Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]=1[F:32])[OH:6])[CH3:2].I[CH2:35][CH3:36]>>[CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([O:14][Si:15]([C:28]([CH3:29])([CH3:31])[CH3:30])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8]=1[F:32])[O:6][CH2:35][CH3:36])[CH3:2]
Reactant: CCOC(=O)C(O)c1c(F)ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1F
Reactant: CCI
Product: CCOC(=O)C(OCC)c1c(F)ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1F
Temperature: 90 °C
Reaction time: 68 h
Yield: 83.3 %

Procedure:
A mixture of (RS)-[3-(tert-butyl-diphenyl-silanyloxy)-2,6-difluoro-phenyl]-hydroxy-acetic acid ethyl ester (70.8 g), Ag2O (69.7 g) and iodoethane (117 g) in Tol (700 ml) was stirred 68 h at 90° C. After filtration and evaporation of the solvent the product was separated from the remaining starting material by MPLC (Hept to Hept/AcOEt 1:9). The procedure was repeated with the recovered starting material. 62.5 g (83%) of (RS)-[3-(tert-butyl-diphenyl-silanyloxy)-2,6-difluoro-phenyl]-ethoxy-acetic acid ethyl ester were obtained. Light yellow oil. MS 498.3 (1, M+); 441.1 (73, [M−tBu]+); 425.2 (33, [M-COOEt]+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH2:16][CH3:17])[N:14]=[C:13]([C:18](=[N:20][NH:21][C:22]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=3)=[O:23])[CH3:19])[C:12]=2[OH:34])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH2:16][CH3:17])[N:14]=[C:13]([C:18](=[N:20][NH:21][C:22]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[O:23])[CH3:19])[C:12]=2[OH:34])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc(C(C)=NNC(=O)c2ccc(C(=O)OC)cc2)c(O)c1-c1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCn1nc(C(C)=NNC(=O)c2ccc(C(=O)O)cc2)c(O)c1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 44.6 %

Procedure:
To methyl 4-[(2-{1-[5-(4-t-butylphenyl)-1-ethyl-4-hydroxy-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]benzoate (0.032 mmol, 15.0 mg), methanol (1.5 mL) was added, and 1 M aqueous sodium hydroxide (0.162 mmol, 0.162 mL) was added at room temperature. After 30 minutes of stirring at room temperature and 1.25 hours of stirring at 60° C., the reactor was cooled to 0° C., and 1 M hydrochloric acid (0.162 mmol, 0.162 mL) and water were added. The precipitated solid was recovered by filtration, washed with water, dried by means of a vacuum pump and purified by silica gel thin layer chromatography (chloroform/methanol=10/1) to give the desired product as a yellow solid (6.4 mg, yield 44%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:37][CH2:38][CH2:39][CH3:40])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH2:25][C:26]3[CH:27]=[C:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:29]=[CH:30][CH:31]=3)[CH2:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:41][N:42]1[CH2:47]CNC[CH2:43]1>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:37][CH2:38][CH2:39][CH3:40])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH2:25][C:26]3[CH:27]=[C:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:29]=[CH:30][CH:31]=3)[CH2:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:43][N:42]([CH3:47])[CH2:41][CH2:24]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(CCCN(C)C)Cc1cccc(CC(=O)OC)c1
Reactant: CN1CCNCC1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(CCCN1CCN(C)CC1)Cc1cccc(CC(=O)OC)c1

Procedure:
The title compound was prepared by the method of example 11step (x) using the product of example11 step (ix) (627 mg) and N-methylpiperazine (1 ml) as a colourless gum 120 mg.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])OC1=O.O[NH:14][C:15](=[NH:17])[CH3:16].CCN(C(C)C)C(C)C>C1COCC1>[CH3:16][C:15]1[N:17]=[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH2:1])[O:11][N:14]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CC(=N)NO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1noc(-c2ccccc2N)n1
Temperature: 180 °C
Yield: 69.2 %

