Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:12]2N=CC=[CH:16][C:11]=2[N:10]=N1.[NH2:25][C:26]1[N:27]=[C:28]([C:38]2[CH:43]=[C:42]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:41]([Cl:52])=[CH:40][C:39]=2[Cl:53])[C:29]2[CH:34]=[C:33]([C:35]([OH:37])=O)[S:32][C:30]=2[N:31]=1.C(N)(C)C>CN(C=O)C>[CH:11]([NH:10][C:35]([C:33]1[S:32][C:30]2[N:31]=[C:26]([NH2:25])[N:27]=[C:28]([C:38]3[CH:43]=[C:42]([O:44][CH2:45][C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:41]([Cl:52])=[CH:40][C:39]=3[Cl:53])[C:29]=2[CH:34]=1)=[O:37])([CH3:16])[CH3:12]
Reactant: Nc1nc(-c2cc(OCc3ccccc3)c(Cl)cc2Cl)c2cc(C(=O)O)sc2n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)N
Product: CC(C)NC(=O)c1cc2c(-c3cc(OCc4ccccc4)c(Cl)cc3Cl)nc(N)nc2s1
Temperature: 60 °C

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.176 g; 3.07 mmol) was added to 2-Amino-4-(5-benzyloxy-2,4-dichloro-phenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid.2NaCl (1.33 g; 2.38 mmol) then DMF (25 ml) was added to afford a turbid brown solution. Isopropylamine (1.01 ml; 11.9 mmol) was added and reaction mixture was heated at 60° C. (oil bath temperature) for 18 hours. Reaction mixture was allowed to cool to room temperature and DMF was removed in vacuo. The residue was partitioned between ethyl acetate (200 ml) and water (200 ml). The phases were separated and the organic phase was washed with saturated aqueous sodium chloride solution (200 ml) the dried over anhydrous sodium sulphate, filtered and the filtrate solvents removed in vacuo to afford a yellow solid. The crude product was purified by flash chromatography on silica gel (50 g IST Flash Si cartridge) eluting with a solvent gradient of 20 to 50% ethyl acetate in hexane. This affords product as a colourless solid (0.612 g; 53%)
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][NH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([NH:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:26][CH2:25]1
Reactant: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)O)cn1
Reactant: NC1CC1
Product: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)NC2CC2)cn1
Yield: 89 %

Procedure:
As described for example 162b, 6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinic acid (200 mg, 0.65 mmol) was converted using cyclopropylamine instead of ethanolamine to the title compound (SiO2, heptane:ethyl acetate=70:30 to 0:100, 201 mg, 89%) which was obtained as a white solid. MS: m/e=349.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][C@@H:19]2[C@H:10]([NH:11][CH2:12][C:13]3[C:14]([CH3:21])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:20][C@@H:19]2[C@H:10]([N:11]([C:36]([NH:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])[CH2:12][C:13]3[C:14]([CH3:21])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1cccc2c1CN[C@@H]1CN(Cc3ccccc3)C[C@@H]21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc2c1CN(C(=O)Nc1ccccc1)[C@@H]1CN(Cc3ccccc3)C[C@@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (±)-trans-2-benzyl-6-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,4-c]isoquinoline from Example 105, Part A (28 mg, 0.1 mmol) in 1 mL of methylene chloride was added triethylamine (0.015 mL, 0.11 mmol) and phenylisocyanate (0.012 mL, 0.11 mmol). The reaction was allowed to stir at ambient temperature for 2 h. The solution was concentrated and purified (ISCO, elution with 0-5% methanol/methylene chloride) to afford 23 mg of the title compound of Example 109 as a white solid. 1H NMR (CDCl3): δ 7.40-7.22 (m, 9H), 7.19-7.15 (m, 1H), 7.14-7.10 (m, 1H), 7.07-7.02 (m, 1H), 6.92-6.88 (m, 1H), 6.28 (s, 1H), 5.19 and 4.22 (ABq, 2H), 3.92 (ABq, 2H), 3.56-3.50 (m, 1H), 3.48-3.40 (m, 2H), 3.33-3.27 (m, 1H), 3.13 (app t, 1H), 3.02 (app t, 1H), 2.35 (s, 3H). LRMS (ESI): 398.3 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.N.[N:13]#[C:14][NH2:15]>O>[NH:1]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)[C:14]([NH2:15])=[NH:13]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: N#CN
Agent: N
Solvent: O
Product: N=C(N)NCc1ccc(C(=O)O)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 1.51 g (10.0 mmol) of 4-aminomethylbenzoic acid, 20 ml of water, 2.0 ml of 28% aqueous ammonia and 1.00 g (23.8 mmol) of cyanamide was stirred at 60° C. overnight. The white precipitate thus formed was taken by the filtration, washed with water and dried to obtain the title compound.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:8]#[C:9]Br.CCCCC>C(N(CC)CC)C.C(OCC)C>[O:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]#[N:8]
Reactant: N#CBr
Reactant: Oc1ccccc1
Solvent: CCCCC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: N#COc1ccccc1

