Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)CCCC)[CH:2]=[CH2:3].N#N.Br[C:20]1[CH:39]=[N:38][C:23]2[N:24]([CH2:36][CH3:37])[C:25]3[N:33]=[C:32]([F:34])[CH:31]=[C:30]([CH3:35])[C:26]=3[NH:27][C:28](=[O:29])[C:22]=2[CH:21]=1.O>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>[CH2:36]([N:24]1[C:23]2[N:38]=[CH:39][C:20]([CH2:3][CH:2]=[CH2:1])=[CH:21][C:22]=2[C:28](=[O:29])[NH:27][C:26]2[C:30]([CH3:35])=[CH:31][C:32]([F:34])=[N:33][C:25]1=2)[CH3:37]
Reactant: CCN1c2ncc(Br)cc2C(=O)Nc2c(C)cc(F)nc21
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Solvent: O
Product: C=CCc1cnc2c(c1)C(=O)Nc1c(C)cc(F)nc1N2CC
Temperature: 90 °C
Yield: 44.4 %

Procedure:
Allyltributyltin (7.77 mL, 25.1 mmol) and Pd(Ph3P)4 (1.32 g, 1.14 mmol) were added to a degassed (N2 through solution for 30 min) solution of 8-bromo-5,11-dihydro-11-ethyl-2-fluoro-4-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (8.0 g, 22.8 mmol) in DMF (114 mL). The mixture was heated to 90° C. for 3 h. The mixture was poured into water (250 mL) and extracted with EtOAc (4×250 mL). The combined organic layers were washed with 20% aqueous NH40H (250 mL) and brine (250 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes:EtOAc, 4:1 to 1:1) to give the title compound (3.16 g, 51% yield).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[C:9]2[C:10]([Cl:28])=[CH:11][C:12]([O:15][CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)=[C:13]([Cl:14])[C:8]=2[S:7][CH:6]=1.C1COCC1.[OH-].[Na+].Cl>CO>[Cl:28][C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:29])=[O:2])=[CH:6][S:7][C:8]=2[C:13]([Cl:14])=[C:12]([O:15][CH2:16][C:17]2[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:22]=2)[CH:11]=1
Reactant: COC(=O)Cc1csc2c(Cl)c(OCc3ccc(C(F)(F)F)nc3C)cc(Cl)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(C(F)(F)F)ccc1COc1cc(Cl)c2c(CC(=O)O)csc2c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a mixture of methyl(4,7-dichloro-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methoxy)-1-benzothiophen-3-yl)acetate (124.5 mg), THF (dry) (2.0 mL), and MeOH (2.0 mL) was added 1N NaOH (0.804 mL) at room temperature. The mixture was stirred at room temperature for 5 h. The mixture was neutralized with 1N HCl and concentrated in vacuo. The precipitate was collected by filtration to give a solid. The solid was crystallized from EtOH-hexane to give the title compound (96.6 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH3:9])[C:5]([OH:8])=[N:6][CH:7]=1.CC1C=CC(S(O[CH2:22][CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])(=O)=O)=CC=1>>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH3:9])[C:5]([O:8][CH2:22][CH2:23][C:24]([CH3:26])([OH:27])[CH3:25])=[N:6][CH:7]=1
Reactant: Cc1c(Br)cnc(O)c1C
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Product: Cc1c(Br)cnc(OCCC(C)(C)O)c1C
Yield: 49.1 %

Procedure:
According to the method of (Example 36) <Step 1>, from 5-bromo-3,4-dimethylpyridin-2-ol (3.0 g) and 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (4.2 g), the subject compound (2.1 g) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][C:21](=O)[C:22](=CN(C)C)[C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH:28][CH2:29][CH2:30][N:31]([C:33](OC(C)(C)C)=O)[NH2:32]>O1CCOCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][C:33]5[N:31]([CH2:30][CH2:29][OH:28])[N:32]=[CH:21][C:22]=5[C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N(N)CCO
Reactant: CN(C)C=C1C(=O)CCc2c1sc1ncnc(Nc3ccc(F)c(Cl)c3)c21
