Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:32])[O:13][CH2:14][C@@H:15]([N:18]([CH3:31])[C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[Cl:30])=[O:20])[CH2:16][NH2:17])[N:2]=1.FC(F)(F)S(O[CH2:39][CH:40]([F:42])[F:41])(=O)=O.CCN(C(C)C)C(C)C>C1COCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:32])[O:13][CH2:14][C@@H:15]([N:18]([CH3:31])[C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[Cl:30])=[O:20])[CH2:16][NH:17][CH2:39][CH:40]([F:42])[F:41])[N:2]=1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CN)COC(=O)Nc1cc2ccccc2cn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CNCC(F)F)COC(=O)Nc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
To a solution of (S)-3-amino-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)propyl isoquinolin-3-ylcarbamate (200 mg, 0.44 mmol) in THF (2.0 mL) were added 2,2-difluoroethyl trifluoromethanesulfonate (94 mg, 0.44 mmol) and DIEA (0.15 mL, 0.88 mmol) at RT The reaction mixture was stirred at RT for 30 min. The solvent was removed. The resulting residue was dissolved in MeOH and mixture was purified on RP-HPLC using a mixture of acetonitrile and water to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-3-(2,2-difluoroethylamino)propyl isoquinolin-3-ylcarbamate (130 mg, 56% for two steps). LRMS (M+H+) m/z 524.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([OH:27])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.N1C(C)=CC=CC=1C.O[N:52]1[C:56](=[O:57])[C:55]2=[CH:58][CH:59]=[CH:60][CH:61]=[C:54]2[C:53]1=[O:62].C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:27][N:52]2[C:56](=[O:57])[C:55]3[C:54](=[CH:61][CH:60]=[CH:59][CH:58]=3)[C:53]2=[O:62])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)[C@H](O)Cc1ccc(OCc2ccccc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)[C@H](Cc1ccc(OCc2ccccc2)cc1)ON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
To a solution of (R)-benzyl 3-(4-(benzyloxy)phenyl)-2-hydroxypropanoate (Compound XLIII-1) 18.1 g (50.0 mmol) in dichloromethane 80 ml, trifluoromethanesulfonic anhydride 10.1 ml (60.0 mmol) and 2,6-lutidine 8.74 ml (75.0 mmol) were added and the mixture was stirred at room temperature for 0.5 hr. N-hydroxyphthalimide 8.16 g (50.0 mmol) and triethylamine 10.5 ml (75.0 mmol) were added to the reaction mixture and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and diluted with ethyl acetate 500 ml and washed with saturated sodium bicarbonate solution 500 ml, water 500 ml and brine 500 ml. The organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified on silica gel column chromatography (Merck 60N spherical, neutral elution by n-hexane:ethyl acetate=90:10 to 70:30) to obtain the title compound 15.0 g (yield 59%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[CH3:11][Mg]Cl.Cl.C(OCC)C>C1COCC1.C(CC(=O)C)(=O)C.[Fe+3]>[Cl:1][C:2]1[N:7]=[C:6]([CH3:11])[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)nc1Cl
Reactant: C[Mg]Cl
Agent: [Fe+3]
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)CC(C)=O
Solvent: C1CCOC1
Product: COc1cnc(Cl)nc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-Dichloro-5-methoxypyrimidine (10 g) was dissolved in THF (100 ml), and while cooling, iron(III) acetylacetone (1.97 g), methyl magnesium chloride (3.0 M: 22.4 ml) were then added to the solution. The obtained mixture was stirred at room temperature overnight. Thereafter, iron(III) acetylacetone (1.97 g), and methyl magnesium chloride (3.0 M: 22.4 ml) were added to the reaction solution further twice. Thereafter, a 1 N hydrochloric acid aqueous solution was added to the reaction mixture, and diethyl ether was then added to the reaction solution to carry out liquid separation and extraction. The organic layer was dried over magnesium sulfate, and the solvent was then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate), so as to obtain the title compound (6.6 g).
