Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:16]([NH:17][C:18](=O)[CH3:19])=[N:15][CH:14]=[CH:13][N:12]=1)=[O:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C1C=CN=CC=1.O1CCOCC1>[CH3:19][C:18]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9](=[O:10])[C:11]2[C:16](=[N:15][CH:14]=[CH:13][N:12]=2)[N:17]=1
Reactant: CC(=O)Nc1nccnc1C(=O)Nc1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: CN(C)c1ccncc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1nc2nccnc2c(=O)n1-c1ccccc1Cl
Temperature: 25 °C

Procedure:
To a mixture of 3-acetamidopyrazine-2-carboxylic acid 2-chlorophenylamide (0.816 g, 2.81 mmol), triphenylphosphine (2.21 g, 8.43 mmol), and 4-dimethylaminopyridine (0.034 g, 0.28 mmol) in dioxane (35 mL) was added diethyl azodicarboxylate (1.33 mL, 8.43 mmol), dropwise via syringe. The reaction was refluxed overnight, cooled to ambient temperature and concentrated. The residue was partitioned between methylene chloride and water. The phases were separated and the organic layer was washed with brine, dried and concentrated. The residue was flash chromatographed on silica gel (1.5×5 inches, packed in hexane) with elution proceeding as follows: 20% ethyl acetate/hexane (250 mL), forerun; 40% ethyl acetate/hexane (1600 mL), unweighed triphenylphosphine oxide; 60% ethyl acetate/hexane (500 mL) and 75% ethyl acetate/hexane (500 mL), nil; 80% ethyl acetate/hexane (1000 mL), 0.62 g (81%) of 2-methyl-3-(2-chloro-phenyl)-3H-pteridin-4-one as a brown foam which was suitable for use without further purification. A sample was triturated with hexane.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][C:15]([CH2:18][O:19][CH3:20])=[CH:16][CH:17]=2)[N:3]=1.SC[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[O:14][C:15]([CH2:18][O:19][CH3:20])=[CH:16][CH:17]=2)[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:7]=1
Reactant: SCCc1ccccn1
Reactant: COCc1ccc(-c2nc(N)nc(S(C)=O)c2C#N)o1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: COCc1ccc(-c2nc(N)nc(SCCc3ccccn3)c2C#N)o1

Procedure:
From 2-amino-4-methanesulfinyl-6-(5-methoxymethyl-furan-2-yl)-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 368 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:3][P:4]([O:15][CH2:16][CH3:17])([CH2:6][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])[CH3:2]>CO.O=[Pt]=O>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][CH:7]([OH:14])[CH2:6][P:4]([O:3][CH2:1][CH3:2])([O:15][CH2:16][CH3:17])=[O:5])[CH3:13]
Reactant: CCOC(=O)CC(=O)CP(=O)(OCC)OCC
Agent: O=[Pt]=O
Solvent: CO
Product: CCOC(=O)CC(O)CP(=O)(OCC)OCC
Reaction time: 36 h
Yield: 101.1 %

Procedure:
The title compound of Example 7 (17 g, 63.8 mmol) was dissolved in 200 mL of methanol. To this solution was added PtO2 (1.7 g, 10% w/w). The mixture was degassed by evacuation of air, then refilling with hydrogen. This degassing procedure was repeated three times. The pressure in the Parr-shaker was set to 50 psi, and the mixture was shaken for 36 hours. The catalyst was filtered through a Celite pad and the filtrate was concentrated on a rotavap to give 17.3 g (~100%) of the title compound as a white solid, m.p. 33° C. to 35° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[N:3]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[C:14]=1[CH:21]1[O:25][CH2:24][CH2:23][O:22]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[N:3]=2)=[C:15]([F:20])[C:14]=1[CH:21]1[O:22][CH2:23][CH2:24][O:25]1
Reactant: COc1nc(Cl)ccc1C#N
Reactant: Oc1ccc(Br)c(C2OCCO2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(Oc2ccc(Br)c(C3OCCO3)c2F)ccc1C#N
Yield: 85 %