Procedure:
To a oven dried 500 mL 3-neck round bottom flask equipped with a overhead stirring, a septa, a thermocouple and the nitrogen inlet, phenol (20.0 g, 0.210 mol), diethyl ether (Et2O, 290 mL) and cyanic bromide (BrCN, 23.0 g, 0.210 mol, 1.0 equiv) were added at room temperature. The resulting solution was cooled down to 0-3° C. before triethylamine (TEA, 61.9 mL, 0.442 mol, 2.1 equiv) was added dropwise via syringe over 25 min. The addition of triethylamine to reaction mixture was mildly exothermic and the reaction temperature went up to as high as 15° C. After addition of triethylamine, the reaction mixture became a white slurry which was stirred vigorously at 0° C. for 2 h at 5-15° C. When the reaction was deemed complete as confirmed by TLC and LCMS, the reaction mixture was diluted with pentane (150 mL, 1.30 mol). The precipitated triethylamine hydrochloride was filtered off and the salt was washed with diethyl ether and pentane (1 to 1 by volume, 200 mL). The filtrate was then concentrated under reduced pressure to remove the majority of the solvent, and the residue, which contains the crude cyanatobenzene (6), was directly used in the subsequent reaction without further purification assuming the theoretical yield.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[C:15](O)[N:14]3[N:18]=[CH:19][CH:20]=[C:13]3[N:12]=2)[CH2:7][CH2:6]1)=[O:4].CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:32]>>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[C:15]([Cl:32])[N:14]3[N:18]=[CH:19][CH:20]=[C:13]3[N:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCC(c2cc(O)n3nccc3n2)CC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COC(=O)C1CCC(c2cc(Cl)n3nccc3n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
4-(7-Hydroxy-pyrazolo[1,5-a]pyrimidin-5-yl)-cyclohexanecarboxylic acid methyl ester (10.6 g), N,N-dimethylaniline (15.0 ml) and POCl3 (120 mL) were mixed and stirred at room temperature for 18 hours. The solution is reduced in vacuo and cooled to 0° C. in ice bath. The reaction is then quenched with sat. NaHCO3(aq) and extracted with DCM (100 mL×3). The combined organics are dried with Na2SO4 and the solvent removed in vacuo. The resulting oil was purified via silica gel column on 20% to 100% ethyl acetate in hexanes gradient to yield the titled compound (2.5 g, 32% over three steps). LC-MS: 294 [M+H].
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1([F:37])[O:35][C:17]2=[CH:18][C:19]3[N:23]=[C:22]([S:24][CH2:25][C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][N:27]=4)[NH:21][C:20]=3[CH:34]=[C:16]2[O:15][CH:14]1[F:36].C(N(CC)CC)C>C(OCC)(=O)C.C(Cl)Cl>[F:37][C:13]1([F:12])[O:35][C:17]2=[CH:18][C:19]3[N:23]=[C:22]([S:24]([CH2:25][C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][N:27]=4)=[O:6])[NH:21][C:20]=3[CH:34]=[C:16]2[O:15][CH:14]1[F:36]
Reactant: COc1ccnc(CSc2nc3cc4c(cc3[nH]2)OC(F)C(F)(F)O4)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccnc(CS(=O)c2nc3cc4c(cc3[nH]2)OC(F)C(F)(F)O4)c1
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
A solution of 0.81 g of approximately 85% pure m-chloroperoxybenzoic acid in 20 ml of ethyl acetate is added dropwise to a solution of 1.5 g of 6,6,7-trifluoro-6,7-dihydro-2-[(4-methoxy-2-pyridyl)methylthio]-1H-[1,4]-dioxino[2,3-f]benzimidazole in 50 ml of methylene chloride at -20° C. to -15° C. in the course of 30 min., with stirring, and stirring is continued at this temperature for 30 min. 0.66 ml of triethylamine is added and the organic solution is washed with 1M potassium bicarbonate solution and then with water, dried with magnesium sulfate and concentrated in vacuo. The residue is allowed to crystallize from ether. 1.2 g (77%) of the title compound of m.p. 166°-167° C. (decomposition), from ethyl acetate, are obtained.
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].Cl[C:6]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:9]=[C:8]([C:21]2[CH:30]=[CH:29][C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[N:22]=2)[N:7]=1>C(O)C>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][C:10]1[N:9]=[C:8]([C:21]2[CH:30]=[CH:29][C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[N:22]=2)[N:7]=[C:6]([O:3][CH2:2][CH3:1])[CH:11]=1
Reactant: Clc1ccc(Cc2cc(Cl)nc(-c3ccc4c(n3)CCCC4)n2)c(Cl)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(Cc2ccc(Cl)cc2Cl)nc(-c2ccc3c(n2)CCCC3)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
1.95 g (0.006 mol) of a 21% strength solution of sodium ethylate in ethanol were added dropwise to the solution of 2.0 g (0.005 mol) of 4-chloro-6-(2,4-dichlorobenzyl)-2-(5,6,7,8-tetrahydroquinolin-2-yl)-pyrimidine in 50 ml of absolute ethanol. The mixture was stirred for 16 hours at 25° C., and the solvent was distilled off in vacuo. The residue was dissolved in water, the solution was extracted three times using dichloromethane, and the organic phase was dried (MgSO4) and concentrated. Drying in vacuo gave 1.7 g (85%) of a white solid of melting point 98° C. to 100° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH2:4][CH2:3]1.[CH:19]1([NH:25][C:26](=[O:29])[CH2:27]Cl)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[C:11]([CH2:10][CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH2:27][C:26]([NH:25][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:29])[CH2:3][CH2:4]1)(=[O:12])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(CCl)NC1CCCCC1
Reactant: NC1CCN(CCCC(=O)c2ccccc2)CC1
Product: O=C(CNC1CCN(CCCC(=O)c2ccccc2)CC1)NC1CCCCC1

