Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[C:8]([N+:12]#[C-:13])([CH3:11])([CH3:10])[CH3:9].[CH:14]1[C:27]2[C:18](=[CH:19][C:20]3[C:25]([C:26]=2[CH:28]=O)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][CH:15]=1>Cl(O)(=O)(=O)=O>[CH:24]1[C:25]2[C:20](=[CH:19][C:18]3[C:27]([C:26]=2[C:28]2[N:1]=[C:2]4[CH:7]=[N:6][CH:5]=[CH:4][N:3]4[C:13]=2[NH:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:21]=[CH:22][CH:23]=1
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Nc1cnccn1
Reactant: O=Cc1c2ccccc2cc2ccccc12
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)Nc1c(-c2c3ccccc3cc3ccccc23)nc2cnccn12

Procedure:
Compound (30) was prepared in accordance with general instructions 1 from 1.0 ml 2-aminopyrazine solution (0.1 M, MC), 0.575 ml tert-butyl isocyanide solution (0.2 M, MC), 0.500 ml anthracene-9-carbaldehyde solution (0.3 M, MC), and 10 μl perchloric acid (w=20%). Calculated mass 366.5; found mass 367.3 (ESI-MS)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:27]=O)=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[NH2:29][CH2:30][CH2:31][OH:32].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH:27]=[N:29][CH2:30][CH2:31][OH:32])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Reactant: NCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1=C(C)NC(C=NCCO)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A mixture of diethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (1.1651 g), 2-aminoethanol (185 mg) and p-toluenesulfonic acid (catalytic amount) in dried benzene (20 ml) was refluxed under azeotropic dehydration for 1.5 hours. After cooling to room temperature, water was added to the resultant solution. The mixture was washed twice with water. The aqueous layer was extracted with diethyl ether and the extract was combined with the benzene solution. The mixed solution was dried over magnesium sulfate and then the solvent was removed from the solution to give viscous oil (1.2397 g) of diethyl 2-methyl-4-(2-nitrophenyl)-6-(2-hydroxyethyl)iminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(O[C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48](O)=O)=[CH:44][CH:43]=2)[CH2:38][CH2:37]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:48][C:45]1[CH:44]=[CH:43][C:42]([CH:39]2[CH2:38][CH2:37][N:36]([CH3:34])[CH2:41][CH2:40]2)=[CH:47][CH:46]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(C2CCN(C)CC2)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 29.1 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (100 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (120 mg) according to an analogous synthetic method to Example 337 described below, the title compound (37 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](Cl)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].[O:18]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.COC(C1C(C)=C2C(NC3C=CC(OC4C=CC=CC=4OC(C(OC(C)(C)C)=O)(C)C)=CC=3)=C(C#N)C=NN2C=1)=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13]([NH:31][C:28]3[CH:27]=[CH:26][C:25]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:30][CH:29]=3)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(Cl)c(C#N)cnn2c1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: COC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)OC(C)(C)C)cc3)c2c1C
Product: CCOC(=O)c1cc2c(Nc3ccc(Oc4ccccc4)cc3)c(C#N)cnn2c1
Yield: 53 %