Procedure:
A solution of 6-chloro-2-methoxynicotinonitrile (1.16 g, 6.88 mmol), 4-bromo-3-(1,3-dioxolan-2-yl)-2-fluorophenol (1.81 g, 6.88 mmol), potassium carbonate (1.14 g, 8.26 mmol), and N,N-dimethylformamide (35 mL) was stirred at 80° C. overnight. Water was added and the solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel column using Combiflash to give 6-(4-bromo-3-(1,3-dioxolan-2-yl)-2-fluorophenoxy)-2-methoxynicotinonitrile (2.31 g, 85% yield).
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[O:3].[CH2:10]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH3:13]>>[CH2:10]([N:14]([C:2]([NH:1][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:3])[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCNc1ccc(N2CCC(=O)CC2)cc1
Reactant: CCOC(=O)CN=C=O
Product: CCCCN(C(=O)NCC(=O)OCC)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from ethyl isocyanatoacetate and 1-[4-(butylamino)phenyl]-4-piperidineone (which was obtained in Example 364) according to the procedure of Example 366 as a pale brown solid; MS (ES) m/z: 376.5 (MH+).
Reaction SMILES: [N:1]([C@H:4]1[C@H:8]([F:9])[CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[NH2:1][C@H:4]1[C@H:8]([F:9])[CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)[C@H](N=[N+]=[N-])C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](F)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
In a round-bottomed flask equipped with a magnetic stir bar and a reflux condenser, to a solution of trans-tert-butyl 3-azido-4-fluoropyrrolidine-1-carboxylate (45 mg, 0.195 mmol) in THF (2.5 mL) was added PPh3 on polystyrene (1.6 mmol/g, 120 mg, 0.193 mmol) and water (0.15 mL). The reaction mixture was stirred at 60° C. for 2 h. The mixture was then filtered and the filtrate dried over MgSO4 and filtered. The solvent was removed under reduced pressure to afford trans-tert-butyl 3-amino-4-fluoropyrrolidine-1-carboxylate as a pale yellow oil. LC-MS-conditions 10: tR=0.48 min; [M-CH3+H]+=190.38.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20].[CH3:34][CH2:35][C@H:36](O)[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(OCC)C>[CH3:34][C@H:35]([O:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])[CH2:36][CH3:37]
Reactant: CC[C@@H](C)O
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Yield: 84.2 %

Procedure:
A solution of DIAD (16.6 mL, 84.0 mmol) in dry THF (100 mL) was added dropwise to a cooled (ice bath) stirred mixture of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (14.5 g, 56.2 mmol); R-(−)-sec-butanol (5 g, 67.0 mmol) and solid-supported triphenylphosphine (28 g, of 3 mmol per g loading, 84.0 mmol) in dry THF (400 mL) whilst maintaining the temperature below 10° C. The mixture was allowed to stir for 3 hours, then diluted with diethyl ether (800 mL) and filtered. Removal of the solvent gave a pale coloured oil, which was purified by column chromatography on silica, eluting with 25% ethyl acetate in hexane; to give the desired product (14.87 g).
Reaction SMILES: [N:1]([C@H:4]1[C:17]2[CH:16]=[CH:15][C:14]3[CH2:13][N:12]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH2:10][C:9]=3[C:8]=2[CH2:7][CH2:6][CH2:5]1)=[N+]=[N-]>CCOC(C)=O.CO.[Pd]>[CH2:18]([N:12]1[CH2:11][CH2:10][C:9]2[C:8]3[CH2:7][CH2:6][CH2:5][C@@H:4]([NH2:1])[C:17]=3[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)CN1CCc2c(ccc3c2CCC[C@H]3N=[N+]=[N-])C1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)CN1CCc2c(ccc3c2CCC[C@H]3N)C1
Reaction time: 8 h

