Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH3:10])=[CH:5][CH:4]=1)[CH3:2].[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:18]([O:17][C:15](=[O:16])[C:14]([C:12]#[N:13])=[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[CH:5][CH:4]=1)[CH3:2])[CH3:19]
Reactant: CCc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)=C(C)c1ccc(CC)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 4′-ethylacetophenone (50 mmol), ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL), ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate in petroleum ether.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[C@@H:45]1[C@H:49]([O:50][C:51](=[O:58])[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:48]([O:59][C:60](=[O:67])[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C@@H:47]([C:68]2[N:72]=[CH:71][N:70]([CH2:73][CH3:74])[N:69]=2)[O:46]1)(=O)C1C=CC=CC=1.C(O[C@H]1[C@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C2C=CC=CC=2)[C@@H](C2N=CN(CC)N=2)O1)(=O)C1C=CC=CC=1>>[C:60]([O:59][C@H:48]1[C@@H:49]([O:50][C:51](=[O:58])[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:45]([N:14]2[CH:13]=[N:12][C:11]3[C:15]2=[N:16][C:17]([C:19]([NH:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:20])=[N:18][C:10]=3[NH:9][CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:46][C@@H:47]1[C:68]1[N:72]=[CH:71][N:70]([CH2:73][CH3:74])[N:69]=1)(=[O:67])[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1
Reactant: CCn1cnc([C@H]2O[C@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)n1
Reactant: O=C(NCCN1CCCCC1)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Agent: CCn1cnc([C@H]2O[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)n1
Product: CCn1cnc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(C(=O)NCCN5CCCCC5)nc43)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)n1

Procedure:
Prepared by the same method as Preparation 27 from 6-[(2,2-diphenylethyl)amino]-N-[2-(1-piperidinyl)ethyl]-9H-purine-2-carboxamide (Preparation 11) and a mixture of (2R,3R,4R,5R)-3,4-bis(benzoyloxy)-5-(1-ethyl-1H-1,2,4-triazol-3-yl)tetrahydro-2-furanyl benzoate and (2S,3R,4R,5R)-3,4-bis(benzoyloxy)-5-(1-ethyl-1H-1,2,4-triazol-3-yl)tetrahydro-2-furanyl benzoate (Preparation 22).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].C(N(CC)CC)C.[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:39]1[CH:38]=[CH:37][N:29]2[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:5](=[O:6])[C:4]4[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=4[S:2][CH3:1])=[CH:41][CH:40]=3)=[O:25])[CH2:27][C:28]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: CSc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 0.05 h
Yield: 64.2 %

Procedure:
To a stirred solution of 0.364 g of 2-(methylthio)benzoyl chloride 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 72 hours at room temperature. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give a solid which is crystallized from ethyl alcohol to give 0.480 g of the desired product as a white solid, m.p. 171°-174° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[C:21]3[CH:20]=[C:19]([NH2:22])[CH:18]=[CH:17][C:16]=3[CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[Cl:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:36]=1[C:37](Cl)=[O:38].CO>ClCCl>[Cl:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:36]=1[C:37]([NH:22][C:19]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:23])[F:24])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[C:21]=2[CH:20]=1)=[O:38]
Reactant: Nc1ccc2c(c1)C(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCC2
Reactant: O=C(Cl)c1c(F)cccc1Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc2c(c1)C(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCC2)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
8-(4-Trifluoromethylbenzenesulfonyl)-5,6,7,8-tetrahydronaphthalen-2-ylamine (25 mg, 0.070 mmol) and diisopropylethylamine (23 μL, 0.14 mmol) were combined in dichloromethane (500 μL) to form a reaction mixture. 2-Chloro-6-fluorobenzoyl chloride (21 mg, 0.11 mmol) was then added and the reaction mixture, and the reaction mixture was stirred for 12 hours at room temperature. Next, methanol (100 μL) was added and the solvent was removed under reduced pressure to provide a residue, which was purified by HPLC to provide the title compound. LCMS (ESI): calc. C24H18ClF4NO3S=511; obs. M+H=512.
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][C:12]#[N:13]>CO.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][C:12]#[N:13]
Reactant: N#CCCc1ccsc1C#CCO
Agent: [Pd]
Solvent: CO
Product: N#CCCc1ccsc1CCCO
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
To a stirred solution of 3-[2-(3-hydroxy-prop-1-ynyl)-thiophen-3-yl]-propionitrile 82 (0.27 g, 1.39 mmol) was dissolved in MeOH (5 mL). To this solution was added Pd/C [10% w/w] (0.15 g, 0.14 mmol). The mixture was then stirred under an atmosphere of hydrogen at room temperature for 4 h then filtered through a Celite pad and concentrated in vacuo. Purification by silica gel column chromatography (eluent: 50% EtOAc in hexane) afforded 83 (0.18 g) as a colorless syrup. 1H NMR (400 MHz, d6-DMSO) δ: 7.27 (d, J=5.0 Hz, 1H), 6.94 (d, J=5.0 Hz, 1H), 4.51 (t, J=5.0 Hz 1H), 3.42 (dd, J=6.0 Hz and 11.5 Hz, 2H), 2.82–2.71 (m, 6H), 1.70 (m, 2H). MS (EI) m/z (M+H+) 196, (M−OH+) 178.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4](Cl)[N:3]=1.[CH3:11][O:12][CH2:13][CH2:14][CH2:15][NH2:16].O>O1CCCC1>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([NH:16][CH2:15][CH2:14][CH2:13][O:12][CH3:11])[N:3]=1
Reactant: COCCCN
Reactant: Nc1nc(Cl)nc(Cl)c1Cl
Solvent: O
Solvent: C1CCOC1
Product: COCCCNc1nc(N)c(Cl)c(Cl)n1
Reaction time: 6 h

