Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].C([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([CH3:36])[C:18]3[C:27]([CH:28]=2)=[S+:26][C:25]2[C:20](=[C:21]([CH3:35])[CH:22]=[C:23]([N:29]([CH3:34])[CH2:30][CH2:31][CH2:32][CH3:33])[CH:24]=2)[N:19]=3)[CH2:11][CH2:10]1)(OC(C)(C)C)=O.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([O-:41])=[O:40].[N:12]1([C:15]2[CH:16]=[C:17]([CH3:36])[C:18]3[C:27]([CH:28]=2)=[S+:26][C:25]2[C:20](=[C:21]([CH3:35])[CH:22]=[C:23]([N:29]([CH3:34])[CH2:30][CH2:31][CH2:32][CH3:33])[CH:24]=2)[N:19]=3)[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1
Reactant: CCCCN(C)c1cc(C)c2nc3c(C)cc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3[s+]c2c1
Reactant: O=C(O)C(F)(F)F
Agent: [I-]
Solvent: ClCCl
Product: CCCCN(C)c1cc(C)c2nc3c(C)cc(N4CCNCC4)cc3[s+]c2c1
Product: O=C([O-])C(F)(F)F

Procedure:
A solution of 3-(4-Boc-piperazin-1-yl)-7-(methyl(n-butyl)amino)-1,9-dimethylphenothiazin-5-ium iodide (25 mg) in dichloromethane (5 mL) and trifluoroacetic acid (2 mL) was stirred for 4 h at room temperature. The resulting mixture was concentrated to dryness, rinsed out by toluene (3×10 mL) and dried under vacuum to provide the title compound.
Reaction SMILES: [CH:1]1([NH:7][CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16]>CN(C=O)C>[CH:1]1([N:7]([CH3:8])[CH2:22][C:21]2[CH:24]=[CH:25][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CNC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc([N+](=O)[O-])cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
In DMF (50 ml) was dissolved N-cyclohexyl-N-methylamine (12.5 g, 0.11 mol), and to the solution were added potassium carbonate (27.6 g, 0.20 mol) and 4-nitrobenzylbromide (21.6 g, 0.10 mol). The mixture was stirred at room temperature for 5 hours. Under reduced pressure, the reaction mixture was concentrated. To the residue was added ethyl acetate, and the mixture was extracted with water. The ethyl acetate layer was washed with saturated sodium chloride solution, dried with MgSO4 and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give N-cyclohexyl-N-methyl-N-(4-nitrobenzyl)amine (24.8 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:22]1([NH2:26])[CH2:25][CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([NH:26][CH:22]3[CH2:25][CH2:24][CH2:23]3)=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)O)c3)nc12
Reactant: NC1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)NC4CCC4)c3)nc12