Procedure:
A suspension of 30 mg of Pd/C (10% w/w) in a solution of (R)-7-azido-3-isobutyl-1,2,3,4,7,8,9,10-octahydrobenzo[f]isoquinoline (296 mg, 1 mmol) in 30 mL of EtOAc was stirred under H2 atmosphere overnight. The reaction mixture was then directly submitted to flash chomatograph (SiO2, EtOAc to EtOAc/2M NH3 in MeOH=100:15 to 100:25 to 100:35) to give (R)-3-isobutyl-1,2,3,4,7,8,9,10-octahydrobenzo[f]isoquinolin-7-amine as a colorless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:17]1[CH2:22][CH2:21][N:20]([C:23]([C:25]2[CH:50]=[CH:49][C:28]([O:29][C:30]3[CH:48]=[CH:47][C:33]([C:34]([NH:36][C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=4)=O)=[CH:32][N:31]=3)=[CH:27][CH:26]=2)=O)[CH2:19][CH2:18]1)[C:8]1[CH:16]=[CH:15][C:14]2[O:13][CH2:12][O:11][C:10]=2[CH:9]=1>C1COCC1>[CH2:7]([N:17]1[CH2:18][CH2:19][N:20]([CH2:23][C:25]2[CH:50]=[CH:49][C:28]([O:29][C:30]3[N:31]=[CH:32][C:33]([CH2:34][NH:36][C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:44])[F:45])=[CH:39][CH:38]=4)=[CH:47][CH:48]=3)=[CH:27][CH:26]=2)[CH2:21][CH2:22]1)[C:8]1[CH:16]=[CH:15][C:14]2[O:13][CH2:12][O:11][C:10]=2[CH:9]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(Oc2ccc(C(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(NCc2ccc(Oc3ccc(CN4CCN(Cc5ccc6c(c5)OCO6)CC4)cc3)nc2)cc1
Temperature: 0 °C

Procedure:
To a suspension of lithium aluminum hydride (0.106 g, 2.80 mmol) in THF (10 mL) was added dropwise a solution of 6-[4-(4-piperonylpiperazine-1-carbonyl)-phenoxy]-N-(4-trifluoromethylphenyl)nicotinamide (0.423 g, 0.700 mmol) in THF (10 mL) under ice cooled stirring. Once the entire amount was added dropwise, the solution temperature was slowly raised, and stirred under reflux, for 2 hours. After cooling, ice water (50 mL) was added to the solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane methanol 40:1), to thereby yield 0.125 g of the title compound.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:24])([CH3:23])[C:13](=[O:22])[N:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[C:28]=1[C:29](Cl)=[O:30]>>[CH3:37][O:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:27]([O:26][CH3:25])[C:28]=1[C:29]([N:19]1[CH2:20][CH2:21][CH:16]([N:14]2[C:13](=[O:22])[C:12]([CH3:24])([CH3:23])[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([OH:2])[CH:4]=3)=[N:15]2)[CH2:17][CH2:18]1)=[O:30]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1O
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4c(OC)cccc4OC)CC3)C(=O)C2(C)C)cc1O

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3-hydroxy-4-methoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B11*HCl) and 2,6-dimethoxybenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield 2-{1-[(2,6-dimethoxyphenyl)carbonyl]piperidin-4-yl}-5-(3-hydroxy-4-methoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one as the product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[C:10]([C:16]2[NH:20][N:19]=[N:18][N:17]=2)=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.Cl[C:22]([C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:25]=1)=[O:23]>C1(C)C=CC=CC=1>[OH:15][C:11]1[C:10]([C:16]2[NH:20][N:19]=[N:18][N:17]=2)=[C:9]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:22]([C:24]2[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:25]=2)=[O:23])[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccc1Sc1cccc(O)c1-c1nnn[nH]1
Reactant: CCOC(=O)COc1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1ccc(C(=O)Nc2ccccc2Sc2cccc(O)c2-c2nnn[nH]2)cc1
Yield: 60.8 %

