Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[S:4].[CH2:7]([C:22]1[CH:23]=[C:24]([CH:32]=[CH:33][CH:34]=1)[O:25][CH:26]([CH2:30][CH3:31])[C:27](O)=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[N+](C1C=C(B(O)O)C=CC=1)([O-])=O>C1(C)C=CC=CC=1>[NH2:6][N:5]1[C:3]([SH:4])=[N:2][N:1]=[C:27]1[CH:26]([O:25][C:24]1[CH:32]=[CH:33][CH:34]=[C:22]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:23]=1)[CH2:30][CH3:31]
Reactant: NNC(=S)NN
Reactant: CCCCCCCCCCCCCCCc1cccc(OC(CC)C(=O)O)c1
Agent: O=[N+]([O-])c1cccc(B(O)O)c1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCc1cccc(OC(CC)c2nnc(S)n2N)c1
Reaction time: 0.25 h
Yield: 62.5 %

Procedure:
To a mixture of 2.65 g (25 mmol) of thiocarbohydrazide and 9.77 g (25 mmol) of 2-(3-pentadecylphenoxy)butanoic acid in 30 mL of toluene was added 0.42 g (2.5 mmol) of 3-nitrobenzene boronic acid was heated at reflux for 24 hr. The reaction was cooled and the reaction was allowed to settle. The supernatant liquid was decanted. To the residual solid was added 20 mL of acetonitrile. The mixture was stirred for 15 minutes. The solid was collected, rinsed with 5 mL of cold acetonitrile and dried in vacuo to afford 7.20 g (60.4%) of the desired product as a white solid. Analytical data are consistent with the assigned structure.
Reaction SMILES: [ClH:1].Cl.[CH:3]1[CH:12]=[CH:11][C:10]2[CH2:13][CH2:14][N:8]3[C:9]=2[C:4]=1[C@H:5]1[CH2:17][NH:16][CH2:15][C@H:6]1[CH2:7]3.C=O.[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCCl.CCOCC>[ClH:1].[ClH:1].[CH3:20][N:16]1[CH2:17][C@H:5]2[C@H:6]([CH2:7][N:8]3[CH2:14][CH2:13][C:10]4[CH:11]=[CH:12][CH:3]=[C:4]2[C:9]3=4)[CH2:15]1
Reactant: c1cc2c3c(c1)[C@H]1CNC[C@H]1CN3CC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOCC
Product: CN1C[C@H]2CN3CCc4cccc(c43)[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of (±)-cis-4,5,7,7a,8,9,10,10a-octahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinoline free base from EXAMPLE 109 (140 mg, 0.70 mmol) in 10 mL of 1,2-dichloroethane was added 37% aqueous formaldehyde (0.125 mL, 1.4 mmol) and sodium triacetoxyborohydride (0.45 g, 2.1 mmol). The resulting mixture was stirred at ambient temperature for 1 h and then the reaction was quenched with water. The mixture was partitioned between chloroform and saturated aqueous sodium carbonate. The organics were washed with brine, dried (K2CO3) and concentrated in vacuo. The residue was dissolved in 1 mL ethanol and 5 mL of ether and then there was added 2M HCl in ether (1.05 mL, 2.1 mmol). A solid precipitated out of solution. The solvents were decanted and the solid was triturated twice with ether and dried in vacuo to afford 100 mg (50%) of the title compound of EXAMPLE 110 as an off white powder LRMS (ES)+: 214.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:5][NH:6][C:7]([CH:9]([CH3:27])[C:10]([NH:12][CH:13]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:8].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.[CH3:52][O:53][C:54]1[CH:55]=[C:56]2[C:61](=[CH:62][CH:63]=1)[CH2:60][NH:59][CH2:58][CH2:57]2.CC#N>CN(C=O)C.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:5][NH:6][C:7](=[O:8])[CH:9]([CH3:27])[C:10]([NH:12][CH:13]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:14]([N:59]1[CH2:58][CH2:57][C:56]2[C:61](=[CH:62][CH:63]=[C:54]([O:53][CH3:52])[CH:55]=2)[CH2:60]1)=[O:15])=[O:11]