Procedure:
A mixture of 1H-benzo[d][1,3]oxazine-2,4-dione (3.5 g) in THF (35 mL) was treated with N-hydroxy-acetamidine (1.7 g), and DIEA (8 mL). The reaction mixture was microwave heated at 180° C. for 5 minutes, concentrated and purified by silica gel chromatography to afford 2.6 g of 2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenylamine: 1H NMR (300 MHz, CDCl3) δ 8.0 (d, 1H), 7.4 (t, 1H), 6.9 (m, 2H), 6.0 (bs, 2H), 2.6 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][C:4]1[CH:11]=[C:9]([I:10])[C:8]([O:12][C:13]2[CH:20]=[C:18]([I:19])[C:17]([OH:21])=[C:15]([I:16])[CH:14]=2)=[C:6]([I:7])[CH:5]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].O>C1COCC1.CN(C)C1C=CN=CC=1>[C:25]([O:23][C:22](=[O:24])[C@H:2]([CH2:3][C:4]1[CH:5]=[C:6]([I:7])[C:8]([O:12][C:13]2[CH:14]=[C:15]([I:16])[C:17]([OH:21])=[C:18]([I:19])[CH:20]=2)=[C:9]([I:10])[CH:11]=1)[NH2:1])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OC(=O)[C@@H](N)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Reaction time: 0.75 h
Yield: 115.5 %

Procedure:
The N-FMOC protected L-Thyroxine (26.3 g, 23.2 mmol) was dissolved in 150 mL THF, 3.28 mL (34.8 mmol) of acetic anhydride added, 283 mg (2.32 mmol) of 4-dimethylaminopyridine added, and reaction stirred under N2 for 45 minutes, then poured into 400 mL H2O and extracted with CHCl3 (3×400 mL). The CHCl3 extracts were combined, dried over Na2SO4, and solvent removed in vacuo. The residue was then purified by silica gel column chromatography, eluting with CH2 Cl2 /MeOH/HOAc (90/10/0.4, v/v), to yield 21.95 g (91%) of the desired O-acetyl thyroxine as a beige solid; 1H NMR (300 MHz, DMSO-D6) d 7.12-7.91 (m, 12H), 4.07-4.31 (m, 4H), 3.07-3.19 (m, 1H), 2.82 (t, 1H), 2.29-2.40 (m, 3H); mass spec (FAB) (M+H)+1042.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6](#[N:10])/[CH:7]=[CH:8]/[CH3:9]>>[N:1]1([CH:8]([CH3:9])[CH2:7][CH2:6][NH2:10])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C/C=C/C#N
Reactant: c1c[nH]cn1
Product: CC(CCN)n1ccnc1

Procedure:
When the above procedure is used to react imidazole with crotononitrile, 3-(1H-imidazol-1-yl)butanamine is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([CH2:22][C:23]3[CH:24]=[N:25][C:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:27][CH:28]=3)([C:18]([O:20][CH3:21])=[O:19])[C:14]([O:16][CH3:17])=[O:15])[N:10]=[CH:9]2)=[CH:4][CH:3]=1.[C:37]1([N:43]=[C:44]=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>C(#N)C.CN(C)C1C=CN=CC=1>[C:33]([O:32][C:30]([NH:29][C:26]1[N:25]=[CH:24][C:23]([CH2:22][C:13]([C:11]2[N:10]=[CH:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:44]([NH:43][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:45])=[CH:7][CH:6]=3)[CH:12]=2)([C:14]([O:16][CH3:17])=[O:15])[C:18]([O:20][CH3:21])=[O:19])=[CH:28][CH:27]=1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: COC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)(C(=O)OC)c1cn(-c2ccc(N)cc2)cn1
Reactant: O=C=Nc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)(C(=O)OC)c1cn(-c2ccc(NC(=O)Nc3ccccc3)cc2)cn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
50 mg (0.10 mmol) of the compound from example 12f were dissolved in 10 ml of acetonitrile. The resulting solution was cooled to 0° C., and 14 mg (0.12 mmol, 13.2 μl) of phenyl isocyanate and 20 mg (0.20 mmol, 28 μl) of triethylamine were added. The mixture was warmed to RT, and a spatula tip of 4-dimethylaminopyridine was added. The reaction mixture was left to stand overnight and then evaporated, and the residue was chromatographed on silica gel. 47 mg of the title compound were obtained.
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([OH:13])=O)[CH2:6][CH2:5]1)[CH3:3].[NH2:14][C@@H:15]([CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)=[O:17]>>[CH2:35]([O:34][CH2:33][C@H:15]([NH:14][C:11](=[O:13])[CH2:10][N:7]1[CH2:6][CH2:5][N:4]([CH2:2][CH3:3])[CH2:9][CH2:8]1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)=[O:17])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCN1CCN(CC(=O)O)CC1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: CCN1CCN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)CC1
Yield: 48.2 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-ethylpiperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 114, (S)-3-(benzyloxy)-2-(2-(4-ethylpiperazin-1-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (20.6 mg, 48.2%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 7.93 (d, 1H), 7.60 (d, 2H), 7.31-7.25 (m, 5H), 7.21 (t, 2H), 7.04-6.99 (m, 4H), 4.69 (m, 1H), 4.51 (s, 2H), 3.76 (m, 1H), 3.71 (m, 1H), 2.97 (s, 2H), 2.46 (m, 3H), 2.38 (m, 3H), 2.33-2.28 (m, 4H), 0.98 (t, 3H). MS (EI) for C30H35FN4O4. found 535.6 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH:9]1[CH2:12][CH:11]([OH:13])[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([NH:7][CH2:8][CH:9]1[CH2:10][CH:11]([O:13][C:22](=[O:23])[C:21]2[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:26][CH:25]=2)[CH2:12]1)=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)NCC1CC(O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.1 %