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: OCCn1ncc2c1CCc1c-2sc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-(3-Chloro-4-fluoro-phenylamino)-8-dimethylaminomethylene-5,8-dihydro-6H-benzo[4,5]thieno[2,3-d]pyrimidin-7-one (10.6 g, 0.026 mol) was heated to near homogeneity in dioxane (250 mL). The heat was turned off and nitrogen was bubbled through the murky solution for ˜20 min while it cooled. The reaction flask was then evacuated and filled with nitrogen three times. In a separate flask, tert-butyl 1-(2-hydroxyethyl)hydrazinecarboxylate (13.9 g, 0.079 mol) was dissolved in toluene, concentrated in vacuo to a residue, redissolved in dioxane, and sparged with nitrogen for ˜10 minutes. The solution of tert-butyl 1-(2-hydroxyethyl)hydrazinecarboxylate was evacuated and filled with nitrogen three times and then was cannulated into the flask containing the enamine. The resulting mixture became a clear red solution upon heating in an oil bath at ˜80° C. After 6 h the reaction mixture was concentrated in vacuo to half its original volume. Xylenes (250 mL) was added and the mixture was again concentrated to half the original volume. Xylenes (250 mL) was added and the mixture was concentrated to half the original volume a final time. During the solvent swap, a yellow-orange solid precipitated. The resulting slurry was submerged in an ice-bath and TFA (200 mL) was added dropwise via an addition funnel. The slurry became a brown-red solution that was allowed to stir overnight at room temperature. Two liquid phases were present the next morning. Solvent (˜200 mL) was removed in vacuo at ˜40° C. The remaining mixture (˜300 mL) was diluted with EtOAc (500 mL) and washed twice with 500 mL portions of 1.0 N NaOH. Significant emulsions formed during the final base wash, so more EtOAc (500 mL) was added with brine (100 mL) before collecting the aqueous layer. The organic layer was then washed with brine (2×300 mL). The organic layer was filtered through a small pad of silica gel (˜1″ diameter×2″) and the pad was washed with EtOAc (750 mL). The filtrate was concentrated to a total volume of ˜200 mL, resulting in the precipitation of solid. The slurry was filtered by vacuum filtration on a Buchner funnel and the resulting solid was allowed to dry overnight on the filter. An orange solid was obtained (7.25 g, 66%, >98% regioisomeric purity by 1H-NMR). 1H NMR (DMSO-d6) δ 8.56 (s, 1H), 8.38 (s, 1H), 7.88 (m, 1H), 7.66 (s, 1H), 7.61 (m, 1H), 7.40 (t, 1H), 4.93 (t, 1H), 4.16 (t, 2H), 3.73 (dt, 2H), 3.42 (t, 2H), 3.10 (t, 2H); LCMS RT=2.76 min; [M+H]+=416.4.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].CCN(C(C)C)C(C)C.[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26]>C(Cl)Cl>[F:23][C:24]([F:28])([F:27])[CH2:25][NH:26][C:2](=[O:3])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1
Reactant: NCC(F)(F)F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(F)(F)F)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 4-nitrophenyl chloroformate (4578 mg, 22715 μmol) and DIEA (2638 μL, 15143 μmol) in DCM (100 mL) at 0° C. was added 2,2,2-trifluoro-ethylamine (1500 μL, 15143 μmol). The resulting mixture was then stirred at 0° C. for 4 h and at RT for overnight. Then, the mixture was concentrated and a white precipitation was observed. The mixture was then filtered to give the title compound as a white solid, which was used in the next step without purification requirement.