Reactant: CC(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)O
Reactant: COc1ccc2c(c1)CCNC2
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc2c(c1)CCN(C(=O)C(Cc1c[nH]c3ccccc13)NC(=O)C(C)C(=O)NCc1cc(F)cc(F)c1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[2-(3,5-Difluoro-benzylcarbamoyl)-propionylamino]-3-(1H-indol-3-yl)-propionic acid (64 mg, 0.15 mmol) was placed in a disposable polypropylene tube and dissolved in DMF (1 ml). TPTU (O-[2-oxo-1(2H)-pyridyl]-N,N,N′,N′-tetramethyluronium-tetrafluoroborate, 49 mg, 0.165 mmol) and 6-methoxy-1,2,3,4-tetrahydro-isoquinoline (24 mg, 0.15 mmol) were added, and the mixture was shaken overnight at r.t. The title compound, MS: m/e=575.3 (M+H+), was isolated from the reaction mixture by automated, preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]=[C:7]2I)(=[O:3])[NH2:2].C([Sn](CCCC)(CCCC)[C:26]1[N:31]=[C:30]([N:32]2[CH2:37][CH2:36][CH:35]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:34][CH2:33]2)[CH:29]=[N:28][CH:27]=1)CCC>CN(C=O)C.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:41]([O:40][C:39]([NH:38][CH:35]1[CH2:36][CH2:37][N:32]([C:30]2[N:31]=[C:26]([C:7]3[C:6]4[C:10](=[CH:11][CH:12]=[C:4]([C:1](=[O:3])[NH2:2])[CH:5]=4)[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]=3)[CH:27]=[N:28][CH:29]=2)[CH2:33][CH2:34]1)=[O:45])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)n1cc(I)c2cc(C(N)=O)ccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3cn(C(=O)OC(C)(C)C)c4ccc(C(N)=O)cc34)n2)CC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
A mixture of tert-butyl 5-carbamoyl-3-iodo-1H-indole-1-carboxylate (460 mg, 1.42 mmol) and tert-butyl 1-(6-(tributylstannyl)pyrazin-2-yl)piperidin-4-ylcarbamate (1d) (807 mg, 1.42 mmol) in DMF (4.6 mL) was purged with argon gas for 5 min, added Cut (405 mg, 2.13 mmol), palladium tetrakis (170 mg, 0.14 mmol) and again purged with argon gas for 5 min. The reaction mixture was stirred at 90° C. under nitrogen atmosphere for 1 h. The reaction mixture was then poured into water. The resulting precipitate was collected by filtration. The filtrate was extracted with diethyl ether. The organic layer was concentrated and combined with the above precipitate to give the crude product, which was purified by column chromatography to obtain the title compound as a brown solid (200 mg, 31%). MS (ESI, pos. ion) m/z: 537.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:6]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(Br)c1
Reaction time: 4 h

Procedure:
A solution of 3-bromo-benzoyl chloride (0.83 g, 3.8 mmol) in DCM (10 mL) was chilled to zero degrees and treated with tert-butylamine (1.2 mL, 11.3 mmol). Reaction was allowed to come to room temperature and stir for 4 h. Mixture was then poured onto water and washed once. Organic phase then washed with brine, dried over sodium sulfate, filtered and evaporated to amber oil (0.9 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:26][CH2:25][C@@H:24]4[C:27](O)=[O:28])=[N:21][CH:22]=3)[C:9]=2[F:30])[CH:5]=[CH:6][CH:7]=1.C([N:34](CC)C(C)C)(C)C.C(OC(Cl)=O)C(C)C.[OH-].[NH4+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:26][CH2:25][C@@H:24]4[C:27]([NH2:34])=[O:28])=[N:21][CH:22]=3)[C:9]=2[F:30])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(Cc2ccc(N3CC[C@@H]3C(=O)O)nc2)c(F)c1-c1cccc(Cl)c1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cc2ccc(N3CC[C@@H]3C(N)=O)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cooled 0-5° C. and stirred solution of (R)-1-[5-(3′-chloro-2-fluoro-6methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-azetidine-2-carboxylic acid (I-144, 0.14 g, 0.33 mmol) in THF (2.5 mL) was added N,N-diisopropylethylamine (0.09 g, 0.69 mmol). The reaction mixture was stirred for 5 min, isobutylchloroformate (0.05 g, 0.36 mmol) was added, and the reaction stirred at 0-5° C. for 30 min. Ammonium hydroxide solution (28%, 1.0 mL, 8.0 mmol) was added, the reaction warmed to room temperature, and stirred for 0.5 h. The reaction mixture was diluted with water (5 mL). The organic layer was separated, the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using 5% methanol in dichloromethane, followed by preparative thin layer chromatography using 5% methanol in dichloromethane to afford 0.07 g (47%) of P-617 as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): 7.99 (d, J=2.8 Hz, 1H), 7.51 (br s, 1H), 7.38-7.46 (m, 3H), 7.4 (br s, 1H), 7.24-7.3 (m, 2H), 7.14 (br s, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.34 (d, J=8.0 Hz, 1H), 4.39 (dd, J=9.6, 6.8 Hz, 1H), 3.7-3.9 (m, 2H), 3.84 (s, 2H), 3.72 (s, 3H), 2.26-2.48 (m, 2H) ppm; MS (APCI+): 426.9 (M+1), LC-MS: 100%.
Reaction SMILES: [CH3:1][N:2]([N:9]=O)C(N[N+]([O-])=O)=N.[OH-].[K+].[N+:13](=[CH2:15])=[N-:14].[CH:16]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CCOCC>[N+:2](=[CH2:1])=[N-:9].[CH:16]1([C:22](=[O:23])[CH:15]=[N+:13]=[N-:14])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Reactant: O=C(Cl)C1CCCCC1
Agent: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: [N-]=[N+]=CC(=O)C1CCCCC1
Reaction time: 1 h

Procedure:
A solution of diazomethane is prepared from N-methyl-N'-nitro-N-nitroso guanidine (12.5 g), potassium hydroxide (50%, 20 ml), and ether (300 ml). TEA (7.7 ml) is added to the diazomethane solution (65%) followed by cyclohexane carboxylic acid chloride (7.4 ml) slowly at 0° . The reaction is stirred at 0° for 1 hr then for 18 hrs at 22° . A porecipitate forms, it is filtered and washed with ether, and the filtrate concentrated. The resulting oil is cooled to -78° , triturated with ether, then warmed to 22° and concentrated with reduced pressure and heat to give the title compound as an oil, NMR (acetone-d6) 5.4 and 1.4-0.8 δ.
