Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][C:10]=1[F:39].C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:64][C:65]1[CH:72]=[CH:71][C:68]([C:69]#[N:70])=[CH:67][CH:66]=1>>[C:69]([C:68]1[CH:71]=[CH:72][C:65]([NH:64][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:37])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[C:10]([F:39])[CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:66][CH:67]=1)#[N:70]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)c(F)cc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)c(F)cc12
Yield: 31.2 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-5-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 47 (0.33 g, 0.55 mmol), was reacted with diisopropylethylamine (0.29 g, 2.2 mmol), diphenylphosphinic chloride (0.26 g, 1.1 mmol), then reacted with 4-aminobenzonitrile (Aldrich) (0.2 g, 1.7 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-5-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide as a white solid (Yield 0.1 g, 31%).
Reaction SMILES: [C:1]([C:9]1[CH:42]=[CH:41][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][O:44][NH2:45]>>[C:37]([O:36][C:34]([N:32]([CH3:33])[CH:27]([CH2:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][N:13]2[C:12]3[CH:41]=[CH:42][C:9]([C:1](=[N:45][O:44][CH3:43])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11]=3[S:15][C:14]2=[O:16])=[CH:25][CH:24]=1)[C:28]([O:30][CH3:31])=[O:29])=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CON
Reactant: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)N(C)C(=O)OC(C)(C)C
Product: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC(C(=O)OC)N(C)C(=O)OC(C)(C)C)cc1

Procedure:
Starting from the compound obtained in Step A, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[I-].[C:13]([CH2:15][P+](C)(C)C)#[N:14].C(#N)CC.C(N(C(C)C)CC)(C)C>>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][CH2:15][C:13]#[N:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[P+](C)(C)CC#N
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: N#CCCc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 64.3 %

Procedure:
To a mixture of 4-nitrobenzyl alcohol (37) (1 g, 6.53 mmol) and (cyanomethyl)trimethylphosphonium iodide (36) (4 g, 16.32 mmol) were added propionitrile (32 mL) and diisopropylethylamine (2.5 g, 19.58 mmol) at room temperature. The mixture was heated at ˜100° C. for 24 hours. The reaction was quenched with water (1 mL), followed by addition of concentrated HCl (5 mL). The resulting reaction mixture was extracted with ethyl acetate (3×100 mL), washed with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a dark brown solid. The crude solid product was purified by flash column chromatography (silica gel, ethyl acetate: hexanes 1:1) to give 740 mg of 3-(4-nitrophenyl)propionitrile (38) as a light orange solid. 1H NMR (DMSO-d6): δ 8.20-8.17 (dd, J=8.7 Hz, 2H), 7.59-7.56 (d, J=9.0 Hz, 2H), and 3.06-3.01 (m, 2H).
Reaction SMILES: [C:1](=[O:23])([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][CH:5]=1.C(Cl)[Cl:25]>>[C:1](=[O:23])([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[O:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:11][Cl:25])=[CH:8][CH:9]=1
Reactant: CSc1ccc(COC(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Reactant: ClCCl