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[C:3]#[C:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([CH2:25][N:26]=[N+:27]=[N-:28])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[OH:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[C:3]1[N:26]([CH2:25][C:24]2[CH:29]=[CH:30][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[N:27]=[N:28][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C#CC(O)c1ccccc1[N+](=O)[O-]
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1C(O)c1ccccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
To a solution of diisopropylamine (6.6 ml, 47.1 mmole) in tetrahydrofuran (80 ml) at -78° C. under an argon atmosphere was added 2.5 N butyllithium (17.4 ml, 43.5 mmole), and the mixture was stirred for 30 minutes. To this reaction mixture were next added a solution of ethyl propionate (4.0 ml, 39.5 mmole) in tetrahydrofuran (20 ml) and a solution of 2-nitrobenzaldehyde (4.0 g, 26.5 mmole) in tetrahydrofuran (20 ml) in this sequence, and the resulting mixture was further stirred at -78° C. for 30 minutes. To the reaction mixture were added tetrahydrofuran (10 ml) followed by water, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous saline in this sequence. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to give ethyl 4-hydroxy-4-(2-nitrophenyl)-2-butynoate as an oily product. After the ethyl 4-hydroxy-4-(2-nitrophenyl)-2-butynoate thus obtained was dissolved in toluene (80 ml), 4-methoxybenzylazide (13.0 g, 79.7 mmole) was added to the solution and stirred under heating at 100° C. for 3 hours. The reaction mixture was then cooled to room temperature. Precipitates were collected by filtration, washed with toluene and desiccated to give ethyl 5-[hydroxy-(2-nitrophenyl)methyl]-1-(4-methoxybenzyl)-1,2, 3-triazole-4-carboxylate (a-2: highly polar product (MP)) (2.55 g, 15.7%). Furthermore, the filtrate was concentrated and purified by silica gel column chromatography (toluene : ethyl acetate =1:1) to give a 3:1 mixture (6.09 g, 37.4%) of ethyl 4-(hydroxy-(2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1, 2,3-triazole-5-carboxylate (a-1: low polar product (LP)) and a compound a-2.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[CH2:9][C@@H:10]([N:13]1[C@H:18]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C@@H:17]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)[CH2:16][C@@:15]([CH2:34][C:35]([O:37][CH3:38])=[O:36])([CH3:33])[C:14]1=[O:39])[CH2:11][CH3:12])=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][CH2:9][C@@H:10]([N:13]1[C@H:18]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[C@@H:17]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)[CH2:16][C@@:15]([CH2:34][C:35]([O:37][CH3:38])=[O:36])([CH3:33])[C:14]1=[O:39])[CH2:11][CH3:12]
Reactant: CC[C@@H](CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@@H](CN)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
A solution of methyl 2-((3R,5R,6S)-1-((S)-1-(bis(tert-butoxycarbonyl)amino)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate (167 mg, 0.246 mmol) prepared in Step A above in dioxane was stirred with HCl (4M, 0.6 mL) at rt for 2 h. Chromatography on silica gel (0 to 20% MeOH/DCM) gave the title compound. Mass Spectrum (ESI) m/z=477 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][CH2:16][C@@H:17]([C:32]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]([C:75]2[CH:80]=[CH:79][C:78]([NH:81][C:82](=[O:107])[C@H:83]([CH2:98][CH2:99][C:100]([O:102]C(C)(C)C)=[O:101])[NH:84][C:85](=[O:97])[CH2:86][C:87]3[C:95]4[C:90](=[CH:91][CH:92]=[CH:93][CH:94]=4)[NH:89][C:88]=3[CH3:96])=[CH:77][CH:76]=2)[C:42]2[CH:47]=[CH:46][C:45]([NH:48][C:49](=[O:74])[C@H:50]([CH2:65][CH2:66][C:67]([O:69]C(C)(C)C)=[O:68])[NH:51][C:52](=[O:64])[CH2:53][C:54]3[C:62]4[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=4)[NH:56