Procedure:
1,850 g (9.31 moles) of 4-amino-2,5,6-trichloropyrimidine are dissolved in 4 liters of tetrahydrofuran. 1,659 g (18.62 moles) of 3-methoxypropylamine are added dropwise thereto over a period of 6 hours. The reaction mixture is heated for five hours at the boil, cooled and stirred into 20 liters of water. The resulting solid is filtered off, dried, stirred with 7 liters of methylene chloride and again filtered off. After the solid thus obtained has been twice recrystallised from toluene, 743 g (31.8% of theory) of the desired pyrimidine, melting point 114° C., are obtained.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].ON1C(=O)CCC1=O.Cl.CN(C)CCCN=C=NCC.[NH2:40][C:41]([CH3:62])([CH3:61])[CH2:42][N:43]1[C:55]2[C:54]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[N:48]=[C:47]([NH2:56])[C:46]=2[N:45]=[C:44]1[CH2:57][O:58][CH2:59][CH3:60]>CN(C=O)C.O>[NH2:56][C:47]1[C:46]2[N:45]=[C:44]([CH2:57][O:58][CH2:59][CH3:60])[N:43]([CH2:42][C:41]([NH:40][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)([CH3:61])[CH3:62])[C:55]=2[C:54]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[N:48]=1
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)NC(=O)CCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.3 %