Procedure:
To an ice-cooled solution of (3-Hydroxy-cyclobutylmethyl)-carbamic acid tert-butyl ester (6.98 g, 34.7 mmol), 4-nitrobenzoic acid (11.59 g, 69.4 mmol) and triphenylphosphine (18.19 g, 69.4 mmol) in THF (1 L) was added a solution of DIAD (14.76 g, 69.4 mmol) in THF (10 mL). After removal of the ice bath, the mixture was stirred at RT for 15 h. The mixture was concentrated to dryness and the oily residue was purified normal phase column chromatography (elution with DCM) yielding the title intermediate as a yellow solid (9.89 g, 22.58 mmol, 65%), HPLC: FtRet=1.354; LC-MS: m/z 368.3 [M+NH4]+.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH3:19][NH:20][CH3:21].O>C1COCC1>[CH3:18][O:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:20]([CH3:21])[CH3:19])=[N:7][CH:6]=3)[S:9][C:10]=2[CH:16]=1
Reactant: COc1ccc2nc(-c3ccc(F)nc3)sc2c1
Reactant: CNC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2nc(-c3ccc(N(C)C)nc3)sc2c1

Procedure:
2-(6-Fluoropyridin-3-yl)-6-methoxy-1,3-benzothiazole (0.201 g) and 2 M dimethylamine in THF (5 mL) were heated in a microwave oven at 100° C. for 5 min. Water was added and the precipitated product was filtered off, washed with water and dried in a desicator over P2O5 to yield 0.193 g of the product as a pale beige solid. 1H NMR δ ppm 8.71 (d, 1H) 8.07 (dd, 1H) 7.84 (d, 1H) 7.65 (d, 1H) 7.08 (dd, 1H) 6.77 (d, 1H) 3.84 (s, 3H) 3.12 (s, 6H); MS m/z (M+H) 286.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH2:17][CH:18]=[CH2:19])[C:11]2=[O:20])=[N:7][N:6]=1)(=[O:4])=[O:3].[Cl:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>C(N(CC)CC)C>[CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:29](=[O:30])[NH:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=3)[CH2:14][CH2:13][N:12]([CH2:17][CH:18]=[CH2:19])[C:11]2=[O:20])=[N:7][N:6]=1)(=[O:4])=[O:3]
Reactant: C=CCN1CCC(O)N(c2nnc(S(C)(=O)=O)s2)C1=O
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: CCN(CC)CC
Product: C=CCN1CCC(OC(=O)Nc2cccc(Cl)c2)N(c2nnc(S(C)(=O)=O)s2)C1=O
Reaction time: 1 h