][C:55]=3[CH3:63])=[CH:44][CH:43]=2)=[CH:37][CH:36]=1)=[O:33])[NH:18][C:19](=[O:31])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][C:22]=1[CH3:30])=[O:14])(C)(C)C>CO>[CH3:96][C:88]1[NH:89][C:90]2[C:95]([C:87]=1[CH2:86][C:85]([NH:84][C@H:83]([C:82]([NH:81][C:78]1[CH:77]=[CH:76][C:75]([CH:41]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:32](=[O:33])[C@H:17]([CH2:16][CH2:15][C:13](=[O:12])[OH:14])[NH:18][C:19](=[O:31])[CH2:20][C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[NH:23][C:22]=4[CH3:30])=[CH:40][CH:39]=3)[C:42]3[CH:47]=[CH:46][C:45]([NH:48][C:49](=[O:74])[C@H:50]([CH2:65][CH2:66][C:67](=[O:68])[OH:69])[NH:51][C:52](=[O:64])[CH2:53][C:54]4[C:62]5[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=5)[NH:56][C:55]=4[CH3:63])=[CH:44][CH:43]=3)=[CH:80][CH:79]=1)=[O:107])[CH2:98][CH2:99][C:100](=[O:101])[OH:102])=[O:97])=[CH:94][CH:93]=[CH:92][CH:91]=2
Reactant: Cc1[nH]c2ccccc2c1CC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)Nc1ccc(C(c2ccc(NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)Cc3c(C)[nH]c4ccccc34)cc2)c2ccc(NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)Cc3c(C)[nH]c4ccccc34)cc2)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]c2ccccc2c1CC(=O)N[C@@H](CCC(=O)O)C(=O)Nc1ccc(C(c2ccc(NC(=O)[C@H](CCC(=O)O)NC(=O)Cc3c(C)[nH]c4ccccc34)cc2)c2ccc(NC(=O)[C@H](CCC(=O)O)NC(=O)Cc3c(C)[nH]c4ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.6 %

Procedure:
A methanol solution containing trifluoroacetic acid (40%, 6 ml) was added to the tris[4-[β-t-butoxycarbonylmethyl-N-[2-(2-methyl-1H-indol-3-yl)acetyl]-L-alanyl]aminophenyl]methane (50 mg) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, a portion of the residue was purified by preparative high performance liquid chromatography using methanol/trifluoroacetic acid (100/0.1) and water/trifluoroacetic acid (100/0.1) as a mixed eluent, to obtain 2.0 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:18][CH3:19])[C:5]([O:16][CH3:17])=[C:6]2[C:11]=1[N:10]=[C:9]([O:12]C)[N:8]=[C:7]2[NH:14][CH3:15].[I-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:18][CH3:19])[C:5]([O:16][CH3:17])=[C:6]2[C:11]=1[N:10]=[C:9]([OH:12])[N:8]=[C:7]2[NH:14][CH3:15]
Reactant: CNc1nc(OC)nc2c(Cl)cc(OC)c(OC)c12
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CNc1nc(O)nc2c(Cl)cc(OC)c(OC)c12
Yield: 36.4 %

Procedure:
A solution of 8-chloro-2,5,6-trimethoxy-4-methylaminoquinazoline (1.80 g, 0.0054 moles), sodium iodide (0.989 g, 0.0066 moles) and glacial acetic acid (50 ml) was refluxed for 8 minutes. The glacial acetic acid was removed in vacuo and the residue was diluted with water (100 ml). After extracting the aqueous solution with dichloromethane (2×25 ml) the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Recrystallization of the residue from ethyl acetate-isopropanol afforded the product (0.530 g), mp 219°-221° C.
Reaction SMILES: [N+:1](=[C:3]1[N:7]=[CH:6][N:5]=[C:4]1[C:8]([NH2:10])=[O:9])=[N-:2].CC[O:13][CH2:14][CH3:15]>CS(C)=O>[CH3:4][C:3]1[N:7]=[C:14]([CH2:15][N:10]2[C:8](=[O:9])[N:7]3[CH:6]=[N:5][C:4]([C:8]([NH2:10])=[O:9])=[C:3]3[N:1]=[N:2]2)[O:13][N:1]=1
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Reactant: CCOCC
Solvent: CS(C)=O
Product: Cc1noc(Cn2nnc3c(C(N)=O)ncn3c2=O)n1
Temperature: 0 °C
Yield: 56 %

Procedure:
An aqueous solution of NaNO2 (84 mg, 1.2 mmol) was added to a cooled (0° C.) solution of (3-methyl-[1,2,4]oxadiazol-5-yl)-acetic acid hydrazide (1.02 mmol) in a 1:1 mixture of CH2Cl2:1M HCl (1.5 mL). The reaction mixture was stirred at this temperature for 5 minutes before being poured onto crushed ice. The crude azide was extracted with CH2Cl2 and then dried (MgSO4), filtered and concentrated in vacuo. Toluene (1.5 mL) was added to the crude residue and the resultant mixture heated to 80° C. for 1 hour whereupon it was cooled and concentrated in vacuo to give a crude orange residue corresponding to 5-isocyanatomethyl-3-methyl-[1,2,4]oxadiazole (quantitative yield assumed) (1H NMR (400 MHz, CDCl3) δ ppm: 4.56 (2H, s), 2.36 (3H, s). IR (μmax, cm−1): 2260.7 (s, N═C═O), 1593.3 (m), 1494.9 (m), 1435.1 (w), 1325.1 (m)) which was then diluted in DMSO (1.5 mL) and added to a solution of 5-diazoimidazole-4-carboxamide (355 mg, 2.58 mmol) in 3.5 mL DMSO. The reaction mixture was stirred at room temperature for 10 minutes before the addition of sufficient ice water to cause precipitation of the crude product which was collected by vacuum filtration and washed with EtOH (1 reaction volume and then Et2O (1 reaction volume) to give the title compound as a yellow solid (56% yield). 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.92 (1H, s), 7.88 (1H, s), 7.74 (1H, s), 5.89 (2H, s), 2.34 (3H, s).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([N+:14]([O-])=O)[CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1.C1CCCCC=1>[Pd].C(O)C>[NH2:14][C:9]1[CH:8]=[C:7]([C:2]2([CH3:1])[O:3][CH2:4][CH2:5][O:6]2)[CH:12]=[CH:11][C:10]=1[OH:13]
Reactant: CC1(c2ccc(O)c([N+](=O)[O-])c2)OCCO1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC1(c2ccc(O)c(N)c2)OCCO1
Temperature: 25 °C
Yield: 76 %

Procedure:
A stirred mixture of 4-(2-methyl-1,3-dioxolan-2-yl)-2-nitrophenol D61 (2.40 g, 10.66 mmol), cyclohexene (4.38 g, 53.3 mmol) and 10% palladium on carbon (0.227 g, 0.213 mmol) in ethanol (75 mL) was heated to reflux for 6 hr under argon. The mixture was cooled to rt and the catalyst was removed by filtration through celite. The filtrate was concentrated to dryness in vacuo and the reside dissolved in 10% MeOH in DCM (20 mL) and passed through a SCX-2 cartridge (25 g) which was then eluted with further 10% MeOH in DCM to wash through any unreacted starting material and then with 2M ammonia in MeOH. The basic eluate was concentrated under vacuum to give the title compound as a yellow-brown solid (1.58 g, 76%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:10][OH:11]>>[CH3:10][O:11][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCc1ccccc1
Reactant: CO
Product: COCCc1ccccc1
Temperature: 149 °C
Reaction time: 2 h

Procedure:
A mixture of (2-bromoethyl)benzene (2.0 g) and methanol (60 mL) in a PEEK vessel equipped with a magnetic stirrer bar was placed into the reactor, and the cover sealed. The mixture was stirred and heated to 149° C. (1.08 MPa) within 10 min and held at this temperature for 2 hours. Samples were withdrawn periodically and analysed. The mixture was then cooled. After 1 hour the conversion to (2-methoxyethyl)benzene was 50% increasing to 80% after 2 hours. GC/MS: m/z (rel.int. %) 136(M +, 13), 104(8), 91(28), 77(6), 65(11), 63(4), 51(9), 50(4), 45(100). 1H NMR, (CDCl3 ; 200 MHz): δ7.23, m, 5H, Ar; 3.6, t, 2H, --CH2 --O--CH3 ; 3.4, s, 3H, --O --CH3 ; 2.9, t, 2H, Ar--CH2 --.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([NH2:20])[CH:19]=1>CCO>[CH3:12][C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:20][C:18]3[CH:19]=[C:14]([CH3:13])[CH:15]=[CH:16][C:17]=3[S:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2ccccc2)c(N)c1
Solvent: CCO
Product: Cc1ccc(Sc2ccccc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
A stirred solution of the product from Example 7d (65 mg, 0.36 mmol) and the product from Example 7f (77 mg, 0.36 mmol) in 3 mL of EtOH was heated at 80° C. for 7 h. Concentrated under vacuum. Recrystallized from THF with a few drops of MeOH. Filtration gave the title compound as the hydrochloride salt as a white solid (62 mg, 43%) 1H NMR (300 MHz, CDCl3) δ ppm: 1.62 (brs, 1 H) 2.43 (s, 3 H) 2.52 (s, 3 H) 6.02 (d, J=7.0 Hz, 1 H) 7.05-7.35 (m, 8 H) 7.70 (brs, 1 H) 8.00 (d, J=7.0 Hz, 1 H) 8.85 (d, J=8.5 Hz, 1 H) 10.80 (brs, 1 H); MS (ESI+) m/z 358 (M-Cl)+; (ESI−) m/z 356 (M−HCl)−.