Procedure:
Using a procedure analogous to Example 1 4-amino-1-(4-phenyl-4-oxobutyl) piperidine may be reacted with N-cyclohexylchloracetamide to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=4[Cl:31])[CH2:17][CH2:16]3)=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.C1N=CN([C:37]([N:39]2[CH:43]=[N:42]C=C2)=[O:38])C=1.C[N:45](C=O)C>>[C:43]([NH:39][C:37]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=4[Cl:31])[CH2:19][CH2:20]3)=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1)=[O:38])(=[NH:42])[NH2:45]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1ccc(N2CCN(c3ncc(-c4cccc(CN)c4)cn3)CC2)c(Cl)c1
Reactant: CN(C)C=O
Product: COC(=O)c1ccc(N2CCN(c3ncc(-c4cccc(CNC(=O)NC(=N)N)c4)cn3)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-(4-{5-[3-(aminomethyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-3-chlorobenzoate (207 mg) was mixed with DMF (5 ml), and CDI (154 mg) was added thereto at 0° C., followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and EtOAc and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with DMF (5 ml), and guanidine hydrochloride (50 mg) and DBU (204 mg) were added thereto, followed by stirring at 70° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, water was then added thereto, and the insoluble matter was collected by filtration. The obtained solid was purified by basic silica gel column chromatography (CHCl3/MeOH) to obtain methyl 4-{4-[5-(3-{[(carbamimidoylcarbamoyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}-3-chlorobenzoate (208 mg).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[C:13](OC)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].C(O)(=O)C>C1COCC1.O>[CH3:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)C(C)(C)C
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)C(C)(C)C)OC
Temperature: -78 °C