Procedure:
To a solution of 6-(carbobenzyloxyamino) caproic acid (8.49 grams (g), 32.0 millimole (mmol)) in DMF (50 mL) at 0° C. was added N-hydroxysuccinimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). After a short period, the solution was added to a 0° C. solution of 1-(2-amino-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in U.S. Patent Publication No. 2004/0091491, 10 g, 32 mmol) in DMF (100 mL). The mixture was allowed to warm to room temperature and was stirred for 3 days. The solution was diluted with water (400 mL) and extracted with ethyl acetate (3×). The organic layers were combined and washed with water (2×) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by HPFC on silica gel three times (gradient elution with CMA in chloroform) to provide 4.90 g of benzyl 6-({2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}amino)-6-oxohexylcarbamate as a white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>C1COCC1>[C:9]([C:8]([C:4]1[CH:3]=[C:2]([NH:1][C:20](=[O:21])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=[CH:6][CH:5]=1)([CH3:12])[CH3:11])#[N:10]
Reactant: CC(C)(C#N)c1cccc(N)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(NC(=O)Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a solution of 2-(3-aminophenyl)-2-methylpropanenitrile (490 mg, 3.06 mmol) and potassium carbonate (552 mg, 4 mmol) in anhydrous THF (4.2 ml) was added dropwise phenyl chloroformate (0.81 ml, 6.4 mmol) as a solution in THF (2 ml). The reaction mixture was stirred at rt overnight. The solvent was removed and the residue taken in DCM, washed with water and brine and the organics combined, dried (MgSO4) and concentrated. The crude was purified by silica gel chromatography (hexane/ethyl acetate 15%) to afford phenyl 3-(2-cyanopropan-2-yl)phenylcarbamate (828 mg, 96%) as a solid. 1H NMR (300 MHz, CDCl3) δ 1.72 (s, 6H), 7.20-7.28 (m, 4H), 7.35-7.41 (m, 4H), 7.65 (s, 1H); LC-MS (ESI) m/z 281 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.ClCCN(CC)CC>>[CH2:5]([N:1]([CH2:2][CH3:3])[CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1)[CH3:4]
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Agent: CCN(CC)CCCl
Agent: Cl
Product: CCN(CC)CCOc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title compound is prepared as described in Example 1 for 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine but using (2-chloro-ethyl)-diethyl-amine hydrochloride. After a 1 h stirring at RT and usual work-up, purification of the crude material by silica gel (179 g) column chromatography (CH2Cl2/MeOH, 80/20→70/30) affords the title compound as a dark brown oil: ES-MS: 209.2 [M+H]+; Rf=0.21 (CH2Cl2/MeOH, 70/30).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:38])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[C:34]([CH2:35][CH3:36])=[CH:33][N:32]=[C:31]([CH3:37])[CH:30]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:35]([C:34]1[C:29]([C:25]2[CH:24]=[C:23]([C:21]3[CH2:20][C:19](=[O:38])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:16])([F:17])[F:15])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)=[CH:30][C:31]([CH3:37])=[N:32][CH:33]=1)[CH3:36]
Reactant: CCc1cnc(C)cc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)ccc2NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cnc(C)cc1-c1cccc(C2=Nc3ccc(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (2-{3-[3-(5-ethyl-2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M133) (0.26 g, 0.49 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (170 mg, 87%).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([F:35])([F:34])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][C:16]1[CH:31]=[CH:30][C:19](/[CH:20]=[C:21](\[C:27](=O)[CH3:28])/[C:22](OCC)=[O:23])=[C:18]([O:32][CH3:33])[CH:17]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(=O)(O)O.[NH2:40][C:41]([NH2:43])=[NH:42]>CO.O.CCOC(C)=O>[NH2:43][C:41]1[N:42]=[C:22]([OH:23])[C:21]([CH2:20][C:19]2[CH:30]=[CH:31][C:16]([O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][C:9]([P:4](=[O:5])([O:6][CH2:7][CH3:8])[O:3][CH2:1][CH3:2])([F:35])[F:34])=[CH:17][C:18]=2[O:32][CH3:33])=[C:27]([CH3:28])[N:40]=1
Reactant: CCOC(=O)/C(=C/c1ccc(OCCOCCC(F)(F)P(=O)(OCC)OCC)cc1OC)C(C)=O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)C(F)(F)CCOCCOc1ccc(Cc2c(C)nc(N)nc2O)c(OC)c1
Temperature: 80 °C
Yield: 15 %