Procedure:
Following the same reaction and purification procedure as above, the acid 3 (50 mg, 0.18 mmol) was reacted with cyclobutanamine (CAS-2516-34-9) (0.03 mL, 0.35 mmol), HATU (103 mg, 0.35 mmol) and DIPEA (0.15 mL, 0.88 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-cyclobutyl-5-fluorobenzamide 6. LC/MS (ESI+): m/z 338 (M+H). 1H NMR (400 MHz, DMSO) δ 8.84 (d, J=7.3 Hz, 1H), 8.63 (d, J=10.3 Hz, 1H), 8.55 (dd, J=7.6, 5.1 Hz, 2H), 8.47-8.40 (m, 1H), 8.29 (d, J=12.0 Hz, 1H), 8.19 (dd, J=15.7, 10.5 Hz, 1H), 8.04 (s, 1H), 7.73 (d, J=9.2 Hz, 1H), 4.47 (dq, J=15.8, 7.9 Hz, 1H), 2.36-2.21 (m, 2H), 2.21-2.03 (m, 2H), 1.84-1.61 (m, 2H).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2C(=O)[N:16]([N:19]=[CH:20][CH:21]([CH3:23])C)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.[CH3:29][OH:30].[BH4-].[Li+].Cl>O1CCCC1.O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:29](=[O:30])[N:16]([NH:19][CH2:20][CH2:21][C:23]3[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=3)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CO
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1NCCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product of Example 269A (0.046 g, 0.10 mmol) in tetrahydrofuran (5 mL) and methanol (0.005 mL, 0.12 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.06 mL, 0.12 mmol). The reaction was stirred at 25° C. for 3 hour, acidified with 1M hydrochloric acid a pH of approximately 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 99:1 dichloromethane/methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.26 (m, 3 H) 4.49 (m, 1 H) 5.90 (m, 1 H) 7.20 (d, J=8.09 Hz, 1 H) 7.27 (t, J=8.46 Hz, 2 H) 7.30 (m, 5 H) 7.54 (m, 2 H) 7.66 (d, J=8.09 Hz, 1 H) 15.93 (s, 1 H). MS (ESI−) m/z 465 (M−H)−.
Reaction SMILES: [C:1]1([C:7]([C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)([C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[N:30]5[N:31]=[C:32]([CH2:34][CH2:35][CH3:36])[N:33]=[C:29]5[C:28](CC5C=CC(C6C=CC=CC=6C6N(C(C7C=CC=CC=7)(C7C=CC=CC=7)C7C=CC=CC=7)N=NN=6)=CC=5)=[C:27]4[CH2:74][CH3:75])=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:88]([C:90]1[CH:97]=[C:96]2[N:92]([N:93]=[C:94]([CH2:135][CH2:136][CH3:137])[N:95]2CC2C=CC(C3C=CC=CC=3C3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)=CC=2)[N:91]=1)[CH3:89].C(C1C(CC2C=CC(C3C=CC=CC=3C3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)=CC=2)=C2N(N=C(CCC)N2)N=1)C.C(C1N(CC2C=CC(C3C=CC=CC=3C3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)=CC=2)N2C(C=1)=NC(CCC)=N2)C>>[CH2:74]([C:27]1[N:26]([CH2:25][C:22]2[CH:21]=[CH:20][C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[N:8]([C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([C:82]4[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=4)[C:76]4[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=4)[N:9]=[N:10][N:11]=3)=[CH:24][CH:23]=2)[N:30]2[C:29]([CH:28]=1)=[N:33][C:32]([CH2:34][CH2:35][CH3:36])=[N:31]2)[CH3:75].[CH2:88]([C:90]1[CH:97]=[C:96]2[N:92]([N:93]=[C:94]([CH2:135][CH2:136][CH3:137])[NH:95]2)[N:91]=1)[CH3:89]
Reactant: CCCc1nc2c(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c(CC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)n2n1
Reactant: CCCc1nn2nc(CC)cc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCc1nc2cc(CC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)n2n1
Agent: CCCc1nn2nc(CC)c(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c2[nH]1
Product: CCCc1nn2nc(CC)cc2[nH]1