Procedure:
Compound 403 was prepared from 403C and 4-phenoxy-phenylamine by a route analogous to that used for the preparation of 388D. Yield: 53%. MS Found: (M+H)+=399.2; 1H NMR (CDCl3) δ 8.1 and 7.9 (s, 1H each), 7.3 (m, 2H), 7.26 (m, 2H), 7.2 (m, 2H), 7.15 (m, 4H), 6.2 (s, 1H), 4.25 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:19]([OH:20])[C@@H:18]([CH3:21])[C:16](=[O:17])[C:15]([CH3:23])([CH3:22])[C@@H:14]([OH:24])[CH2:13][C:11](=[O:12])[O:10][C@H:9](/[C:25](/[CH3:33])=[CH:26]/[C:27]2[N:31]=[C:30]([CH3:32])[S:29][CH:28]=2)[CH2:8][CH:7]=[C:6]([CH3:34])[CH2:5][CH2:4][CH2:3]1.CC1(C)O[O:37]1>C(Cl)Cl>[CH3:1][C@@H:2]1[C@H:19]([OH:20])[C@@H:18]([CH3:21])[C:16](=[O:17])[C:15]([CH3:22])([CH3:23])[C@@H:14]([OH:24])[CH2:13][C:11](=[O:12])[O:10][C@H:9](/[C:25](/[CH3:33])=[CH:26]/[C:27]2[N:31]=[C:30]([CH3:32])[S:29][CH:28]=2)[CH2:8][C@@H:7]2[O:37][C@:6]2([CH3:34])[CH2:5][CH2:4][CH2:3]1
Reactant: CC1(C)OO1
Reactant: CC1=CC[C@@H](/C(C)=C/c2csc(C)n2)OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC1
Agent: C/C1=C/C[C@@H](/C(C)=C/c2csc(C)n2)OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC1
Solvent: ClCCl
Product: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2O[C@]2(C)CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
To a solution of desoxyepothilone B (0.0022 g, 0.0041 mmol) in CH2Cl2 (0.25 mL) at −50° C. was added dimethyidioxirane (0.1 mL, 0.0095 mmol) dropwise. The resulting solution was stirred at −50° C. for 1 h. The dimethyldioxirane and solvent were removed by a stream of N2. The residue was purified by flash column chromatography (hexanes/ethyl acetate, 1:1) gave 0.0015 g (70%) of epothiolone B (2) as a pale yellow oil which was identical with an authentic sample in 1H NMR, IR, mass spectrum, and [α]D.
Reaction SMILES: [N:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C:4]=2[NH:3][CH:2]=1.CN(C=O)C.[H-].[Na+].[S:24](Cl)([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>O.C(Cl)Cl>[S:24]([N:3]1[C:4]2[CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:8][C:9]=2[N:1]=[CH:2]1)([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCc2nc[nH]c2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cnc3c2CN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 27.8 %

Procedure:
A flask was charged with tert-butyl 6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (0.44 g, 2.0 mmol, WO2009158394, Example M-In-1) and DMF (10 mL). The mixture was cooled to about 0° C. and NaH (60% dispersion in mineral oil, 0.095 g, 2.4 mmol) was added. The mixture was stirred at about 0° C. for about 20 min followed by the addition of TsCl (0.41 g, 2.2 mmol). The resulting mixture was stirred at about 0° C. for about 90 min and then at about rt for about 3.5 h. The mixture was poured into DCM (40 mL) and water (20 mL) was added. The layers were separated and the organic solution was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0 to 50% EtOAc in DCM to give tert-butyl 3-tosyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (0.21 g, 28%): LC/MS (Table 2, Method n) Rt=2.53 min; MS m/z: 378 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:30](Cl)(=[O:32])[CH3:31]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:30](=[O:32])[CH3:31])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc([C@@H]2Sc3cc(OC)ccc3NC(=O)[C@@H]2O)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3cc(OC)ccc3NC(=O)[C@@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A solution of 500 mg of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 358 mg of pyridine in 8 ml of dimethylformamide is ice-cooled, and a solution of 130 mg of acetyl chloride in 2 ml of dimethylformamide is dropwise added thereto. The mixture is stirred at room temperature for one hour. After the reaction is completed, the mixture is poured into ice-water. The aqueous mixture is extracted with chloroform, and the extract is washed with 10% hydrochloric acid and water, successively. Then, the extract is dried and evaporated under reduced pressure to remove solvent. The residue is recrystallized from a mixture of dimethylformamide and ethanol. 465 mg of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 1/3 hydrate are obtained.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)=[CH:5][C:6]=1[CH:7]=O.[CH:27]1([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:3][C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=3)([C:14]([F:16])([F:15])[F:17])[O:11][N:10]=2)=[CH:5][C:6]=1[CH2:7][NH:32][C:30]([CH:27]1[CH2:29][CH2:28]1)=[O:31]
Reactant: Cc1oc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C=O
Reactant: NC(=O)C1CC1
Agent: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1oc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1CNC(=O)C1CC1
Yield: 86.4 %