Product: O=C(OCc1ccc(SCCl)cc1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A cold (5° C.) solution of p-(methylthio)benzyl p-nitrobenzyl carbonate (1.0 g, 3 mmol) in CH2Cl2 (50 mL) was treated dropwise (2 min) with S02Cl2 (0.425 g, 3.15 mmol). After stirring the resulting solution for 30 min at 5° C., the solvent was evaporated to leave the title compound as an oil which solidified (1.10 g yield, 99.7%). The solid was used without purification in the next step.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39])[NH2:32]>>[CH3:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:31]1[N:32]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:28][N:30]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: Cc1ccccc1C(N)=NO
Product: Cc1ccccc1-c1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 33 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-2-methylbenzenecarboximidamide were reacted according to the General Method 1. Yield: 14 mg (13% of theory)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C1COCC1.O.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH:13]3[CH2:14][CH2:15][N:16]([C:32](=[O:34])[CH3:33])[CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2[nH]c(C3CCNCC3)nc2-c2ccncc2)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CCC(c2nc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
To a stirring solution of 4-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]piperidine (0.76 mmol,0.30 g) in THF (5 mL) was added triethylamine (2.7 mmol,0.27 g) and acetyl chloride (0.91 mmol,71.5 mg) and the reaction stirred at room temperature overnight. The reaction was diluted with water (50 mL) and saturated sodium bicarbonate (10 mL) and the aqueous phase extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. The residue was chromatographed over silica, eluting with 2.5% to 5% MeOH:CH2Cl2. The product containing fractions were combined and evaporated to give a yellow oil. This oil was crystallized from diethyl ether to give 75 mg of the title compound as a white powder. mp=235°-6° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5](Cl)=[O:6].[Cl:18][C:19]1[CH:32]=[CH:31][C:22]2[NH:23][C:24]([C@@H:26]([NH2:30])[CH2:27][O:28][CH3:29])=[N:25][C:21]=2[CH:20]=1>C1COCC1>[Cl:18][C:19]1[CH:32]=[CH:31][C:22]2[NH:23][C:24]([C@@H:26]([NH:30][C:5](=[O:6])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([F:1])[CH:3]=3)[CH2:27][O:28][CH3:29])=[N:25][C:21]=2[CH:20]=1
Reactant: COC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(Cl)c1ccc(N2CCOCC2=O)c(F)c1
Solvent: C1CCOC1
Product: COC[C@H](NC(=O)c1ccc(N2CCOCC2=O)c(F)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 41d from 3-fluoro-4-(morpholin-3-on-4-yl)benzoic acid-chloride and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxyethylamine with TEA in THF.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH:9]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[F:18])[NH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([O:23][C:24](=[O:37])[NH:25][CH2:26][CH2:27][CH:28]([N:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1)[CH3:29])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:37])[NH:25][CH2:26][CH2:27][CH:28]([N:30]1[CH2:35][CH2:34][CH:33]([NH:10][CH:9]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[F:18])[CH2:8][NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:32][CH2:31]1)[CH3:29])([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(CCNC(=O)OC(C)(C)C)N1CCC(=O)CC1
Reactant: NC(CNC1CCCCC1)c1cc(F)ccc1F
Product: CC(CCNC(=O)OC(C)(C)C)N1CCC(NC(CNC2CCCCC2)c2cc(F)ccc2F)CC1
Yield: 89.3 %