Procedure:
In the same manner as described in Example 38, 0.49 g of 5,7-bis[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-6-ethyl-2-propyl-5 H-pyrazolo[1,5-b][1,2,4]triazole (compound 47a), 2.30 g of 6-ethyl-2-propyl-1-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-pyrazolo[1,5-b][1,2,4]triazole (compound 47b), 0.18 g of 6-ethyl-2-propyl-7-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-pyrazolo[1,5-b][1,2,4]triazole (compound 47c) and 2.28 g of 6-ethyl-2-propyl-5-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole (compound 47d) were obtained from 2.17 g of 6-ethyl-2-propyl-1H-pyrazolo[1,5-b][1,2,4]triazole.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[O:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:26](=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][C:28]=1[C:33]([F:36])([F:35])[F:34].Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:26]([C:27]2[C:28]([C:33]([F:36])([F:34])[F:35])=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:37])=[CH:11][C:10]=1[O:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)c1cccnc1C(F)(F)F
Reactant: COc1cc(Br)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2cccnc2C(F)(F)F)ccc1OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 4-benzyloxy-3-methoxy-bromobenzene (2.0 g, 6.82 mmol) in tetrahydrofuran (50 mL) at −78° C. under argon was added 2 N butyllithium solution in hexanes (3.75 mL, 7.5 mmol) dropwise. The resulting mixture was allowed to stir for one hour, whereupon a solution of N-methoxy-N-methyl-2-trifluoromethyl-nicotinamide (1.76 g, 7.5 mmol) in tetrahydrofuran (20 mL) was added dropwise. The mixture was then allowed to reach room temperature over two hours, then poured onto cold 2 N aqueous hydrochloric acid (150 mL). The mixture was extracted with diethylether, and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate and filtered. Evaporation of the solvent left a brown oil that was chromatographed over silica gel (petroleum ether/ethyl acetate, 2:1) to give (4-benzyloxy-3-methoxy-phenyl)-(2-trifluoromethyl-pyridin-3-yl)-methanone, 1.72 g (65%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[NH:9][C:10]([C:12](=[O:23])[NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:22][CH2:21]4)[CH2:16][CH2:15]3)=[N:11][C:7]=2[CH:6]=1)=[O:4].Br[CH2:27][C:28]1[O:32][N:31]=[C:30]([C:33]2[S:34][C:35]([Cl:38])=[CH:36][CH:37]=2)[CH:29]=1.CC#N.O>C(O)=O>[Cl:38][C:35]1[S:34][C:33]([C:30]2[CH:29]=[C:28]([CH2:27][N:9]3[C:8]4[CH:24]=[CH:25][C:5]([C:3]([OH:2])=[O:4])=[CH:6][C:7]=4[N:11]=[C:10]3[C:12](=[O:23])[NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:22][CH2:21]4)[CH2:16][CH2:15]3)[O:32][N:31]=2)=[CH:37][CH:36]=1.[Cl:38][C:35]1[S:34][C:33]([C:30]2[CH:29]=[C:28]([CH2:27][N:11]3[C:7]4[CH:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:25]=[CH:24][C:8]=4[N:9]=[C:10]3[C:12](=[O:23])[NH:13][CH:14]3[CH2:15][CH2:16][N:17]([CH:20]4[CH2:21][CH2:22]4)[CH2:18][CH2:19]3)[O:32][N:31]=2)=[CH:37][CH:36]=1
Reactant: COC(=O)c1ccc2[nH]c(C(=O)NC3CCN(C4CC4)CC3)nc2c1
Reactant: Clc1ccc(-c2cc(CBr)on2)s1
Solvent: CC#N
Solvent: O=CO
Solvent: O
Product: O=C(O)c1ccc2c(c1)nc(C(=O)NC1CCN(C3CC3)CC1)n2Cc1cc(-c2ccc(Cl)s2)no1
Product: O=C(O)c1ccc2nc(C(=O)NC3CCN(C4CC4)CC3)n(Cc3cc(-c4ccc(Cl)s4)no3)c2c1

Procedure:
1-[3-(5-Chloro-thiophen-2-yl)-isoxazol-5-ylmethyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid and 3-[3-(5-Chloro-thiophen-2-yl)-isoxazol-5-ylmethyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-3H-benzoimidazole-5-carboxylic acid were prepared by a procedure according to example 81 starting from 240 mg (0.70 mmol) 2-(1-Cyclopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid methyl ester and 201.3 mg (0.70 mmol) 5-bromomethyl-3-(5-chloro-thiophen-2-yl)-isoxazole. Hydrolysis of the resulting esters and purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave the title compounds as their formiates in form of white amorphous solids. Structural assignment of both isomers was achieved by NOE-spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH3:23])=[O:21].Cl>ClCCl>[CH3:23][O:22][C:20](=[O:21])[NH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1
Reactant: COC(=O)Cl
Reactant: COc1cccc2sc(N)nc12
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Nc1nc2c(OC)cccc2s1
Reaction time: 0.17 h

Procedure:
2-Amino-4-methoxybenzothiazol (23.6 g, 131 mmol) and pyridine (12.6 ml, 157 mmol) in dichloromethane (230 ml) are slowly treated with methyl chloroformate (10.6 ml, 137 mmol) at 0° C. After 10 minutes, further methyl chloroformate (1.0 ml, 13 mmol) and pyridine (1.0 ml, 12 mmol) are added. After 10 minutes, the mixture is poured into 200 ml 1M aqueous hydrochloric acid, the organic layer is separated, diluted with dichloromethane (250 ml) and washed with brine (50 ml). The organic phase is dried and the solvent evaporated in vacuo. 31.0 g (99.4%) white solid. MS: m/e=238 (M+H+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[O:7]([CH2:14][C:15]([NH:17][C@H:18]1[C:21](=[O:22])[N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])[C@H:19]1[C:34]([O:36]C)=[O:35])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1.O>[O:7]([CH2:14][C:15]([NH:17][C@H:18]1[C:21](=[O:22])[N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])[C@H:19]1[C:34]([OH:36])=[O:35])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)[C@H]1[C@@H](NC(=O)COc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@H](NC(=O)COc3ccccc3)[C@@H]2C(=O)O)c(OC)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of anhydrous K2CO3 (249 mg, 1.8 mmol) in tetrahydrofuran (8 ml) and water (12 ml) is degassed with argon and then methyl cis-3-phenoxyacetamido-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate (150 mg, 0.35 mmol) is added. The reaction is stirred 1.5 hours at room temperature, the organic solvent is evaporated and the aqueous layer is acidified and extracted with methylene chloride. The dried extracts are evaporated to give a solid which is recrystallized from ethyl acetate-hexane to give pure cis-3-phenoxyacetamido-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylic acid, mp 169°-170°(d).
Reaction SMILES: Br[C:2]1[C:3]([F:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>O.C1COCC1.C(OCC)(=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:3]([F:9])=[N:4][CH:5]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Fc1ncc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ncc(Cl)cc1-c1ccc(Cl)cc1
Yield: 95.7 %