Reaction SMILES: [CH2:1]([N:8]([CH3:23])[C:9](=[O:22])[C:10](=O)[NH:11][N:12]=[C:13](OCC)[CH2:14][CH2:15][CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH2:39])=[CH:34][CH:33]=1)#[N:25]>C(O)C>[CH2:1]([N:8]([CH3:23])[C:9]([C:10]1[N:39]([CH2:38][C:35]2[CH:34]=[CH:33][C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:24]#[N:25])=[CH:37][CH:36]=2)[C:13]([CH2:14][CH2:15][CH2:16][CH3:17])=[N:12][N:11]=1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccccc1-c1ccc(CN)cc1
Reactant: CCCCC(=NNC(=O)C(=O)N(C)Cc1ccccc1)OCC
Solvent: CCO
Product: CCCCc1nnc(C(=O)N(C)Cc2ccccc2)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
A mixture of 319 mg (1 mmole) of ethyl valerate 5-benzyl-5-methylsemioxamazone (from Step C), 312 mg (1.5 mmole) of [(2'-cyanobiphenyl-4-yl)methyl]amine (from Step D), and 3 ml of dry ethanol was stirred under N2 in an oil bath at 50° C. for 2 hours and then at 70° C. for an additional 22 hours. The solution was concentrated in vacuo, and a solution of the residue in 30 ml of ethyl acetate was washed with 2×25 ml of 2 N HCl followed by 25 ml of saturated NaHCO3. The dried (MgSO4) ethyl acetate phase was filtered and concentrated. Column chromatography of the residue on silica gel (gradient elution using 0.25-5% isopropanol in CH2Cl2 gave 353 mg (76%) of the title compound as a hard glass, mp >40° C. (gradual), homogeneous by TLC in 19:1 CH2Cl 2 --MeOH; mass spectrum (FAB) m/e 464 (M+i)+. NMR indicated approximately a 1:1 ratio of amide rotamers.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:21])([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([C:24]1[N:29]=[C:28]([NH:30][CH2:31][CH:32]2[CH2:39][CH2:38][C:35]3([CH2:37][CH2:36]3)[CH2:34][CH2:33]2)[C:27]([C:40](O)=[O:41])=[CH:26][N:25]=1)#[N:23].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([NH:21][C:40]([C:27]2[C:28]([NH:30][CH2:31][CH:32]3[CH2:39][CH2:38][C:35]4([CH2:37][CH2:36]4)[CH2:34][CH2:33]3)=[N:29][C:24]([C:22]#[N:23])=[N:25][CH:26]=2)=[O:41])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(Cc2ccccc2)CC1
Reactant: N#Cc1ncc(C(=O)O)c(NCC2CCC3(CC2)CC3)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(NC(=O)c2cnc(C#N)nc2NCC2CCC3(CC2)CC3)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of the 4-amino-4-benzylpiperidine-1-carboxylic acid tert-butyl ester (0.38 mmol, step 66.1) and 2-cyano-4-[(spiro[2.5]oct-6-ylmethyl)amino]pyrimidine-5-carboxylic acid (0.38 mmol) in DMF (1.3 mL) are added HOAt (0.51 mmol) and EDCI-HCl (0.51 mmol) at 0° C. After warming to room temperature and stirring for 15 h, the reaction mixture is diluted with AcOEt and washed with 1N aq. KHSO4, sat. aq. NaHCO3, and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give 4-benzyl-4-({2-cyano-4-[(spiro[2.5]oct-6-ylmethyl)-amino]-pyrimidine-5-carbonyl}amino)piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([O:11][CH3:10])[CH:17]=2)=[N:3][CH:4]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1cc(Br)cnc1Br
Product: COc1cccc(-c2ncc(Br)cc2C)c1
Yield: 23 %

Procedure:
Obtained (1.00 g, yield 23%) following the procedure described in Intermediate 27, starting with 2,5-dibromo-3-methylpyridine (15.94 mmol, 4.0 g), 3-methoxyphenylboronic acid (15.93 mmol, 2.42 g).