Procedure:
Using general procedure A, N2-cyclohexyl-1-(2,5-difluorophenyl)-ethane-1,2-diamine (750 mg, 2.95 mmol) and [3-(4-oxo-piperidin-1-yl)-butyl]-carbamic acid tert-butyl ester (797 mg, 2.95 mmol) afforded {3-[4-(2-cyclohexylamino-1-{2,5-difluorophenyl}-ethylamino)-piperidin-1-yl]-butyl}-carbamic acid tert-butyl ester (1.34 g, 89%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]#[N:14])=[C:11]([CH2:15][CH3:16])[NH:10][C:9]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1.O.IC.[C:25](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]#[N:14])=[C:11]([CH2:15][CH3:16])[N:10]([CH3:25])[C:9]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1[nH]c(CC)c(C#N)c1-c1ccc(Br)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(Br)cc2)c(C#N)c(CC)n1C
Temperature: 30 °C
Reaction time: 14 h
Yield: 97.9 %

Procedure:
Step DI: Suspend ethyl 3-(4-bromophenyl)-4-cyano-5-ethylpyrrole-2-carboxylate (7.0 kg, 20.17 mol, 1 eq, prepared in step C above) in acetone (70 L) in a 100-L reactor. Add water (0.7 L), iodomethane (3.153 kg, 1.38 L, 22.21 mol, 1.1 eq), and potassium carbonate (5.58 kg, 40.37 mol, 2 eq). Stir the mixture at 30° C. for 14 h. Concentrate the reaction mixture by removing 41 L of solvent by distillation at 50° C. under reduced pressure. Add water (55 L) slowly over 45 min at 20-22° C. Cool the suspension to 0° C. within 1 h and stir for an additional h at this temperature. Collect the precipitate by filtration and wash with a cold (0-5° C.) mixture of acetone/water (1.2+3 L.) and then with water (4.2 L). Dry the product in 100-L rotary evaporator under reduced pressure at 60° C. for 66 h to obtain 7.133 kg of title compound as a beige powder (98% yield). 1H NMR (CDCl3, 500.0 MHz): δ 1.08 (t, J=7.1 Hz, 3H), 1.34 (t, J=7.1 Hz, 3H), 2.88 (q, J 2 0=7.1 Hz, 2H), 3.92 (s, 3H), 4.13 (q, J=7.1 Hz, 2H), 7.26 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.8 Hz, 2H); 13C NMR DMSO-d6, 125.7 MHz): δ 12.96, 13.44, 18.79, 60.16, 92.04, 115.22, 119.96, 121.12, 130.73, 131.58, 131.86, 132.05, 147.87, 159.82; Anal. Calcd for C17H17BrN2O2: C, 56.52; H, 4.74; Br, 22.12; N, 7.75; 0, 8.86. Found: C, 56.32; H, 4.72; N, 7.73; IR (KBr): 3347, 2979, 2938, 2216, 1698, 1441, 1510, 1476, 1400, 1379, 1258, 1212, 1110, 771 cm−1.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C@H:17]([CH3:41])/[CH:18]=[CH:19]/[CH2:20][O:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:10][C:11](N(OC)C)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:42]([O:49][C@H:50]([C@@H:55]([CH3:67])[CH2:56][CH2:57][CH2:58][O:59][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61])[C@@H:51]([CH3:54])[C:52]#[CH:53])([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43].[Li]CCCC.CCOC(C)=O.CCCCCC>C(Cl)(Cl)Cl>[Si:1]([O:8][C@@H:9]([CH2:10][C:11](=[O:12])[C:53]#[C:52][C@H:51]([CH3:54])[C@H:50]([O:49][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C@@H:55]([CH3:67])[CH2:56][CH2:57][CH2:58][O:59][Si:60]([C:63]([CH3:65])([CH3:64])[CH3:66])([CH3:62])[CH3:61])[C@H:17]([CH3:41])[CH:18]=[CH:19][CH2:20][O:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C#C[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CCCO[Si](C)(C)C(C)(C)C
Reactant: CON(C)C(=O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@H](C=CCOC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](CC(=O)C#C[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CCCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C

Procedure:
The procedure for 32 was used with 15 (1.31 g, 2.28 μmol), 64 (1.20 g, 3.01 mmol) and n-BuLi (1.88 mL, 1.20 mmol) to yield the ynone (1.79 g, 86%) after flash column chromatography (EtOAc/hexane 1:19) as a colorless oil: IR (CHCl3) 2929, 2856, 2209, 1675, 1471, 1462, 1385, 1254, 1093, 836, 775, 705 cm−1; 1H NMR (300 MHz, CDCl3) ε7.56-7.53 (m, 6H), 7.38-7.25 (m, 9H), 5.79 (dd, J=15.6, 7.2 Hz, 1H), 5.67 (dt, J=15.6, 4.9 Hz, 1H), 4.36 (m, 1H), 3.69-3.66 (m, 4H), 3.63 (t, J=4.1 Hz, 1H), 2.86 (m, 1H), 2.72 (m, 1H), 2.45 (m, 1H), 1.76 (m, 1H), 1.67-1.51 (m, 3H), 1.34 (m, 1H), 1.29 (d, J=7.1 Hz, 3H), 1.14 (d, J=6.8 Hz, 3H), 1.00-0.97 (m, 28H), 0.18-0.13 (m, 18H); 13C NMR (75 MHz, CDCl3) δ 186.0, 144.2, 132.8, 128.6, 127.9, 127.7, 126.8, 96.7, 86.8, 83.1, 77.8, 71.6, 64.8, 63.2, 50.1, 42.3, 37.2, 31.7, 30.9, 30.2, 26.0, 25.9, 25.8, 18.3, 18.2, 18.0, 17.3, 15.4, 14.8, −3.9, −4.1, −4.6, −4.7, −5.3; LRMS (ESI) 933.6 [M+Na]+, 795.5, 665.2, 496.1, 413.2, 243. 1; HRMS (ESI) calcd for C55H86O5Si3Na 933.5681 [M+Na]+, found 933.5692; [α]20D−9.5 (c 0.55, CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:16]([O-])=O)[CH:3]=1>[Zn]>[NH2:16][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1[N+](=O)[O-]
Agent: [Zn]
Product: CC(C)(C)OC(=O)Nc1ccc(F)cc1N