Procedure:
Dimethyl methylphosphonate (13.6 g, 0.11 mol) was dissolved in anhydrous THF (100 ml) under argon atmosphere. To the solution stirred at -78° C. was added dropwise n-butyl lithium (1.61N, 68.3 ml, 0.11 mol) over 30 minutes, and then a solution of commercially available methyl pivalate (5.0 g, 0.043 mol) in anhydrous THF (10 ml) was also added dropwise over 30 minutes. The reaction mixture was warmed to room temperature. Under ice cooling, acetic acid (7 ml) and water (10 ml) were added. After concentrating, water (20 ml) was added to the resulting residue. The mixture was extracted with ethyl acetate (50 ml×2), and the ethyl acetate layers were washed with water (20 ml×1) and with brine (20 ml×1), dried over anhydrous soldium sulfate, concentrated. Distillation of the residue gave dimethyl 3,3-dimethyl-2-oxo-butylphosphonate as a colorless clear oil (6.53 g, 0.031 mol, 72.6%, b.p.=90°-93° C./0.35 mmHg). The structure was identified by the following data.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.Cl.[NH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([OH:38])[CH2:34][CH2:33]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:31][C@H:32]2[CH2:37][CH2:36][C@H:35]([OH:38])[CH2:34][CH2:33]2)=[O:17])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)N[C@H]2CC[C@H](O)CC2)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (114 mg, 0.271 mmol) obtained in Example 12 in methylene chloride (3 ml), trans-4-aminocyclohexanol hydrochloride (49 mg, 0.325 mmol), 1-hydroxybenzotriazole (37 mg, 0.271 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (62 mg, 0.325 mmol) and 4-methylmorpholine (71 μl, 0.650 mmol) were added, and the mixture was stirred for 17 hours at room temperature. Ethyl acetate was added to the reaction solution, and the mixture was washed sequentially with saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with methanol:methylene chloride (=1:40) was concentrated under reduced pressure, to obtain the title compound (129 mg, 0.249 mmol, 92%) as an amorphous substance.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:27]([O:29][CH2:30][CH3:31])=[CH2:28])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>[CH2:30]([O:29][C:27]([C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1)=[CH2:28])[CH3:31]
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
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: C=C(OCC)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.6 %

Procedure:
To a degassed solution of 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (2.50 g, 5.86 mmol) in DMF (20 mL) was added Pd(Ph3P)4 (0.542 g, 0.469 mmol). The solution was stirred for 20 min at rt, and then tributyl(1-ethoxyvinyl)stannane (2.117 g, 5.86 mmol) was added. The mixture was heated at 100° C. until LC-MS showed the reaction was complete. The reaction mixture was filtered through celite and the filtrate was washed with water, dried over Na2SO4, and concentrated. The resulting crude product was purified by column chromatography with gradient hexanes:EtOAc to give 1.2 g (62%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ ppm 9.19 (s, 1H), 8.94 (m, 1H), 8.20 (m, 1H), 7.99 (s, 1H), 7.89 (d, 1H), 7.55 (m, 1H), 6.12 (s, 2H), 5.61 (d, 1H), 4.61 (d, 1H), 4.05 (q, 2H), 1.51 (t, 3H). LCMS (method B): [MH]+=360, tR=2.40 min.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH:13]=[C:14]1[NH:18][C:17](=[O:19])[CH2:16][S:15]1>>[NH:13]=[C:14]1[NH:18][C:17](=[O:19])[C:16](=[CH:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)[S:15]1
Reactant: N=C1NC(=O)CS1
Reactant: O=Cc1ccc2ncccc2c1
Product: N=C1NC(=O)C(=Cc2ccc3ncccc3c2)S1