Procedure:
In 10 ml of toluene was suspended 0.63 g of 3-(2-aminophenylthio)-2-(1H-tetrazol-5-yl)phenol (prepared in Reference Example 12)-followed by addition of a solution of 0.58 g of ethyl 4-chloroformylphenoxyacetate in 2 ml of toluene, and the mixture was refluxed for 2 hours. The solvent was then distilled off and the residue was subjected to silica gel column chromatography using 0.5% methanol-chloroform as the eluent to give 0.66 g of the title compound as white crystals, m.p. 155°-157° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.Cl.[CH3:29][O:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17]([N:34]2[CH2:35][CH2:36][CH:31]([O:30][CH3:29])[CH2:32][CH2:33]2)(=[O:19])=[O:18])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: COC1CCNCC1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1CCN(S(=O)(=O)c2cc(-c3sc(NC(C)=O)nc3C)c(Br)s2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (300 mg; 0.72 mmol; 1 eq), is dissolved in anhydrous DCM (20 ml). The reaction is put under nitrogen. Triethylamine (0.5 ml; 3.61 mmol; 5 eq) and 4-methoxy-piperidine hydrochloride (314.3 mg; 3.61 mmol; 5 eq) are added successively and the reaction mixture is stirred for 30 minutes at room temperature. It is then washed with water, NH4Cl sat., brine and dried over MgSO4, affording the title compound (250 mg; 60%).
Reaction SMILES: [N:1]([C:4](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[N+]=[N-]>C1(C)C(C)=CC=CC=1>[Cl:16][C:13]1[C:12]([F:17])=[C:11]2[C:10]([CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[NH:1]2)=[CH:15][CH:14]=1
Reactant: COC(=O)C(=Cc1ccc(Cl)c(F)c1)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: COC(=O)c1cc2ccc(Cl)c(F)c2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.1 %

Procedure:
A solution of methyl 2-azido-3-(4-chloro-3-fluorophenyl)propenoate (15.08 g, 59 mmol) in xylene (200 mL) was added dropwise to stirred xylene (1 L) under reflux. The mixture was stirred for 3 h, cooled to room temperature, concentrated in vacuo and purified by column chromatography [SiO2; isopropyl ether-hexane (5:2)] to give the product (2.3 g, 17% yield) as a colourless solid: IR νmax (Nujol)/cm−1 3298, 1709, 1460, 1377, 1204 and 737; NMR δH (400 MHz, CDCl3) 3.85 (3H, s) 7.09-7.15 (1H, m) 7.21 (1H, m) 7.38 (1H, m) and 9.05 (1H, brs).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[CH:24]1([C:27]([N:29]2[C:37]3[C:32](=[CH:33][C:34]([S:38](Cl)(=[O:40])=[O:39])=[CH:35][CH:36]=3)[CH2:31][CH2:30]2)=[O:28])[CH2:26][CH2:25]1>C(Cl)Cl>[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([S:38]([C:34]2[CH:33]=[C:32]3[C:37](=[CH:36][CH:35]=2)[N:29]([C:27]([CH:24]2[CH2:25][CH2:26]2)=[O:28])[CH2:30][CH2:31]3)(=[O:39])=[O:40])[CH2:19][CH2:18]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C(C1CC1)N1CCc2cc(S(=O)(=O)Cl)ccc21
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc3c(c2)CCN3C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
Diisopropylethylamine (0.33 ml, 2.0 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (0.2 g, 1.0 mmol) in DCM (5 ml) at room temperature. To this mixture was added 1-cyclopropanecarbonyl-2,3-dihydro-1H-indole-5-sulfonyl chloride (0.29 g, 1.0 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (100 ml) and washed sequentially with HCl (1M solution, 50 ml), NaOH (1M solution, 50 ml) and brine (50 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting solid was collected by filtration, dried with diethyl ether and dried under vacuum give the title compound (0.36 g, 73% yield) as a pale yellow solid. Tr=2.02 min m/z (ES+) (M+Na+) 472.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][N:24]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][N:24]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(C(c3ccccc3)c3ccccc3)C2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)O)cn1)[C@@H]1CCN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.9 %

Procedure:
To a stirred solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl) [(3R)-1-(diphenylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (205 mg) in methanol (5 mL) was added 1N-NaOH solution (0.8 mL). The mixture was stirred at ambient temperature for 12 hours. Methanol was evaporated in vacuo and the aqueous layer was washed with diisopropyl ether. The aqueous layer was acidified by hydrochloric acid to pH 4, and the precipitate was collected and washed with water to give (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(diphenylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylic acid (161 mg) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][N:6]=1)=[O:4].[CH3:12][N:13]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[CH:31]=[C:30]([OH:32])[C:24]3[CH2:25][C:26]([CH3:29])([CH3:28])[O:27][C:23]=3[CH:22]=2)=[O:20])=[N:14]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:32][C:30]2[C:24]3[CH2:25][C:26]([CH3:28])([CH3:29])[O:27][C:23]=3[CH:22]=[C:21]([C:19](=[O:20])[NH:18][C:15]3[CH:16]=[CH:17][N:13]([CH3:12])[N:14]=3)[CH:31]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(F)cn1
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C)(C)C3)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2cc(C(=O)Nc3ccn(C)n3)cc3c2CC(C)(C)O3)cn1
Temperature: 160 °C
Yield: 56.4 %