Procedure:
Tetrahydro-1-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)-3-allyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) and 3-chlorophenyl isocyanate (3.5 ml; 0.06 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer. The mixture is stirred and triethylamine (1 drop) is added thereto. After the addition is completed the reaction mixture is allowed to stand for a period of about 1 hour. The mixture is then washed with hexane and is dried to yield the desired product tetrahydro-1-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)-3-allyl-6-[N-(3-chlorophenyl)carbamoyloxy]-2(1H)-pyrimidinone.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:14][C:13]3[CH:15]=[C:16]([C:19]4[CH:20]=[C:21]5[NH:27][C:26]([CH3:28])=[N:25][C:22]5=[N:23][CH:24]=4)[CH:17]=[CH:18][C:12]=3[O:11][CH2:10][CH2:9]2)[C:3]=1[CH3:29].[CH2:30]([NH2:32])[CH3:31]>CN1CCCC1=O.C(OCC)(=O)C>[CH2:30]([NH:32][C:2]1[C:3]([CH3:29])=[C:4]([N:8]2[CH2:14][C:13]3[CH:15]=[C:16]([C:19]4[CH:20]=[C:21]5[NH:27][C:26]([CH3:28])=[N:25][C:22]5=[N:23][CH:24]=4)[CH:17]=[CH:18][C:12]=3[O:11][CH2:10][CH2:9]2)[N:5]=[CH:6][N:7]=1)[CH3:31]
Reactant: CCN
Reactant: Cc1nc2ncc(-c3ccc4c(c3)CN(c3ncnc(Cl)c3C)CCO4)cc2[nH]1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCNc1ncnc(N2CCOc3ccc(-c4cnc5nc(C)[nH]c5c4)cc3C2)c1C
Yield: 28.4 %

Procedure:
A suspension of 4-(6-chloro-5-methylpyrimidin-4-yl)-7-(2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (44 mg, 0.11 mmol), and ethylamine (29 mg, 0.65 mmol), in N-methylpyrrolidinone (2 mL) was stirred at 100° C. for 6 h. The reaction mixture was diluted with ethyl acetate (75 mL), washed with saturated sodium bicarbonate (75 mL) and brine (50 mL), and dried over sodium sulfate. Concentration and purification by preparatory HPLC (0.1% aqueous ammonium acetate-acetonitrile) gave N-ethyl-5-methyl-6-[7-(2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]pyrimidin-4-amine (13 mg, 30% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.50 (s, 1H), 8.07 (s, 1H), 8.04 (d, 1H), 7.56-7.48 (m, 2H), 7.11 (d, 1H), 4.57 (s, 2H), 4.33 (d, 2H), 3.79 (d, 2H), 3.53-3.39 (q, 2H), 2.64 (s, 3H), 2.04 (s, 3H), 1.21 (t, 3H); MS (EI) for C23H25N7O: 416 (MH+).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH2:9][CH2:10][C:11](=[O:13])[CH3:12])[CH:8]=1)([O-])=O.[C:14]([O:18][C:19]([NH:21][CH:22]([CH2:26][CH2:27][CH3:28])[C:23](O)=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19](=[O:20])[NH:21][CH:22]([C:23](=[O:24])[NH:1][C:4]1[N:5]=[CH:6][N:7]([CH2:9][CH2:10][C:11](=[O:13])[CH3:12])[CH:8]=1)[CH2:26][CH2:27][CH3:28])([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(=O)CCn1cnc([N+](=O)[O-])c1
Reactant: CCCC(NC(=O)OC(C)(C)C)C(=O)O
Product: CCCC(NC(=O)OC(C)(C)C)C(=O)Nc1cn(CCC(C)=O)cn1