Procedure:
The title compound was prepared from the tert-butyl 4-fluoro-2-nitrophenylcarbamate (Example A6; 3 mmol) by reduction with zinc according to the general procedure B. Obtained as a yellow solid (66%), MS (EI) 227 [(M+1)+].
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[C@@H:6]([CH3:14])[CH2:5][N:4]([CH2:15][C:16]2[CH:20]=[CH:19][N:18](C(OC(C)(C)C)=O)[N:17]=2)[CH2:3]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][C@@H:2]1[CH2:3][N:4]([CH2:15][C:16]2[CH:20]=[CH:19][NH:18][N:17]=2)[CH2:5][C@H:6]([CH3:14])[N:7]1[C:8](=[O:13])[C:9]([F:10])([F:12])[F:11]
Reactant: C[C@@H]1CN(Cc2ccn(C(=O)OC(C)(C)C)n2)C[C@H](C)N1C(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(Cc2cc[nH]n2)C[C@H](C)N1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.3 %

Procedure:
D8 (2.20 g, 5.63 mmol) was taken up in 25% TFA in DCM (50 ml) and stirred for 4 h at 25° C. The solvent was removed in vacuo and the residue dissolved in DCM (50 ml), washed with saturated NaHCO3, dried (Na2SO4) and concentrated to yield the title compound as an orange foam (1.64 g). δH (CDCl3) 1.43 (6H, d), 2.48 (2H, dd), 2.97 (2H, d), 3.88 (2H, s), 4.15-4.75 (2H, br d), 6.40 (1H, d), 7.64 (1H, d), 8.93 (1H, br s). MS (ES): MH+ 291.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C@H:14]([CH2:36][CH3:37])[C:15]([NH:17][C:18]1[CH:19]=[N:20][C:21]([O:24][C:25]2[C:33]3[CH:32]([CH2:34][CH3:35])[O:31][CH2:30][C:29]=3[CH:28]=[CH:27][CH:26]=2)=[CH:22][CH:23]=1)=[O:16]>ClCCl>[CH2:36]([C@H:14]1[NH:13][C:2](=[O:4])[N:17]([C:18]2[CH:19]=[N:20][C:21]([O:24][C:25]3[C:33]4[CH:32]([CH2:34][CH3:35])[O:31][CH2:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)=[CH:22][CH:23]=2)[C:15]1=[O:16])[CH3:37]
Reactant: CCC1OCc2cccc(Oc3ccc(NC(=O)[C@H](N)CC)cn3)c21
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCC1OCc2cccc(Oc3ccc(N4C(=O)N[C@H](CC)C4=O)cn3)c21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 71.2 %

Procedure:
In a 50 ml round-bottomed flask (2R)-2-amino-N-{6-[(3-ethyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinyl}butanamide (Intermediate 110, 9 mg) was dissolved in dichloromethane (2 ml) to give a pale yellow solution that was cooled at 0° C. TEA (0.017 ml, 0.119 mmol) was added. 0.5 ml of a solution of triphosgene (14 mg in 2 ml of dichloromethane) was added dropwise to the reaction mixture at 0° C. The reaction mixture was stirred at 0° C. After 20 minutes, the reaction was completed. The reaction mixture was evaporated under vacuum to afford the crude product as a pale yellow oil which was purified via Biotage SP1 (with Cyclohexane/EtOAc as eluents from 2:1 to 1:2 in 15 CV; then 1:2 for 10 CV; 10 g SNAP Silica column). The collected fractions afforded the title compound (5R)-5-ethyl-3-{6-[(3-ethyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione (6.9 mg) as a white solid.
Reaction SMILES: C(O[N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:30]=[C:29]([N:31]([CH3:33])[CH3:32])[CH:28]=[CH:27][C:14]=2[C:15]([NH:17][C:18]2[C:19]([C:23]([O:25][CH3:26])=[O:24])=[CH:20][S:21][CH:22]=2)=[O:16])[CH2:8][C:7]1=C=O)(C)(C)C.[C:36]([O:40][C:41](N1CCC(OC2C=C(N(C)C)C=CC=2C(O)=O)CC1)=[O:42])([CH3:39])([CH3:38])[CH3:37].NC1C(C(OC)=O)=CSC=1>>[C:36]([O:40][C:41]([N:6]1[CH2:7][CH2:8][CH:9]([O:12][C:13]2[CH:30]=[C:29]([N:31]([CH3:33])[CH3:32])[CH:28]=[CH:27][C:14]=2[C:15]([NH:17][C:18]2[C:19]([C:23]([O:25][CH3:26])=[O:24])=[CH:20][S:21][CH:22]=2)=[O:16])[CH2:10][CH2:11]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CN(C)c1ccc(C(=O)O)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: COC(=O)c1cscc1NC(=O)c1ccc(N(C)C)cc1OC1CCN(OC(C)(C)C)C(=C=O)C1
Agent: COC(=O)c1cscc1N
Product: COC(=O)c1cscc1NC(=O)c1ccc(N(C)C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 51 %