Procedure:
A mixture of 5-fluoro-pyridine-2-carboxylic acid methyl ester (179a) (342 mg, 2.20 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (633 mg, 2.20 mmol), and Cs2CO3 (1.44 g, 4.40 mmol) in DMF was heated to 160° C. in a microwave for 30 min, cooled to room temperature, quenched with H2O, and extracted with 3×EtOAc. The combined organic layer was washed with 2×H2O, dried over Na2SO4 and concentrated. The residue was purified by Biotage column chromatography with 75-90% EtOAc in hexanes to give a white solid (524 mg, 56% yield). 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=3.03 Hz, 2 H) 8.13 (d, J=8.59 Hz, 1 H) 7.22-7.36 (m, 2 H) 7.06 (d, J=5.05 Hz, 2 H) 6.77 (d, J=2.27 Hz, 1 H) 4.01 (s, 3 H) 3.78 (s, 3 H) 2.89 (s, 2 H) 1.49 (s, 6 H); LCMS for C22H22N4O6 m/z 423.20 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([O:8]S(C)(=O)=O)[CH2:5][O:6][CH3:7].[C:13]1(O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][CH2:3][CH:4]([CH2:5][O:6][CH3:7])[O:8][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COCC(COC)OS(C)(=O)=O
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC(COC)Oc1ccccc1
Temperature: 90 °C

Procedure:
A stirred mixture of 2.0 g of methanesulfonic acid 2-methoxy-1-methoxymethyl-ethyl ester, 1.4 g of phenol and 2,8 g of powdered potassium carbonate in 50 mL of dry N,N-dimethylformamide was heated at 90° C. for 24 hours. After cooling, water was added at room temperature and the mixture extracted with diethyl ether. The combined ether extracts were washed with aqueous sodium hydroxide (2 N) and water, dried (sodium sulfate) and concentrated. The crude product (1.0 g) was used in the next step without further purification. EI-MS: 198 (M+).
Reaction SMILES: [F:1][CH:2]([F:39])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>>[F:39][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]([CH:27]3[CH2:32][CH2:31][N:30]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:29][CH2:28]3)[CH2:21][CH2:22][CH2:23][N:24]([CH3:25])[CH3:26])[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN(C)C)C2CCNCC2)n1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN(C)C)C2CCN(S(C)(=O)=O)CC2)n1
Yield: 99 %

Procedure:
Reaction of N1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N3,N3-dimethyl-N1-(4-piperidinyl)-1,3-propanediamine with methanesulfonyl chloride gave N1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N3,N3-dimethyl-N1-[1-(methylsulfonyl)-4-piperidinyl]-1,3-propanediamine in 99% yield.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:19]([CH:29]([NH2:31])[CH3:30])=[CH:20][C:21]([CH3:28])=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)[CH:15]=[CH:16][CH:17]=1.C(N(CC)C(C)C)(C)C>C(O)C>[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:19]([CH:29]([NH:31][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)[CH3:30])=[CH:20][C:21]([CH3:28])=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)[CH:15]=[CH:16][CH:17]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: Cc1cc(C(C)N)c(-c2cccc(F)c2)c2ncccc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c2ncccc12

Procedure:
A mixture of 6-bromo-9H-purine (0.0712 g, 0.358 mmol), 1-[8-(3-fluorophenyl)-5-methylquinolin-7-yl]ethanamine (0.050 g, 0.18 mmol), and N,N-diisopropylethylamine (0.0623 mL, 0.358 mmol) in ethanol (0.6 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resulting residue was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the product. LCMS calculated for C23H20FN6 (M+H)+: m/z=399.2; Found: 399.0.