Procedure:
To a solution of (E)-ethyl 2-(4-(2-(3-(diethoxyphosphoryl)-3,3-difluoropropoxy)ethoxy)-2-methoxybenzylidene)-3-oxobutanoate (1 equiv.) in MeOH (0.20 M) was added guanidine carbonate (1.1 equiv.) and the reaction mixture was heated to 80° C. for 3 h. At this point the reaction mixture was allowed to cool to room temperature and it was then diluted with water and EtOAc. The resulting mixture was transferred to a separatory funnel and washed with EtOAc three times. The combined organic layers were dried over anhydrous Na2SO4 and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH™ system using a gradient of 0-10% MeOH/DCM to provide the title compound (15%) as a solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[N:18]=[CH:17][C:16]2[N:15]([CH3:19])[C:14](=[O:20])[C@@H:13]([CH2:21][CH3:22])[N:12]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:11]=2[N:10]=1.[C:28](O)([C:30](F)(F)F)=[O:29]>C(O)(=O)C>[CH:23]1([N:12]2[C:11]3[N:10]=[C:9]([C:8]4[CH:7]=[CH:6][N:5]=[CH:4][C:3]=4[CH2:2][NH:1][C:28](=[O:29])[CH3:30])[N:18]=[CH:17][C:16]=3[N:15]([CH3:19])[C:14](=[O:20])[C@H:13]2[CH2:21][CH3:22])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CN)nc2N1C1CCCC1
Solvent: CC(=O)O
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CNC(C)=O)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 102, with (R)-2-(3-(aminomethyl)pyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 105) instead of (R)-2-(3-aminopyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 91), and with acetic acid instead of benzoic acid. LCMS (0.05% TFA): 409.2 m/z (M+H)+; 1H-NMR (CDCl3, 500 MHz): δ: 8.98 (bs, 1H), 8.82 (d, 1H, J=5.0 Hz), 8.39 (d, 1H, J=5.0 Hz), 8.05 (s, 1H), 7.31 (bs, 1H), 4.84 (s, 2H), 4.46 (m, 1H), 4.37 (m, 1H), 3.44 (s, 3H), 2.03 (m, 1H), 1.95 (s, 3H), 1.94˜1.68 (m, 9H), 0.91 (t, 3H, J=7.5 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[N:12]#[C:13][NH2:14].[Na].O.Cl>CN1CCCC1=O>[CH3:11][O:10][C:4]1[N:3]=[C:2]([NH:14][C:13]#[N:12])[C:7]([O:8][CH3:9])=[CH:6][N:5]=1
Reactant: COc1ncc(OC)c(Cl)n1
Reactant: N#CN
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ncc(OC)c(NC#N)n1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 76.4 %

Procedure:
4-Chloro-2,5-dimethoxypyrimidine (CDMP; 15 g, 0.086 mol) was dissolved in N-methyl-2-pyrrolidinone (NMP; 62.5 g) at ambient temperature. Sodium hydrogen cyanamide (12.1 g, 2.2 eq) was added all at once, and the mixture was heated to 50° C. with stirring for 2.5 h. The resulting slurry was cooled to 25° C., and 150 mL of water was added. Concentrated hydrochloric acid was added drop-wise until a pH of 5.5 was reached. The thick slurry was filtered and washed twice with 10 mL of water to afford 2,5-dimethoxy-4-cyanoamino-pyrimidine (2) as a white solid (11.83 g, 76% yield).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl:29][C:30]1[S:31][C:32]([CH:36]=O)=[C:33]([Cl:35])[N:34]=1.C(O)(=O)C.[OH-].[Na+]>ClCCCl>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:36][C:32]2[S:31][C:30]([Cl:29])=[N:34][C:33]=2[Cl:35])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=Cc1sc(Cl)nc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(NCc2sc(Cl)nc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.3 %

Procedure:
Add sodium triacetoxyborohydride (1.70 g, 8.02 mmol) to a stirred solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.0124 g, 5.06 mmol), 2,4-dichloro-thiazole-5-carbaldehyde (1.0113 g, 5.56 mmol), glacial acetic acid (0.31 mL, 5.42 mmol), and 1,2-dichloroethane (40 mL). Stir for 18 hours under nitrogen at room temperature. Pour the reaction into 2N NaOH (100 mL) and extract with ethyl acetate (3×100 mL). Dry the ethyl acetate over sodium sulfate and then filter off the sodium sulfate. Concentrate on a rotary evaporator and purify the crude product by flash chromatography on silica gel eluting with 35% ethyl acetate/hexanes then with 100% ethyl acetate to yield 1.1547 g (62%) of 4-{[(2,4-dichloro-thiazol-5-yl)methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=366.1 (M+1); 1H NMR (CDCl3): δ=4.04 (br s, 2H), 3.96 (s, 2H), 2.87-2.81 (m, 2H), 2.72-2.65 (m, 1H), 1.90-1.86 (m, 2H), 1.48-1.39 (m, 10H), 1.33-1.23 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1nc2ccsc2nc1N
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1nc2ccsc2nc1NCc1ccccc1
Yield: 61.6 %