Reaction SMILES: [OH:1][C:2]1[CH:6]([CH:7]([CH3:9])[CH3:8])[NH:5][C:4](=[O:10])[CH:3]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1>>[OH:1][C:2]1[CH:6]([CH:7]([CH3:9])[CH3:8])[NH:5][C:4](=[O:10])[C:3]=1[CH:11]([C:21]1[NH:22][C:23]2[C:28]([C:20]=1[CH3:19])=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1c[nH]c2ccccc12
Reactant: O=Cc1ccccc1
Reactant: CC(C)C1NC(=O)C=C1O
Product: Cc1c(C(C2=C(O)C(C(C)C)NC2=O)c2ccccc2)[nH]c2ccccc12

Procedure:
Using general procedure C, 4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one (Lit. 11) was reacted with benzaldehyde and 3-methyl-1H-indole to give the title compound as a yellow solid. MS: 361.0 ([M+H]+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:23]=[CH:22][C:8]2[N:9]=[C:10](COC3C=CC(Cl)=CC=3Cl)[O:11][C:7]=2[CH:6]=1)=[O:4].[Br-].[Al+3].[Br-].[Br-].O.Cl>CSC.ClCCl>[O:11]1[C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:23]=[CH:22][C:8]=2[N:9]=[CH:10]1
Reactant: COC(=O)c1ccc2nc(COc3ccc(Cl)cc3Cl)oc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Solvent: CSC
Product: O=C(O)c1ccc2ncoc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 61.2 %

Procedure:
To a solution of 2-(2,4-dichloro-phenoxymethyl)-benzoxazole-6-carboxylic acid methyl ester (100 mg, 0.29 mmol) in dimethyl sulfide (8 ml) and dichloromethane (58 ml) was added aluminum bromide (1.24 g, 4.64 mmol). The reaction mixture was stirred at room temperature for 2.5 h, after which water and 10% HCl were added. After stirring at room temperature for 1 h, the mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2Cl2:MeOH=4:1) to give 2-2,4-dichloro-phenoxymethyl)-benzoxazole-6-carboxylic acid as a white solid (59.15 mg mg, 61.2% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C@H:11]2[C@@H:20](O)[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=3)[O:13][CH2:12]2)[CH:5]=1.[H][H].CO>C(O)(=O)C.ClCCl.[OH-].[Pd+2].[OH-]>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=3)[O:13][CH2:12]2)[CH:5]=1
Reactant: COC(=O)c1cccc(C[C@@H]2COc3ccc(O)cc3[C@@H]2O)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc(CC2COc3ccc(O)cc3C2)c1
Yield: 81 %

Procedure:
A mixture of 5.0 g (0.017 mole) of (3R-cis)-3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acid methyl ester (prepared by esterification of the corresponding carboxylic acid (prepared according to the method of co-pending U.S. Pat. Application of Murtiashaw, et al., U.S. Ser. No. 07/964,336 filed Oct. 21, 1992) and 1.0 g palladium hydroxide in 100 mL glacial acetic acid was shaken in a Parr hydrogenator under 50 psi hydrogen at room temperature for 3 hours. The mixture was filtered through Celite and the filtrate concentrated to give an oil. Flash chromatography on silica gel eluting with 5% methanol in dichloromethane yielded 4.3 g (81% of the title product as an oil). NMR (CDCl3): δ2.30 (m, 1H); 2.50 (dd, 1 ,H) ; 2.75 (m, 3H); 3.80 (dd, 1H); 3.92 (s, 3H); 4.15 (dd, 1H). MS (Cl, NH3) m/e: 316 (100).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C:5]1[C:6](=[O:14])[C:7]([CH3:13])=[C:8]([CH3:12])[C:9](=O)[CH:10]=1>O.CO>[CH3:13][C:7]1[C:6](=[O:14])[C:5]([CH3:4])=[CH:10][C:9](=[N:2][OH:3])[C:8]=1[CH3:12]
Reactant: CC1=CC(=O)C(C)=C(C)C1=O
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CO
Product: CC1=CC(=NO)C(C)=C(C)C1=O
Reaction time: 2 h
Yield: 66.9 %

Procedure:
A solution of 7.04 g of hydroxylamine hydrochloride in 30 ml of water was added at room temperature to a solution of 16.9 g of trimethylbenzoquinone (prepared as described in Preparation 10) in 150 ml of methanol, and the resulting mixture was stirred for 2 hours, after which it was allowed to stand for 2 days. At the end of this time, the reaction mixture was diluted with 1000 ml of water. The precipitate which separated out was collected by filtration and recrystallized from a mixture of ethyl acetate and hexane, to give 11.2 g of the title compound, melting at 188°-190° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([N:19]([CH3:21])[CH3:20])[CH:15]([F:22])[CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH2:29]([C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30]>>[CH2:29]([C:31]1[N:32]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][CH2:17][C@H:16]([N:19]([CH3:20])[CH3:21])[C@H:15]([F:22])[CH2:14]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30]
Reactant: CN(C)C1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CC1F
Reactant: CCc1nc2ccccc2[nH]1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC[C@H](N(C)C)[C@H](F)C3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, racemic 1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-3-fluoro-N,N-dimethylpiperidin-4-amine and 2-ethylbenzimidazole were reacted. The enantiomers were separated by SFC to give 226. LCMS m/z: 522.3 (MH+)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:32]1([C:37]([CH2:39][N:40]2[C:46]3[CH:47]=[C:48]([CH3:51])[CH:49]=[CH:50][C:45]=3[N:44]([C:52](=[O:57])[C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:43][CH:42]([NH2:58])[C:41]2=[O:59])=[O:38])[S:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.O>[C:32]1([C:37]([CH2:39][N:40]2[C:46]3[CH:47]=[C:48]([CH3:51])[CH:49]=[CH:50][C:45]=3[N:44]([C:52](=[O:57])[C:53]([CH3:54])([CH3:55])[CH3:56])[CH2:43][CH:42]([NH:58][C:14]([NH:1][C:2]3[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=3)=[O:16])[C:41]2=[O:59])=[O:38])[S:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc2c(c1)N(CC(=O)c1cccs1)C(=O)C(N)CN2C(=O)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C(C)(C)C)c3ccc(C)cc3N(CC(=O)c3cccs3)C2=O)c1
Reaction time: 0.17 h
Yield: 234.4 %

Procedure:
Ethyl 3-aminobenzoate (0.23 g) was dissolved in tetrahydrofuran (10 ml), and the solution was cooled on ice-water. Triphosgene (0.15 g) was added thereto at internal temperature 7° C., triethylamine (0.53 g) was added dropwise thereto over 10 minutes period, the mixture was allowed to come to room temperature, and stirred for 10 minutes. Subsequently, a suspension of 1-(2-thenoylmethyl)-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (0.52 g) in tetrahydrofuran (10 ml ) was added, and the resultant mixture was stirred for one hour. Water was added to the reaction mixture, extracted with methylene chloride, the organic layer was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=1:1), to thereby obtain 0.70 g of the titled compound as white crystals (Yield: 88%).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[O:28][C:27]([CH2:29][N:30]4[CH2:33][CH:32]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:41]1[N:46]2[CH:47]=[CH:48][N:49]=[C:45]2[CH:44]=[CH:43][CH:42]=1>O1CCOCC1.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.C1C=C(C([O-])=O)SC=1.[Cu+]>[N:49]1[CH:48]=[CH:47][N:46]2[C:41]([C:11]3[N:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[C:8]4[O:28][C:27]([CH2:29][N:30]5[CH2:31][CH:32]([N:34]6[CH2:39][CH2:38][O:37][CH2:36][CH2:35]6)[CH2:33]5)=[CH:26][C:9]=4[N:10]=3)=[CH:42][CH:43]=[CH:44][C:45]=12
Reactant: Brc1cccc2nccn12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2oc(CN3CC(N4CCOCC4)C3)cc2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: c1cc(-c2nc(N3CCOCC3)c3oc(CN4CC(N5CCOCC5)C4)cc3n2)n2ccnc2c1
Yield: 47.5 %

Procedure:
A mixture of 4-morpholin-4-yl-6-(3-morpholin-4-yl-azetidin-1-ylmethyl)-2-tributylstannanylfuro[3,2-d]pyrimidine (227 mg, 0.35 mmol), 5-bromoimidazo[1,2-a]pyridine (84 mg, 0.43 mmol), tetrakis(triphenylphosphine)palladium (40 mg, 10 mol %) and CuTC (16 mg, 24 mol %) in 1,4-dioxane (4 mL) was purged with argon gas then subjected to microwave irradiation at 140° C. for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g); the cartridge was washed with MeOH/DCM before the desired product was eluted with 2 M NH3 in MeOH/DCM. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:NH3/MeOH (2 M); gradient from 100:0 to 96:4)), followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to afford 250 as a cream foam (79 mg, 47%). LCMS (Method G): RT=3.22 min, M+H+=476. 1H NMR (CDCl3, 400 MHz) δ 9.14 (s, 1 H); 7.87 (dd, J=7.2, 1.2 Hz, 1H); 7.77 (d, J=8.9 Hz, 1 H); 7.74 (d, J=1.2 Hz, 1 H); 7.31 (dd, J=8.9, 7.2 Hz, 1 H); 6.76 (s, 1 H); 4.10 (t, J=4.7 Hz, 4 H); 3.89 (t, J=4.7 Hz, 4 H); 3.84 (s, 2 H); 3.74 (t, J=4.5 Hz, 4 H); 3.62 (t, J=6.2 Hz, 2 H); 3.15-3.02 (m, 3 H) and 2.35 (m, 4 H)
Reaction SMILES: [CH2:1]=O.[N:3]1([C:9]([S:11][CH3:12])=[S:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21]>C(O)C>[OH:21][C:16]1[C:15]([O:14][CH3:13])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:1][N:6]1[CH2:7][CH2:8][N:3]([C:9]([S:11][CH3:12])=[S:10])[CH2:4][CH2:5]1
Reactant: CSC(=S)N1CCNCC1
Reactant: C=O
Reactant: COc1ccccc1O
Solvent: CCO
Product: COc1cccc(CN2CCN(C(=S)SC)CC2)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
In 10 ml of ethanol was dissolved 0.86 g of 35% formalin. To the solution was dropwise added under chilling with ice a solution of 2.35 g of methyl 1-piperazinecarbodithioate in 5 ml of ethanol. The mixture was then stirred for 30 min. at room temperature. The mixture was refluxed overnight under heating after addition of a solution of 1.24 g of 2-methoxyphenol in 5 ml of ethanol under chilling with ice. The reaction mixture was cooled to room temperature. Precipitated crystals were collected by filtration and washed with 5 ml of ethanol to give 1.44 g of the desired compound as a white powder, m.p. 151°-152° C. (decomp.), yield 45.9%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].F[C:12]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].CCCCCC.C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:12]1[CH:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: N#Cc1ccc(C(F)(F)F)cc1F
Reactant: Nc1ccccc1S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#Cc1ccc(C(F)(F)F)cc1Sc1ccccc1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
2-Aminothiophenol (8.17 g, 65 mmol) was added to a mixture of sodium hydride (2.35 g of 80% dispersion, 1.2 eq) in dimethylformamide (DMF, 100 ml) at 0° C. under a nitrogen atmosphere. After stirring for 30 mins 2-fluoro-4-trifluoromethylbenzonitrile (11.68 g, 0.95 eq) was added and the reaction mixture stirred at 0° C. for 1 hr then kept at 10° C. overnight. The solvent was evaporated in vaccuo and the residue taken up in ether (100 ml) and washed with sodium bicarbonate solution (1M, 100 ml). The organic layer was separated and dried (sodium sulphate, Na2SO4), and evaporated to give a yellow solid. The title compound (12.5 g, m.p. 102°-104° C., Rf 0.67, hexane/EtOAc 2:1) was obtained in pure form by chromatography on silica eluting first with hexane/ethyl acetate (6:1) then (4:1).
Reaction SMILES: [N+](=[CH2:3])=[N-].[NH2:4][C@H:5]([C:18]([OH:20])=[O:19])[CH2:6][C:7]#[C:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>CCOCC.C(O)C>[NH2:4][C@H:5]([C:18]([O:20][CH3:3])=[O:19])[CH2:6][C:7]#[C:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NCC#CC[C@H](N)C(=O)O
Solvent: CCOCC
Solvent: CCO
Product: COC(=O)[C@@H](N)CC#CCNC(=O)OC(C)(C)C

Procedure:
Titrate a solution of diazomethane in ether into a solution of 1-amino-1-(S)-carboxy-5-(t-butoxycarbonyl amino)-3-pentyne (4 g) in ethanol (200 ml) until a yellow color remains. Evaporate the solvent to obtain 1-amino-1-(s)-methoxycarbonyl-5-(t-butoxycarbonylamino)-3-pentyne.