Procedure:
A mixture of 3-bromo-5-chloro-2-fluoro-pyridine, (CAN 884494-87-5; 2.0 g, 9.50 mmol), 4-chlorophenylboronic acid (CAN 1679-18-1; 1.5 g, 9.50 mmol); tetrakis(triphenylphoshine)-palladium (0.55 g, 0.48 mmol) and potassium carbonate (2.6 g, 19 mmol) in water (50 mL) and THF (50 mL) was heated at reflux temperature for 18 h. The reaction mixture was cooled, diluted with ethyl acetate, phases were separated and the water phase was extracted with ethyl acetate. The organic phases were pooled, dried with MgSO4 and the solvent was removed in vacuo. The residue was purified by column chromatography (on silica gel with a gradient of heptane to heptane:ethyl acetate=9:1 to yield the title product (2.2 g, 95%) as white solid; MS (ESI): 241.0 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:9]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8][N:7](CC2C=CC=CC=2)[CH2:6]1)=[O:4].[H][H].Cl.C1C2(CCCCC2)C(C(O)=O)CN1.N1C=CC=CC=1.[CH2:44]([O:51][C:52](Cl)=[O:53])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CO.ClCCl>[CH3:1][O:2][C:3]([CH:5]1[C:9]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8][N:7]([C:52]([O:51][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:53])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(Cc2ccccc2)CC12CCCCC2
Reactant: O=C(Cl)OCc1ccccc1
Reactant: [H][H]
Agent: Cl
Agent: O=C(O)C1CNCC12CCCCC2
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CC12CCCCC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of (4) (3 g; 10.44 mmol) and 10% Pd (OH)2/C (0.60 g; 20% w/w) in methanol (50 mL) was stirred for 24 hours at 40° C. under at atmosphere of dry hydrogen gas. The catalyst was filtered off through a celite pad, and the filtrate was concentrated in vacuo to.give 2 g (10.14 mmol; 97%) of (5) as a colorless oil which was used without any further purification. To a solution of (5) (2 g; 10.14 mmol) in dry dichloromethane (100 mL) was successively added, at 0° C., under an argon atmosphere, pyridine (2.04 mL; 25.35 mmol), and benzylchloroformate (2.89 mL; 20.24 mmol). The reaction mixture was then allowed to stir at room temperature for 2 days. The reaction mixture was washed (2×50 mL) with IN HCl, dried over MgSO4, and concentrated in vacuo. The crude oil was purified by silica-gel flash chromatography in ether/heptane (1:1) to give 2.97 g (8.96 mmol; 88%) of (6) as a colorless oil.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH:25]([O:28][CH3:29])[O:26][CH3:27].O>CN(C=O)C>[CH3:27][O:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23][N:12]1[CH:13]=[C:8]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][N:2]=2)[C:9](=[O:15])[NH:10][C:11]1=[O:14]
Reactant: COC(CCBr)OC
Reactant: O=c1[nH]cc(-c2cnccn2)c(=O)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2cnccn2)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.5 %

Procedure:
A mixture of 5-pyrazin-2-yl-1H-pyrimidine-2,4-dione hydrochloride (Prep125, 2.19 mmol), and K2CO3 (302 mg, 2.19 mmol) in DMF (20 ml) was stirred 30 minutes at room temperature. 90% 3-Bromo-1,1dimethoxy-propane (365 μl, 2.41 mmol) was added in two portions during 2 days. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography eluting with DCM-MeOH—NH4OH (98-2-0.2) to give 221 mg of the title compound (35% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH3:6][OH:7].[CH2:8]=[O:9]>C(N(CC)CC)C>[OH:7][CH2:6][N:1]([CH2:8][OH:9])[CH2:2][C:3]([OH:5])=[O:4]
Reactant: NCC(=O)O
Reactant: C=O
Reactant: CO
Solvent: CCN(CC)CC
Product: O=C(O)CN(CO)CO