Reaction SMILES: [C:1]1([N:11]2[C:15]([S:16][CH2:17][C:18]([OH:20])=O)=[N:14][N:13]=[N:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:18](=[O:20])[CH2:17][S:16][C:15]1[N:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:12]=[N:13][N:14]=1
Reactant: Nc1ccccc1Cl
Reactant: O=C(O)CSc1nnnn1-c1cccc2ccccc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=C(CSc1nnnn1-c1cccc2ccccc12)Nc1ccccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
2-{{1-(1-Naphthalenyl)-1H-tetrazol-5-yl}thio}acetic acid (500 mg, 1.75 mmol) and 2-chloroaniline (202 μL, 1.92 mmol) were dissolved in dry pyridine (8 mL). This solution was cooled to 0° C. and POCl3 (0.179 mL) was added dropwise. The mixture was stirred at 0° C. for 1 h, quenched with a few drops of water, and concentrated under reduced pressure. The crude product was dissolved in CH2Cl2 (100 mL) and the resulting solution was successively washed with water (2×30 ml) and brine (30 ml), dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (CH2Cl2:(CH3)2CO, 95:5) to afford the title compound (643 mg, 85% yield) as a solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:20](O)[CH2:19][N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:17]2=[O:30])=[N:13][C:12]=1[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:20]=[CH:19][N:18]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[C:17]2=[O:30])=[N:13][C:12]=1[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)CC2O)sc1C(=O)NCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-n2ccn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1ccccc1
Yield: 64 %

Procedure:
To a solution of N-benzyl-2-(3-(4-fluorobenzyl)-5-hydroxy-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide (0.22 g, 0.50 mmol) in chloroform (10 mL) was added trifluoroacetic acid (10 mL) at ambient temperature. The resulting reaction mixture was heated to reflux for 8 hours. The solvent was removed in vacuo and the residue was purified by column chromatography to afford the title compound in 64% yield (0.12 g): mp 167-168° C.; 1H NMR (300 MHz, CDCl3) δ 7.34-6.96 (m, 10H), 6.30-6.29 (m, 6.12 (s, 1H), 4.76 (s, 2H), 4.55 (d, J=5.4 Hz, 2H), 2.59 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.6, 162.0, 153.4, 152.9, 150.5, 131.4, 129.8, 128.8, 127.8, 117.7, 120.0, 116.1, 115.8, 113.0, 107.6, 46.7, 44.1, 17.2; MS (ES+) m/z 423.2 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:9][CH2:10][O:11][CH2:12][CH3:13].[OH2:14]>C1COCC1>[CH2:10]([O:11][C:12](=[O:14])[CH:13]=[C:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:9]
Reactant: O
Reactant: CCOCC
Reactant: O=C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a flame-dried 500-mL round-bottomed flask containing NaH (5.10 g of a 60% dispersion in mineral oil, 128 mmol, 1.10 equiv) in 120 mL anhydrous THF at 0° C. under argon was added triethylphosphonoacetate (25.6 mL, 128 mmol, 1.10 equiv) dropwise through an addition funnel. The mixture was allowed to warm to rt, stirring for an additional 1 h. A solution of cyclopentanone (10.3 mL, 116 mmol) in 10 mL anhydrous THF was added dropwise over 20 min through an addition funnel, and the mixture was allowed to stir at rt for 2.5 h. Ether (200 mL) and water (100 mL) were then added, and the layers were separated. The organic phase was washed successively with water (100 mL) and brine (100 mL), dried (Na2SO4), and concentrated under reduced pressure, giving 17.5 g (98%) of the desired ester as a colorless oil.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24](=[O:45])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33](OC3C=CC([N+]([O-])=O)=CC=3)=[O:34])[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:46][C:47]([CH3:65])([CH3:64])[CH2:48][C:49]1[CH:63]=[CH:62][C:52]([CH2:53][NH:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])=[CH:51][CH:50]=1.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([N:17]2[CH2:18][CH2:19][CH:20]([O:23][C:24](=[O:45])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33](=[O:34])[N:54]([CH2:53][C:52]3[CH:62]=[CH:63][C:49]([CH2:48][C:47]([CH3:46])([CH3:65])[CH3:64])=[CH:50][CH:51]=3)[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:21][CH2:22]2)=[O:16])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCNCc1ccc(CC(C)(C)C)cc1