Procedure:
Following the general method as outlined in Example 1, starting from quinoline-6-carbaldehyde (intermediate 5) and 2-imino-1,3-thiazolidin-4-one, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][C@@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12][CH2:11]2)[N:3]=1.[CH3:19][C:20]#[N:21].O>>[NH2:1][C:2]1[N:7]=[C:6]([N:21]2[CH2:12][CH2:11][CH2:10][CH2:15][CH2:19][CH2:20]2)[N:5]=[C:4]([NH:9][C@@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12][CH2:11]2)[N:3]=1
Reactant: CC#N
Reactant: Nc1nc(Cl)nc(N[C@H]2CC[C@@H](C(=O)O)CC2)n1
Solvent: O
Product: Nc1nc(N[C@H]2CC[C@@H](C(=O)O)CC2)nc(N2CCCCCC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of crude cis-4-(4-amino-6-chloro-1,3,5-triazin-2-ylamino)cyclohexanecarboxylic acid (˜0.46 mmol) in CH3CN/H2O (5 ml/1 ml) was added hexamethyleneimine (240 μl, ˜5 equivalents). The reaction mixture was stirred at room temperature overnight. The reaction solution was condensed and the crude product was purified by RP-HPLC (Luna 5μ C8(2), 100×21 mm, 15-65% CH3CN/H2O, 0.1% TFA, 18 min) to give the product (65 mg). MS (ES+): m/e 335.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH3:34])=[CH:27][CH:26]=4)[CH2:23][CH2:22][C:21]([C:35]([O:37]C)=[O:36])=[CH:20][C:19]=3[CH:39]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][CH3:34])=[CH:29][CH:30]=4)[CH2:23][CH2:22][C:21]([C:35]([OH:37])=[O:36])=[CH:20][C:19]=3[CH:39]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2ccc(OCCC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3c2ccc(OCCC)cc2)cc1
Temperature: 50 °C
Yield: 86.3 %

Procedure:
In methanol (50 ml) and THF (50 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.25 g). To the solution was added 1N sodium hydroxide solution (5 ml), and the mixture was heated at 50° C. overnight, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.21 g) as yellow crystals.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C@@H:9]([CH3:15])[C:10](OCC)=[O:11])=[CH:6][CH:5]=1>C(O)C>[Br:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C@@H:9]([CH3:15])[CH2:10][OH:11])=[CH:6][CH:5]=1
Reactant: CCOC(=O)[C@H](C)Oc1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@@H](CO)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Sodium borohydride (1.15 g) was added to a solution of (2S)-2-(4-bromophenoxy)propanoic acid, ethyl ester (7.5 g, Example 15a)) in ethanol (20 ml) at 5° C. The resulting solution was allowed to warm to room temperature and was stirred for 10 hours before being concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 ml) and 2N hydrochloric acid (50 ml). The mixture was extracted into ethyl acetate and the combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The product was used directly in the next step without further purification (6.32 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH3:18])[CH2:4][CH2:3]1.O.NN>C(O)C.[Ni].O>[CH3:18][O:17][C:9]1[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:8]=1[N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1
Reactant: COc1ccc([N+](=O)[O-])cc1N1CCN(C)CC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(N)cc1N1CCN(C)CC1
Yield: 52967 %

Procedure:
To a solution of the product of step (a) (5.07 g) in ethanol (70 ml) was added a paste of Raney Nickel in water (2 g). To the warmed suspension was added, with constant agitation, hydrazine hydrate (5 ml) dropwise during 20 min with occasional warming. After the main effervescence had ceased, the suspension was heated for 15 min and then filtered with the aid of ethanol under nitrogen. The residues were kept moist and washed with ethanol and the combined filtrate and washings were evaporated to dryness with the aid of ethanol. The dark residue was re-evaporated with ethanol (20 ml), resuspended in ether (40 ml) and the mixture filtered. The residue was washed with ether and dried to give a solid consisting of the title compound (2,365 g)
Reaction SMILES: O[CH2:2][C:3]1[C:11]2[O:10][CH2:9][O:8][C:7]=2[CH:6]=[CH:5][C:4]=1CO.S(Cl)([Cl:16])=O.[CH2:18]([Cl:20])Cl>>[Cl:16][CH2:2][C:3]1[C:11]2[O:10][CH2:9][O:8][C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:18][Cl:20]
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2c(c1CO)OCO2
Reactant: ClCCl
Product: ClCc1ccc2c(c1CCl)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 0° C. solution of (4-hydroxymethyl-1,3-benzodioxol-5-yl)methanol (8.55 g, 47.0 mmoles) from Example 58A in anhydrous methylene chloride (50 mL) was treated dropwise with thionyl chloride (17 mL, 235 mmoles). The mixture was stirred one hour at room temperature and then concentrated under reduced pressure to afford the title compound. MS (DCI) m/z 218 (M+H)+.