Procedure:
4-(4-nitro-1H-imidazol-1-yl)butan-2-one was reduced and coupled with 2-[(tert-butoxycarbonyl)amino]pentanoic acid to afford the title compound; MS 353 m/z (M+1).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].Cl.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([C:22]3[CH:31]=[C:30]4[C:25]([CH2:26][CH2:27][N:28]([C:32](=[O:39])[CH2:33][CH:34]5[CH2:38][CH2:37][NH:36][CH2:35]5)[CH2:29]4)=[CH:24][CH:23]=3)[N:19]=[C:18]([NH2:40])[N:17]=2)[CH2:12][CH2:11]1>>[NH2:40][C:18]1[N:19]=[C:20]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][N:28]([C:32](=[O:39])[CH2:33][CH:34]4[CH2:38][CH2:37][N:36]([C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3])[CH2:35]4)[CH2:29]3)=[CH:24][CH:23]=2)[CH:21]=[C:16]([N:13]2[CH2:12][CH2:11][N:10]([CH3:9])[CH2:15][CH2:14]2)[N:17]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCNC3)CC4)nc(N)n2)CC1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Product: CC(C)OC(=O)N1CCC(CC(=O)N2CCc3ccc(-c4cc(N5CCN(C)CC5)nc(N)n4)cc3C2)C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 118, Step 3 starting from isopropyl chloroformate and 4-(4-methylpiperazin-1-yl)-6-[2-(pyrrolidin-3-ylacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=522.2.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[C:8]#[N:9].O.O.[Sn](Cl)Cl>CO>[NH2:13][C:12]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[O:4][C:3]1[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=1[Br:1]
Reactant: N#Cc1ccc([N+](=O)[O-])c(Oc2ccccc2Br)c1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: N#Cc1ccc(N)c(Oc2ccccc2Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a mixture of 3-(2-bromophenoxy)-4-nitrobenzonitrile, 1 (5 g; 15.67 mmol) in methanol (100 mL) was added tin(II) chloride dihydrate (17.68 g; 78.36 mmol). The mixture was stirred at rt overnight, and the solvent was removed via evaporation. Ethyl acetate (100 mL) and 1N NaOH (100 mL) were added, and the solvents were removed via evaporation. Ethyl acetate (200 mL) was added, and white solid formed. The solid was removed via filtration, washed with ethyl acetate, and the combined filtrates were evaporated. The residue was purified via column chromatography (eluent gradient: 10% to 30% ethyl acetate in heptane) to yield 3.0 g (66%) of 4-amino-3-(2-bromophenoxy)-benzonitrile, 2a. MS m/z (MH+) 288.7/289.7.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.C[O-].[Na+].[Br:16][C:17]1[C:22]([O:23][CH2:24][CH3:25])=[CH:21][C:20]([NH:26][C:27](=O)[O:28]CC)=[C:19]([F:32])[CH:18]=1>CN(C=O)C>[Br:16][C:17]1[C:22]([O:23][CH2:24][CH3:25])=[CH:21][C:20]([N:26]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:27]2=[O:28])=[C:19]([F:32])[CH:18]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CCOC(=O)Nc1cc(OCC)c(Br)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Br
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Ethyl 3-amino-4,4,4-trifluorocrotonate (3.42 g) was dissolved in DMF (19 ml). To this solution, a suspension of sodium methoxide (1.10 g) in DMF was added dropwise at 5° C., and the mixture was stirred at 5° C. for 30 minutes. Then, a DNF solution of ethyl N-(4-bromo-5-ethoxy-2-fluorophenyl)-carbamate was added dropwise thereto, and the mixture was stirred at 130° C. for 4 hours. After the reaction, DMF was distilled off under reduced pressure. Then, the residue was acidified by adding diluted hydrochloric acid thereto. This was extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off, and the resulting residue was crystallized from a mixed solvent of ethyl acetate and n-hexane (1:3 v/v) to obtain the objective 3-(4-bromo-5-ethoxy-2-fluorophenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (3.63 g).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]#[C:20][CH2:21][CH2:22][NH:23]C(=O)OCC1C=CC=CC=1)[CH:13]=[CH:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[CH2:12]([CH:22]([NH2:23])[CH2:21][CH2:20][CH2:19][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2])[CH:10]=2)[CH:15]=1)[C:11]1[CH:16]=[CH:17][CH:18]=[CH:9][CH:10]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(C#CCCNC(=O)OCc3ccccc3)ccc2c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(CCCC(N)Cc3ccccc3)ccc2c1
Reaction time: 6 h
Yield: 87.6 %