Reactant: O=C(NCCCCCCOC(=O)Oc1ccc([N+](=O)[O-])cc1)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCN(Cc1ccc(CC(C)(C)C)cc1)C(=O)OCCCCCCNC(=O)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Yield: 112.5 %

Procedure:
A solution of the carbonate (2.0 g, 3.2 mmol) produced in Example 5, 4-(2,2-dimethyl-propyl)-benzyl-heptylamine (1.1 g, 3.9 mmol) and triethylamine (2.2 ml, 16 mmol) in 30 ml of anhydrous dimethylformamide was stirred under nitrogen at room temperature overnight. The reaction was diluted with methylene chloride, extracted one time with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 2.73 g of a light brown oil. Purification of this oil by chromatography on silica gel (230-400 mesh) using 10% ethyl acetate-methylene chloride as the eluent gave 2.11 g (87%) of the title compound as a clear oil, MS m/e 758 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:33])[C@@H:5]([O:30][CH2:31][CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:23](OC(C)(C)C)=O)=[CH:9][CH:8]=1)C.[OH2:34].[OH-:35].[Li+].ClCCl.CO>O>[C:16]([O:34][C:12]([C:7]1[CH:8]=[CH:9][C:23]([NH:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:30][CH2:31][CH3:32])[C:4]([OH:3])=[O:33])=[CH:12][CH:11]=2)=[CH:5][CH:6]=1)=[O:35])([CH3:21])([CH3:17])[CH3:15]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccccc2NC(=O)OC(C)(C)C)cc1)OCC
Reactant: O
Reactant: [OH-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: CCO[C@@H](Cc1ccc(OCCc2ccccc2Nc2ccc(C(=O)OC(C)(C)C)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 140426.7 %

Procedure:
3-{4-[-(tert-Butoxycarbonylaminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid ethyl ester (27 g; 0.06 mmole) was dissolved in TBF (250 ml), and water (250 ml) was added during followed by addition of lithium hydroxide hydrate (3.75 g; 0.089 mmole) dissolved in a small amount of water. The reaction mixture was stirred at room temperature overnight and then concentrated by evaporation The residue was washed once with ethyl acetate. The water phase was acidified upon cooling with hydrochloric acid (2M) and extracted with ethyl acetate. The organic phase was washed with brine dried with magnesium sulfate and evaporated. The residue was redissolved in dichloromethane and chromatography on silica using a gradient system of dichloromethane: methanol (0-100%) gave 21.3 g (83% yield) 3-{4-[2-(4-tert-butoxycarbonylamiinophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)=[O:10])=[CH:5][CH:4]=1.[C:21]([CH2:23][C:24]([NH2:26])=[S:25])#[N:22].C(Cl)(Cl)Cl>N1CCCCC1.O>[OH:10][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:26][C:24](=[S:25])[C:23]([C:21]#[N:22])=[C:11]1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Reactant: N#CCC(N)=S
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(C2=C(C#N)C(=S)NC2(O)c2ccc(OC)cc2)cc1
Reaction time: 12 h

Procedure:
16.5 g. 4,4'-Dimethoxybenzil, 6.0 g. cyanothioacetamide and 15 drops of piperidine were boiled for 2 hours in 200 ml. chloroform on a water separator. The yellow precipitate obtained was filtered off with suction, washed with some chloroform and dried at 80° C. and 0.1 mm.Hg for 12 hours. The desired product is obtained in a yield of 17.6 g. in the form of yellow crystals; m.p. 193° C. (decomp.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([O:22][CH3:23])[C:15]([CH2:24][CH3:25])=[CH:14][CH:13]=1)(=[O:10])=[O:9].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/B(O)O)=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH:11][C:12]2[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([O:22][CH3:23])[C:15]([CH2:24][CH3:25])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:29][CH:28]=1