Procedure:
37.5 g. of glycine are added to a hot solution of 500 ml. anhydrous methanol, 47.0 g. of triethylamine and 30.0 g. of paraformaldehyde. N,N-bis-hydroxymethyl-glycine obtained in the reaction mixture is reacted without isolation with 55.0 g. of diethyl-phosphite and the reaction mixture is boiled under stirring for 1 hour. To the obtained solution containing dialkyl-[N-(N-hydroxy-methylene-glycine)-methylene]-phosphite 210 ml. of conc. hydrochloric acid are added and the formed N-phosphonomethyl-glycine-ethyl ester is heated for 1.5 hours at 115° C. to hydrolyze it to N-phosphonomethyl-glycine. The reaction mixture is processed and thus 66-68 g. of N-phosphonomethyl-glycine are obtained in crystalline form, purity: above 96%.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[C:31]([F:34])([F:33])[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:78][CH:79]1[CH2:84][CH2:83][O:82][CH2:81][CH2:80]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:78][CH:79]5[CH2:84][CH2:83][O:82][CH2:81][CH2:80]5)=[O:27])=[CH:24][C:23]=4[C:31]([F:34])([F:32])[F:33])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3C(F)(F)F)ncc21
Reactant: NC1CCOCC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCOCC4)cc3C(F)(F)F)ncc21
Reaction time: 0.17 h
Yield: 49.8 %

Procedure:
To a mixture of 0.075 g (0.155 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-trifluoromethyl-benzoic acid (I-204) and 8 mL of dimethylformamide was added 0.0313 g (0.232 mmole) of 1-hydroxybenzotriazole, 0.0880 g (0.232 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.080 g (0.617 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.024 g (0.237 mmole) of 4-aminotetrahydropyran was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-90:10) gave 0.0439 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(tetrahydro-pyran-4-yl)-3-trifluoromethyl-benzamide (I-207) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.[C:11](=O)([O-])[O-].[Ca+2].C(O)C>C(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]=[CH:11][NH:10][C:5]=2[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(N)c(N)c1
Agent: [Ca+2]
Solvent: CCO
Solvent: O=CO
Product: COc1ccc2nc[nH]c2c1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
4-Methoxy-1,2-phenylenediamine (5.00 g, 36 mmol) was dissolved in formic acid (10 ml) and heated at reflux for 2 hours. The solution was allowed to cool to room temperature overnight then treated with calcium carbonate (5.0 g). After dilution with ethanol (150 ml) the mixture was heated at reflux for 1 h then filtered, the residue being washed with hot ethanol (50 ml). The combined filtrates were evaporated at reduced pressure to give an oil from which a solid crystallised. The material was slurried with diethyl ether (50 ml) then filtered to give an orange solid which was recrystallised from ethyl acetate to give 5-methoxybenzimidazole (5.33 g, 99%) as a yellow crystalline solid.
Reaction SMILES: C([O:3][C:4](=[O:15])/[CH:5]=[CH:6]/[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.[Li+].[OH-]>C1COCC1>[C:9]1([CH2:8][CH2:7]/[CH:6]=[CH:5]/[C:4]([OH:15])=[O:3])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)/C=C/CCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)/C=C/CCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of the intermediate 32.1 from above in 1:1 aqueous 1N LiOH:THF (250 mL) was refluxed for 18 h. It was then cooled to room temperature and washed with ethylacetate (2×200 mL). The aqueous was acidified to pH2 by the addition of conc. HCl, and extracted with ethylacetate (3×200 mL). These last organic extracts were combined, dried with MgSO4 and concentrated to afford the intermediate trans-5-phenyl-2-pentenoic acid (32.2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[BH4-].[Na+]>C(O)C.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][OH:6]
Reactant: COc1ccc(C=O)cc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CO)cc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of 3-bromo-4-methoxybenzaldehyde (4.98 g) in ethanol (50 mL) and tetrahydrofuran (10 mL) was added sodium borohydride (1.31 g) under ice-water cooling. The mixture was stirred at 0° C. for 2 hours. After evaporation of the solvent, the residue was partitioned between ethyl acetate and water. The separated organic layer was washed successively with water and brine, and dried over magnesium sulfate. The organic layer was evaporated in vacuo to give 3-bromo-4-methoxybenzyl alcohol as a colorless oil (4.98 g).