Procedure:
Using methods substantially equivalent to those described in Example 12-C, methyl 4-[2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)-4-(dimethylamino)benzoylamino]-thiophene-3-carboxylate was prepared in a 51% yield from 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(dimethyl-amino)benzoic acid and methyl 4-aminothiophene-3-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)[CH3:2]>[C].[Pd].O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][O:14]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(/C=C/c2ccco2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CCC2CCCO2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.4 %

Procedure:
To an anhydrous tetrahydrofuran (25 mL) solution of 4-((E)-2-furan-2-yl-vinyl)-benzoic acid ethyl ester (2.2 g, 9.39 mmol) described in Manufacturing Example 80-1-1 was added 10% palladium-carbon (50% hydrate, 1 g), which was stirred for 6 hours under hydrogen atmosphere at room temperature. The reaction liquid was filtered, and the filtrate was concentrated under a reduced pressure to obtain the title compound (2.2 g, 100%) as a crude product.
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[C:28]([F:48])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10](OC2C=CC=CC=2)=[O:11])C=CC=CC=1.[CH3:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1>CN(C)C=O>[F:48][C:28]1[CH:27]=[C:26]([O:25][C:23]2[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:10]([N:54]3[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]3)=[O:11])[CH:24]=2)[CH:31]=[CH:30][C:29]=1[NH:32][C:33]([C:35]1([C:38]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)=[O:47])[CH2:36][CH2:37]1)=[O:34]
Reactant: CN1CCNCC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)c(F)c3)ccn2)CC1
Reaction time: 8 h

Procedure:
To a solution of roughly purified [4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (200 mg) in N,N-dimethylformamide (2.0 ml) was added 1-methylpiperazine (0.170 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. To the resultant residue was added diethyl ether:heptane=1:2 to precipitate a solid. The solvent was concentrated under reduced pressure, and the residue was dried under reduced pressure to provide the titled compound as white powder (27.0 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C@@H:12]([C:16]([OH:18])=[O:17])[C@H:13]([CH3:15])[OH:14].C([O-])([O-])=O.[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([NH:11][C@H:12]([C@@H:13]([OH:14])[CH3:15])[C:16]([OH:18])=[O:17])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)O
Temperature: 75 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
2-chloro-4-fluorobenzonitrile (60702-69-4) (2.0 g, 12.86 mmol) was mixed together with H-D-Thr-OH (1.84 g, 15.43 mmol) in DMSO (30 mL). K2CO3 (3.73 g, 27.0 mmol) was added to the reaction mixture and stirred at 75° C. for 24 h. The reaction mixture was cooled down to room temperature and poured slowly into a 10% citric acid solution and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times to get the crude product. The crude product was chromatographed with a gradient of hexane EtOAc and then with EtOAc, 100% to get the pure final product 1.8 g): 1H NMR (500 MHz, acetone-d6, δ in ppm) 7.51 (d, J=9 Hz, 1H), 6.95 (s, 1H), 6.82 (d, J=9 Hz, 1H), 5.17 (d, J=9 Hz, 1H), 4.42 (m, 1H), 4.22 (d, J=6 Hz, 1H), 2.34 (s, 3H), 1.28 (d, J=6 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[NH:4][C:5](=[S:9])[NH:6][C:7]=1[CH3:8].[OH-].[Na+].CI.[C:15](O)(=O)C>O>[CH3:1][C:2]1[C:3](=[O:10])[NH:4][C:5]([S:9][CH3:15])=[N:6][C:7]=1[CH3:8]
Reactant: CC(=O)O
Reactant: Cc1[nH]c(=S)[nH]c(=O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CSc1nc(C)c(C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a stirred solution of 5,6-dimethyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (10.0 g, 64.0 mmol, Example 1, Step A) and sodium hydroxide (10.0 g, 260.0 mmol) in water (150 mL) at ambient temperature was added methyl iodide (15.0 g, 320.0 mmol), and the reaction mixture was stirred at ambient temperature overnight. Then the reaction mixture was acidified with acetic acid (50 mL), and the solid was collected by filtration and dried to afford 7.0 g (64%) of the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.87 (s, 3H), 2.18 (s, 3H), 2.45 (s, 3H), 12.38 (bs, 1H).