Procedure:
A suspension of 83 (8.0 g, 17.41 mmol) and 10% Pd/C (3.6 g) in MeOH (240 mL) was subjected to hydrogenation conditions (1 atm) for 6 h at room temperature. The reaction mixture was filtered through a plug of diatomaceous earth and the plug was washed with MeOH. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, 90:9:1 CHCl3/CH3OH/NH4OH) to afford amine 95 (3.2 g, 56%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 7.64 (d, J=6.3 Hz, 1H), 7.60 (s, 1H), 7.55 (s, 1H), 7.30 (d, J=1.5 Hz, 1H), 7.15 (s, 1H), 7.03 (dd, J=8.9 Hz, 2.3 Hz, 1H), 2.76 (t, J=7.4 Hz, 2H), 2.70 (t, J=7.2 Hz, 2H), 1.79-1.69 (m, 2H), 1.59-1.49 (m, 2H), 1.04 (s, 9H), 0.25 (s, 6H).
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.S(Cl)([Cl:14])=O>>[CH3:1][N:2]=[C:3]([Cl:14])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1
Reactant: CNC(=O)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Product: CN=C(Cl)c1ccc(Cl)cc1
Yield: 83.3 %

Procedure:
N-Methyl 4-chlorobenzamide (42.6 g, 251 mmole) and thionyl chloride (153.3 g, 1.28 mole) were reacted as in Example I to yield 39.3 g (83.4%) of the title compound, b.p. 125° C. (15 mm Hg).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[S:45](Cl)(=[O:47])=[O:46])#[N:38].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[S:45]([N:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:10][CH:11]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH:18]=1)(=[O:47])=[O:46])#[N:38]
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: c1cc(CNc2ccc(OCCN3CCCC3)cc2)cc(OC2CCCCO2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccccc1S(=O)(=O)N(Cc1cccc(OC2CCCCO2)c1)c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[3-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (0.091 g, 0.23 mmol) and triethylamine (0.097 mL, 0.69 mmol) in 2 mL methylene chloride was added 2-cyanobenzenesulfonyl chloride (0.093 g, 0.46 mmol). The reaction mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was washed with an additional 2 mL of methylene chloride. The combined organic layers were concentrated to afford the title compound of Step A.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]O)[CH2:5][CH2:4]1)[CH3:2].Cl.N1CCC(CC[CH2:21][OH:22])CC1>>[CH2:1]([N:3]1[CH2:4][CH2:5][CH:6]([CH2:9][CH2:10][CH2:21][OH:22])[CH2:7][CH2:8]1)[CH3:2]
Reactant: OCCCC1CCNCC1
Reactant: CCN1CCC(CCO)CC1
Agent: Cl
Product: CCN1CCC(CCCO)CC1

Procedure:
Prepared similarly to Intermediate 20 from 3-(4-piperidinyl)-1-propanol hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4](Cl)[N:3]=1.[Na].[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18]>>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH2:8])[CH:5]=1
Reactant: COCCOCCO
Reactant: Nc1cc(Cl)nc(N)n1
Agent: [Na]
Product: COCCOCCOc1cc(N)nc(N)n1
Temperature: 80 °C
Yield: 109 %

Procedure:
28.9 g (0.20 mol) of 2,4-diamino-6-chloropyrimidine was added to a solution of 4.6 g (0.20 mol) of sodium in 178 ml of 2-(2-methoxyethoxyl)ethanol and heated to 80° C. for 48 h while stirring was performed. After termination of the reaction, the precipitated NaCl was separated and the solution was concentrated to dryness. The residue was taken in ethanol multiple times and concentrated again in order to remove remaining 2-(2-methoxyethoxyl)ethanol. After drying, 6-[2-(2-methoxyethoxyl)ethoxy]pyrimidine-2,4-diamine (49.8 g, 109%) was obtained as brown oil, which still contained 2-(2-methoxyethoxyl)ethanol as a contaminant.