Procedure:
Ethyl 3-aminothieno[2,3-b]pyrazine-2-carboxylate (0.450 g, 2.02 mmol) was treated with neat NaH (0.058 g, 2.42 mmol) and benzyl bromide (0.380 g, 2.22 mmol) as described in Example 94A. Purification by column chromatography on silica gel eluting with a solvent gradient from 10:1 to 3:1 hexanes:ethyl acetate gave the title compound (0.39 g, 62%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ1.39 (t, 3H), 4.37 (q, 2H), 5.38 (d, 2H), 7.19-7.42 (m, 5H), 7.88 (br t, 1H), 8.55 (m, 2H). MS (DCI/NH3) m/e 3 14 (M+H)+.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]([N:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([O:38]C)=[C:34]([Br:40])[CH:33]=3)=[CH:28][CH:27]=2)[CH3:24])=[O:22])=[CH:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)=O.CC(C)=O.O>C(Cl)Cl>[CH2:5]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]([N:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([Br:40])[CH:33]=3)=[CH:28][CH:27]=2)[CH3:24])=[O:22])=[CH:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccc(-c2ccc(CN(C)C(=O)c3cn(Cc4ccccc4)c4ccccc34)cc2)cc1Br
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: O
Solvent: CC(C)=O
Product: CN(Cc1ccc(-c2ccc(O)c(Br)c2)cc1)C(=O)c1cn(Cc2ccccc2)c2ccccc12
Reaction time: 3.5 h
Yield: 98.3 %

Procedure:
Boron tribromide (41.4 mL of a 1 M solution in methylene chloride; 41.4 mmol) was added under nitrogen dropwise over 30 minutes to a solution of 1-benzyl-N-[(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methyl]-N-methyl-1H-indole-3-carboxamide (7.46 g, 13.8 mmol), prepared in the previous step, in 200 mL of methylene chloride at dry ice-acetone temperature. After the addition the dry ice-acetone bath was replaced with an ice bath and the stirring was continued for 3.5 h. At ice bath temperature 50 mL of water was added dropwise. The reaction was then partitioned between additional amounts of methylene chloride and water. The aqueous layer was separated and extracted three times with methylene chloride. The combined extracts were dried (MgSO4) and the solvent removed under reduced pressure to give 1-benzyl-N-[(3′-bromo-4′-hydroxy-1,1′-biphenyl-4-yl)methyl]-N-methyl-1H-indole-3-carboxamide (7.13 g, 98%) as a light tan solid, mp 164-170° C. Elemental Analysis for C30H25BrN2O2 Calc'd: C, 68.58; H, 4.80; N, 5.33. Found: C, 67.27; H, 4.78; N, 5.19
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[F:13][C:14]1[CH:15]=[C:16]([S:20]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: Fc1ccc(C2CCCN2)cc1
Product: O=S(=O)(c1cccc(F)c1)N1CCCC1c1ccc(F)cc1

Procedure:
The title compound, off-white solid, m.p. 101° C. and MS: m/e=323 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 3-fluoro-benzenesulfonyl chloride.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=1)C1C=CC=CC=1.[BrH:19]>>[BrH:17].[BrH:19].[Br:17][C:15]1[CH:16]=[C:11]([NH2:10])[CH:12]=[N:13][CH:14]=1
Reactant: O=C(Nc1cncc(Br)c1)OCc1ccccc1
Agent: Br
Product: Nc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of the product of Example 231A (200 mg, 0.6512 mmol) in a hydrogen bromide solution (33 weight % HBr in acetic acid, 3 mL) was stirred at room temperature for 4 hours. The solvent was removed by rotary evaporation in vacuo and the residue azeotroped with dry toluene (10 mL) to afford the title compound as a light peach colored solid (205 mg, 94%).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH3:12])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1>CCOC(C)=O.[Pd]>[CH2:11]([N:10]1[C:3]2[CH:2]=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[N:9]1)[CH3:12]
Reactant: CCn1ncc2ncnc(Cl)c21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCn1ncc2ncncc21
Reaction time: 2 h
Yield: 93.9 %

Procedure:
A mixture of 7-chloro-1-ethyl-1H-pyrazolo[4,3-d]pyrimidine (105 mg), TEA (0.088 mL) and 10% Pd—C (30 mg) in AcOEt (5 mL) was hydrogenated under balloon pressure at room temperature for 2 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (80 mg).