Procedure:
A mixture of 2-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-3-carbaldehyde (250 mg, Example 3, step I), cyclopropanecarboxylic acid amide (160 mg), trifluoroacetic acid (0.142 ml) and triethylsilane (0.301 ml) in toluene (4 ml) is refluxed overnight. After 23 hours the reaction mixture is concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield cyclopropanecarboxylic acid {2-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-3-ylmethyl}-amide (251 mg, compound 2.2 in Table 2) as a yellowish foam. MS (HPLC/MS): 495 (MH+). Retention time: 2.02 min.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH:3]([CH3:28])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]2=[O:27])=[CH:12][CH:11]=1)[C:5]([O:7]CC)=[O:6].CO.[OH-].[Na+].Cl>C1COCC1.O>[F:30][C:2]([F:1])([F:29])[CH:3]([CH3:28])[CH:4]([C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]2[CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:20]=[CH:19][C:18]2=[O:27])=[CH:14][CH:15]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(c1ccc(Cn2cc(C(F)(F)F)ccc2=O)cc1)C(C)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C(C(=O)O)c1ccc(Cn2cc(C(F)(F)F)ccc2=O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.80 g (6.43 mmol) of ethyl 4,4,4-trifluoro-3-methyl-2-(4-{[2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl]methyl}phenyl)butanoate were dissolved in 18.2 ml each of THF, methanol and water, and 51.5 ml (128.6 mmol) of 10% strength aqueous sodium hydroxide solution were added. The mixture was stirred at RT overnight. The reaction mixture was then diluted with water, acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. This gave 2.82 g of product, which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]([N:15]3[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[O:14])=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>>[F:29][C:30]([F:35])([F:34])[C:31]([O-:33])=[O:32].[C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]([N:15]3[CH2:21][CH2:20][CH2:19][NH2+:18][CH2:17][CH2:16]3)=[O:14])=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)Nc2ncc(-c3ccccc3)s2)CC1
Product: O=C(Nc1ncc(-c2ccccc2)s1)N1CCC[NH2+]CC1
Product: O=C([O-])C(F)(F)F

Procedure:
tert-butyl 4-{[(5-phenyl-1,3-thiazol-2-yl)amino]carbonyl}-1,4-diazepane-1-carboxylate (211.0 mg, 0.52 mmol) was treated with trifluoroacetic acid (2.0 ml) for fifteen minutes. The solvent was removed and the residue put under high vacuum to afford 4-{[(5-phenyl-1,3-thiazol-2-yl)amino]carbonyl}-1,4-diazepan-1-ium trifluoroacetate 25. 1H-NMR (500 MHz, DMSO-d6): 8.73 (1H, br s), 8.68 (1H, br s) 7.78 (1H, s), 7.57 (2H, d, J=7.57), 7.40 (2H, t, J=7.57), 7.28 (1H, t, J=7.57), 3.76 (2H, br s), 3.63 (2H, br s), 3.21 (4H, br s), 1.98 (2H, br m). High res. ES MS: Theoretical Mass 303.1274, Measured Mass 303.1276(C15H19N4OS+H+)
Reaction SMILES: [C:1]([P:5]([C:7]([CH3:10])([CH3:9])[CH3:8])Cl)([CH3:4])([CH3:3])[CH3:2].[CH2:11]([Mg]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>C1COCC1>[CH2:11]([P:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)P(Cc1ccccc1)C(C)(C)C
Temperature: 25 °C

Procedure:
Di-t-butylchlorophosphine (75.0 g (0.415 mole)) and 0.5 mole of 12M solution of benzylmagnesium chloride in THF (200 ml) were refluxed under argon for 2 days. The reaction mixture was allowed to cool off to RT and an aqueous solution of ammonium chloride was added slowly. The organic phase was separated, and dried with magnesium sulfate. After removal of the solvent, the product was purified by distillation in vacuum. The yield of benzyl-di-t-butylphosphine was 94.3 g (96%) with b.p. 56-59° C./0.1 mm. 31-P-NMR (CDCl3)+36.63 ppm. 1H NMR (CDCl3) 1.18 (s, 9H, Me3C), 1.20 (s, 9H, Me3C), 2.90 (d, 2JPH=2.92 Hz, P—CH2-Ph), 7.1-7:6 (m, 5H, aromatic protons).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:10][C:11](O)=[O:12])=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[CH3:23][N:24]([CH3:26])[NH2:25]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:16])([F:17])[F:18])[CH2:10][C:11]([NH:25][N:24]([CH3:26])[CH3:23])=[O:12])=[CH:5][C:4]=1[C:19]([F:20])([F:22])[F:21])#[N:2]
Reactant: N#Cc1ccc(N(CC(=O)O)CC(F)(F)F)cc1C(F)(F)F
Reactant: CN(C)N
Product: CN(C)NC(=O)CN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 3 using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,2,2-trifluoroethyl)glycine and 1,1-dimethylhydrazine: 1H NMR (400 MHz, CD3OD) δ 7.77 (d, J=9.6 Hz, 1H), 7.14 (bs, 2H), 7.08 (s, 1H), 4.36 (q, J=9.0 Hz, 2H), 4.26 (s, 2H), 2.69 (s, 3H), 2.61 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11](Cl)[N:10]=2)[CH:7]=1.[OH-].[NH4+:20]>CC(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:20])[N:10]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1Nc1ccnc(Cl)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Product: Nc1nccc(Nc2cc(Br)ccc2[N+](=O)[O-])n1
Temperature: 90 °C
Reaction time: 20 h

