reaction time: 2 h

Procedure:
To a solution of 2-amino-5-methoxy-benzoic acid (1.50 g, 8.97 mmol) in anhydrous acetonitrile (15 mL) at 50-55° C. were simultaneously added pyridine (1.42 g, 17.9 mmol) and a solution of triphosgene (0.870 g, 2.96 mmol) in anhydrous dichloromethane (20 mL) over 20 minute span, and the reaction was stirred at 50-55° C. for 2 hours. The solvent was removed and the residue was mixed with water (100 mL), the solid was filtered and rinsed with cold water (30 mL) and dried. The crude product was further washed with ether (20 mL) to give 6-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione. Yield: 1.40 g (81%).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)CB([C:37]2[CH:56]=[CH:55][C:40]([C:41]([N:43]3[CH2:47][CH2:46][CH2:45][C@H:44]3[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:42])=[CH:39][CH:38]=2)C1>>[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([CH2:11][CH2:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:37]3[CH:56]=[CH:55][C:40]([C:41]([N:43]4[CH2:47][CH2:46][CH2:45][C@H:44]4[C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])=[O:42])=[CH:39][CH:38]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: Brc1cnc(N2CCOCC2)c2nc(CCc3ccc4ccccc4n3)cn12
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)c1ccc(B2CC(C)(C)C(C)(C)C2)cc1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(CCc4ccc5ccccc5n4)cn23)cc1
Yield: 88.7 %

Procedure:
Compound 3a (250 mg, 0.570 mmol) was subjected to Suzuki coupling conditions with (S)-tert-butyl 1-(4-(3,3,4,4-tetramethylborolan-1-yl)benzoyl)pyrrolidine-2-carboxylate (686 mg, 1.71 mmol) using the reaction conditions described in Example 1, Step G to obtain compound 17b as a brown solid (320 mg, 81% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C37H40N6O4: 633.3 (M+H). Found 633.2.
Reaction SMILES: Cl.[F:2][C:3]([F:27])([F:26])[C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH:6]([O:17][CH:18]1[CH2:21][NH:20][CH2:19]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[CH2:32]([N:35]=[C:36]=[O:37])[CH:33]=[CH2:34]>C(Cl)Cl>[F:27][C:3]([F:2])([F:26])[C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH:6]([O:17][CH:18]1[CH2:21][N:20]([C:36]([NH:35][CH2:32][CH:33]=[CH2:34])=[O:37])[CH2:19]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:15])[F:16])=[CH:9][CH:8]=1
Reactant: C=CCN=C=O
Reactant: FC(F)Oc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: C=CCNC(=O)N1CC(OC(c2ccc(OC(F)F)cc2)c2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-(difluoromethoxy)benzhydryloxy]azetidine hydrochloride (175) (100 mg, 0.24 mmol) in anhydrous DCM (4 mL) was added MP-carbonate (2.62 mmol/g; 280 mg, 0.72 mmol), molecular sieves and allyl isocyanate (22 μL, 0.24 mmol). After shaking at ambient temperature for 2 h, the mixture was poured onto a DCM-wet SCX-2 cartridge (2 g). Elution with DCM (20 mL) and evaporation afforded the desired product (68 mg, 61%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][CH2:22][CH2:23][CH2:24][P:25]([O:30][CH2:31][CH3:32])(=[O:29])[O:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:21][CH2:22][CH2:23][CH2:24][P:25](=[O:29])([O:30][CH2:31][CH3:32])[O:26][CH2:27][CH3:28])[C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(CCCCCl)OCC
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O)OCC
Temperature: 70 °C

Procedure:
20.4 g (0.08 mol) of 7-benzyl-3-methylxanthine were suspended in 200 ml of dimethylformamide (DMF), treated with 22 g (0.96 mol) of diethyl 4-chlorobutanephosphonate and 13.8 g (0.1 mol) of activated potassium carbonate and heated at 70° C. for 4 hours and filtered, the filtrate was concentrated under reduced pressure and the oily residue which remained was taken up in ethyl acetate, filtered again and crystallized from diisopropyl ether.