Reactant: CCc1ccc(NS(=O)(=O)c2ccccc2Br)c(C(=O)OC)c1OC
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Product: CCc1ccc(NS(=O)(=O)c2ccccc2/C=C/c2ccc(Cl)cc2)c(C(=O)OC)c1OC

Procedure:
The title compound-was prepared from Example 574D (0.215 g, 0.5 mmol) and trans-2-(4-chlorophenyl)vinyl boronic acid according to the procedure of Example 230B, yielding 0.252 g, 100%. 1H NMR (DMSO-d6) δ 1.02 (t, 3H), 2.42 (q, 2H), 3.52 (s, 3H), 3.54 (s, 3H), 6.90 (d, 1H), 7.16 (d, 1H), 7.22 (d, 1H), 7.40-7.70 (m, 7H), 7.80 (d, 1H), 7.90 (d, 1H), 10.00 (s, 1H); MS (ESI(−)) m/e 484 (M−H)−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10][OH:11]>C(O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: OCCC#Cc1ncccn1
Agent: [Pd]
Solvent: CCO
Product: OCCCCc1ncccn1
Yield: 85.7 %

Procedure:
4-(2-Pyrimidinyl)-3-butynol (1.5 g) in ethanol (40 ml) was added to pre-reduced 10% palladium on charcoal (50% aqueous paste) in ethanol (60 ml) and hydrogenated at room temperature and atmospheric pressure. The catalyst was removed by filtration through hyflo and the solvent evaporated in vacuo. The residual oil was purified by FCC. Elution with System C (19:1) and (9:1) gave the title compound as a pale yellow oil (1.32 g)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1([C@H:22]([NH2:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>C1COCC1>[C:16]1([C@H:22]([NH:24][CH:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@H](NC1CCCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
A mixture of 4-oxoazepane-1-carboxylic acid tert-butyl ester (90 g, 422 mmol) and (R)-1-phenylethanamine (56.4 g, 465 mmol) in THF (1000 mL) was stirred at rt for 15 min and STAB (107.4 g, 510 mmol) was added. The mixture was cooled to 0° C. in an ice bath, then acetic acid (26.7 g, 450 mmol) was added. The mixture was stirred overnight at rt then concentrated in vacuo, residue dissolved in DCM (800 mL) and washed with sat. NaHCO3 sol. (2×300 mL), dried (Na2SO4). The solvents were removed in vacuo, and the residue was purified by column chromatography (gradient 0% to 3% MeOH in DCM) to give tert-butyl 4-{[(1R)-1-phenylethyl]amino}azepane-1-carboxylate (90 g, 67.0%) as a mixture of two diastereoisomers.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].C([Mg]Br)(C)C.[CH:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.C(OCC)C>[C:11]1([CH:10]([OH:17])[CH2:3][C:2]#[CH:1])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: C#CCBr
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: C#CCC(O)c1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To 0.425 ml (1.43 mmol) of tetraisopropoxytitanium and 10 ml of ethyl ether solution of propargyl bromide (0.127 ml, 1.43 mmol) was added dropwise at −50° C. 1.90 ml of 1.43M ethyl ether solution containing isopropylmagnesium bromide (2.72 mmol). After stirring at −50° C. to −40° C. for 1 hour, the reaction liquid was given 0.102 ml (1.0 mmol) of benzaldehyde at −40° C. and heated to −20° C. over 30 minutes. With 1N hydrochloric acid added, the solution was heated to room temperature and separated into layers. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate. After drying with anhydrous magnesium sulfate, the solution was freed of solvent by vacuum distillation. The residues were purified by silica gel chromatography. Thus there was obtained 124 mg of 4-phenyl-1-butyn-4-ol (85% yields based on benzaldehyde).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: C1COCCN1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)N2CCOCC2)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