Procedure:
To a solution of N-(5-bromo-2-nitrophenyl)-2-chloropyrimidin-4-amine (6 g, 18.21 mmol) in 2-propanol (70 mL), in a pressure vessel, was carefully added ammonium hydroxide solution (150 mL) at RT. The reaction vessel was sealed and stirred at 90° C. (at 4.5 bar pressure) for 20 hr. The reaction mixture was cooled to 0° C. The resulting precipitate was collected by vacuum filtration, washed with water and dried in the vacuum oven to afford the title compound as an orange solid: 1H NMR (250 MHz, DMSO) δ 6.17 (1H, d, J=5.63 Hz), 6.34 (2H, br. s.), 7.39 (1H, dd, J=8.83, 1.98 Hz), 7.89-7.99 (2H, m), 8.34 (1H, d, J=2.13 Hz), 9.62 (1H, s); LC-MS: m/z+309.9, 311.7 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].CC([N-]C(C)C)C.[NH:18]1[C:22](C2C=C(Cl)C=CC=2F)=[N:21][N:20]=[N:19]1.C(Cl)[Cl:32].CO>C1COCC1>[Cl:32][C:7]1([I:9])[CH:6]=[CH:5][CH:3]([NH2:4])[C:2]([C:22]2[NH:21][N:20]=[N:19][N:18]=2)([CH3:1])[CH2:8]1
Reactant: Cc1cc(I)ccc1N
Reactant: Fc1ccc(Cl)cc1-c1nnn[nH]1
Reactant: ClCCl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(c2nnn[nH]2)CC(Cl)(I)C=CC1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of 2-methyl-4-iodoaniline (3.52 g, 0.0151 mol) in THF (25 mL) at −78° C., LDA (2 molar solution in THF, 11.33 mL, 0.02267 mol) was added dropwise. After stirring for 0.5 hours, a solution of 1-(tetrazol-5-yl)-2-fluoro-5-chlorobenzene (1.5 g, 0.00756 mol) in THF (15 mL) was added dropwise. The reaction was stirred for 16 hours as it warmed up to room temperature. The reaction mixture was quenched with aqueous conc. NH4Cl solution and extracted with CH2Cl2. The organic layer was dried (MgSO4) and the solvent removed giving a crude product as an oil. The oil with CH2Cl2->CH2Cl2:MeOH (9.7:0.3) gave 1.5 g (48%) of the desired product: mp 205-208;
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]2=[N:12][S:13][N:14]=[C:10]2[C:9]([C:15]2[S:19][C:18]([CH2:20][OH:21])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1.[CH:22]([CH:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=C.[H-].[Na+].O.[CH3:35]N(C=O)C>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]2[C:10](=[N:14][S:13][N:12]=2)[C:9]([C:15]2[S:19][C:18]([CH2:20][O:21][CH2:35][C:28]3[CH:27]=[CH:26][C:25]([CH:24]=[CH2:22])=[CH:30][CH:29]=3)=[CH:17][CH:16]=2)=[CH:8][CH:7]=1
Reactant: OCc1ccc(-c2ccc(-c3cccs3)c3nsnc23)s1
Reactant: C=CC(Cl)c1ccccc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: C=Cc1ccc(COCc2ccc(-c3ccc(-c4cccs4)c4nsnc34)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.37 g (4.15 mmol) of TBT-CH2OH and 0.71 mL (5 mmol) of vinylbenzyl chloride in 60 mL DMF was added 200 mg (8.3 mmol) sodium hydride. The mixture was stirred at room temperature overnight, poured into 300 mL water and extracted with DCM (3×30 mL). The combined organic phases were consecutively washed with water and brine solution and dried over MgSO4. Purification by silica gel column chromatography with hexane:chloroform in a ratio 3:1 (v/v) gave orange powder of St-TBT (1.2 g, 64.8%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].I[CH2:31][CH:32]([OH:35])[CH2:33][OH:34].O>CN(C)P(N(C)C)(N(C)C)=O.CCOCC>[F:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:31][CH:32]([OH:35])[CH2:33][OH:34])=[O:5]
Reactant: OCC(O)CI
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)c(F)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A solution of 7.34 g. of 2-fluoro-4-(hexadecylamino)benzoic acid, 4.80 g. of 25% aqueous sodium hydroxide, and 12.6 g. of 3-iodo-1,2-propanediol in 50 ml of hexamethylphosphoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield 2,3-dihydroxypropyl 2-fluoro-4-(hexadecylamino)benzoate.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][CH:21]=[C:20]([C:23]([OH:25])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.Cl.[CH3:27][O:28][CH2:29][CH2:30][NH:31][C:32]([C@H:34]1[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36][CH2:35]1)=[O:33]>>[CH3:27][O:28][CH2:29][CH2:30][NH:31][C:32]([C@H:34]1[CH2:35][CH2:36][C@H:37]([NH:40][C:23]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:7]4[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:15]=3[NH:22][CH:21]=2)=[O:25])[CH2:38][CH2:39]1)=[O:33]
Reactant: COc1ccc(-c2ncnc3c(C(=O)O)c[nH]c23)c(OCC2CC2)c1
Reactant: COCCNC(=O)[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: COCCNC(=O)[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A73) and trans-4-amino-cyclohexanecarboxylic acid (2-methoxy-ethyl)-amide hydrochloride (A196) the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C@H:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N:21]2[CH:25]=[CH:24][C:23]([CH3:26])=[N:22]2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([N:27]2[CH2:51][CH2:50][C:30]3([CH2:34][N:33]([C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:36])[CH:32]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:31]3)[CH2:29][CH2:28]2)[N:3]=1.[C:52]1([OH:58])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C@@H:9]([O:8][C:6]2[CH:7]=[C:2]([O:58][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[N:3]=[C:4]([N:27]3[CH2:51][CH2:50][C:30]4([CH2:34][N:33]([C:35]([O:37][CH2:38][C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=5)=[O:36])[CH:32]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:31]4)[CH2:29][CH2:28]3)[N:5]=2)[C:10]([F:12])([F:11])[F:13])=[C:15]([N:21]2[CH:25]=[CH:24][C:23]([CH3:26])=[N:22]2)[CH:16]=1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)C1CC2(CCN(c3nc(Cl)cc(O[C@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C1CC2(CCN(c3nc(Oc4ccccc4)cc(O[C@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 80 °C