Under an atmosphere of argon protective gas, 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (50 mg, 101 μmol) was dissolved in absolute THF (2.5 ml), morpholine (26 μl, 303 μmol; 3 eq.) and triethylamine (10.2 mg, 101 μmol; 1 eq.) were added at room temperature and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Kromasil C-18, 5 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (44 mg, 80% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[N+:19]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([NH:29][NH:28][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:31][CH:30]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: NNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: -50 °C
Reaction time: 1 h
Yield: 119.2 %

Procedure:
(2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 1a)(8.3 g, 30.9 mmol), 4-nitrobenzohydrazide (6.16 g, 34.0 mmol) and anhydrous THF (200 mL) were placed in a 500 mL round bottomed flask and the mixture was cooled to −50° C. 1-Hydroxybenzotriazole hydrate (4.2 g, 30.9 mmol) was added to the mixture together with N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide HCl (7.34 g, 38.3 mmol) at −50° C. followed by triethylamine (5.3 mL, 38.3 mmol). The reaction mixture was maintained at −15° C. and stirred for 1 h after which stirring continued overnight while the mixture slowly warmed to room temperature. After 18 h the mixture was filtered under vacuum and the residue washed with THF (50 mL). The THF solution was concentrated to ca. 20 mL, whereupon ethyl acetate (200 mL) was added followed by water (100 mL). The phases were partitioned and the organic phase washed with water (150 mL), brine (150 mL), dried (Na2SO4) and concentrated to furnish a light yellow solid as the title compound (15.9 g, 80%) that was used without further purification. 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.88 (br s, 2H), 8.35 (d, J=6.7 Hz, 2H), 8.16 (d, J=6.7 Hz, 2H), 7.53 (d, J=7.5 Hz, 1H), 6.69 (d, J=7.5 Hz, 1H), 5.56 (d, J=6.6 Hz, 1H), 4.46-4.36 (m, 1H), 4.18-4.10 (m, 1H), 3.26 (s, 3H), 1.37 (d, J=7.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH2:12].[S:13](Cl)(=[O:16])(=[O:15])[NH2:14].CCOC(C)=O.O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH:12][S:13]([NH2:14])(=[O:16])=[O:15]
Reactant: NS(=O)(=O)Cl
Reactant: NC1CCc2c(Cl)ccc(F)c21
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)NC1CCc2c(Cl)ccc(F)c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-chloro-7-fluoro-2,3-dihydro-1H-inden-1-amine (CAS No. 1337690-24-0, 371 mg, 2.00 mmol) and TEA (0.697 mL, 5.00 mmol) in DCM (10 mL) was added sulfamoyl chloride (462 mg, 4.00 mmol) at 0° C. The reaction mixture was stirred for 3 hours at room temperature. To the reaction mixture were added AcOEt and water, and the layers were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4. The solvent was concentrated in vacuo and the residue was purified by silicagel column chromatography (gradient 20% to 33% AcOEt in n-heptane) to afford the title compound (165 mg, 0.623 mmol) as a racemate.
Reaction SMILES: Cl[C:2]1[C:7](C(OCC)=O)=[CH:6][N:5]=[CH:4][N:3]=1.C1O[C:20]2[CH:19]=[CH:18][C:17]([OH:22])=[CH:16][C:15]=2O1.[C:23](=O)([O-:25])[O-:24].[Cs+].[Cs+].[H-].[Na+]>CN(C)C=O>[CH2:23]1[O:25][C:7]2[C:2](=[N:3][C:4]([O:22][C:17]3[CH:18]=[CH:19][CH:20]=[CH:15][CH:16]=3)=[N:5][CH:6]=2)[O:24]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cncnc1Cl
Agent: [Cs+]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(Oc2ncc3c(n2)OCO3)cc1

Procedure:
In reaction 1 of Scheme (10.2.0) the 4-chloro-5-carboethoxy-pyrimidine of Formula (3.0.0) in anhydrous dimethylformamide (DMF) is reacted with 3,4-methylenedioxyphenol of Formula (3.0.1) in the presence of cesium carbonate, or sodium hydride, to form the methylenedioxyphenoxy-pyrimidine of Formula (3.0.2). The reaction mixture comprising (3.0.0) and (3.0.1) is heated to a temperature of from 80° to 100° C., preferably 90° C., for a time period of from 1 hour to 24 hours, preferably 18 hours.