Procedure:
To a solution of 2-benzyl 3-ethyl 8-(4-chloro-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (by-product from Step 3, Example 30a) (250 mg, 0.347 mmol) in 1,4-dioxane (9.0 mL) was added phenol (1.00 g, 10.6 mmol) and Cs2CO3 (3.65 g, 11.2 mmol). The reaction was heated at 80° C. for 12 h, then cooled to RT diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification on a 12 g Isco RediSep silica cartridge (EtOAc/heptane) provided 2-benzyl 3-ethyl 8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-6-phenoxypyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]#[N:10])[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)(=[S:23])C>C(O)(=O)C>[N:1]1([C:6]2[CH:7]=[C:8]([C:9](=[S:23])[NH2:10])[CH:11]=[CH:12][C:13]=2[O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: N#Cc1ccc(Oc2ccccc2)c(-n2ccnc2)c1
Reactant: CC(O)=S
Solvent: CC(=O)O
Product: NC(=S)c1ccc(Oc2ccccc2)c(-n2ccnc2)c1
Temperature: 50 °C

Procedure:
A reaction mixture prepared by suspending 65.2 mg of 3-(1H-imidazol-1-yl)-4-phenoxybenzonitrile in a mixture of 0.3 mL of acetic acid and 1.0 mL of thioacetic acid was heated at 50° C. for 14 hours under a nitrogen atmosphere. A crude product of 3-(1H-imidazol-1-yl)-4-phenoxybenzene-1-carbothioamide was obtained by concentrating under reduced pressure.