Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(F)C(C2N=NN(C)N=2)=C(C2C=C([F:17])C([C@H](N)C)=NC=2)C=1.FC1CCC(O)(C(O)=O)CC=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[Cl:70][C:71]1[CH:72]=[C:73]([F:103])[C:74]([C:97]2[N:98]=[N:99][N:100]([CH3:102])[N:101]=2)=[C:75]([C:77]2[CH:78]=[C:79]([F:96])[C:80]([C@H:83]([NH:85][C:86]([C:88]3([OH:95])[CH2:93][CH2:92][C:91]([F:94])=[CH:90][CH2:89]3)=[O:87])[CH3:84])=[N:81][CH:82]=2)[CH:76]=1>ClCCl.CCOC(C)=O>[Cl:70][C:71]1[CH:72]=[C:73]([F:103])[C:74]([C:97]2[N:98]=[N:99][N:100]([CH3:102])[N:101]=2)=[C:75]([C:77]2[CH:78]=[C:79]([F:96])[C:80]([C@H:83]([NH:85][C:86]([C:88]3([OH:95])[CH2:93][CH2:92][C:91]([F:17])([F:94])[CH2:90][CH2:89]3)=[O:87])[CH3:84])=[N:81][CH:82]=2)[CH:76]=1
Reactant: C[C@@H](N)c1ncc(-c2cc(Cl)cc(F)c2-c2nnn(C)n2)cc1F
Reactant: C[C@@H](NC(=O)C1(O)CC=C(F)CC1)c1ncc(-c2cc(Cl)cc(F)c2-c2nnn(C)n2)cc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)C1(O)CC=C(F)CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)C1(O)CCC(F)(F)CC1)c1ncc(-c2cc(Cl)cc(F)c2-c2nnn(C)n2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of the compound of Reference Example 4 (0.192 g, 0.547 mmol), 4-fluoro-1-hydroxycyclohex-3-ene-1-carboxylic acid (0.114 g, 0.71 mmol), (1H-1,2,3-benzotriazol-1-yloxy)[tris-(dimethylamino)]phosphonium hexafluorophosphate (0.339 g, 0.77 mmol) in 5 mL of dichloromethane was added triethylamine (0.138 g, 1.37 mmol). The reaction mixture was allowed to stir at ambient temperature for 1 hour. After the reaction was judged complete by LC/MS analysis, the volume of the reaction was reduced in vacuo. The residue was taken up in EtOAc and washed in succession with water, 0.25 N HCl and saturated aqueous sodium bicarbonate solution prior to drying over sodium sulfate. Filtration and solvent removal provided material which was subjected to chromatography on silica gel eluting with 0-50% EtOAc in hexanes to yield a mixture of diastereomers of N-((1R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}ethyl)-4-fluoro-1-hydroxycyclohex-3-ene-1-carboxamide, which gave a proton NMR spectrum consistent with theory and a mass ion (ES+) of 493.1 for M+H+: 1H NMR (500 MHz, CDCl3) δ 8.12 (s, 1H), 8.03 (bd, J=7.1 Hz, NH), 7.35 (d, J=8.9 Hz, 1H), 7.28-7.25 (m, 2H), 5.43 (quint, J=6.7 Hz, 1H), 5.16 (d, J=13.4 Hz, 1H), 4.35 (s, 3H), 2.79 (d, J=17.8 Hz, 1H), 2.68 (s, OH), 2.43 (m, 1H), 2.26 (m, 1H), 2.21-2.10 (m, 2H), 1.91 (m, 1H), 1.45 (d, J=6.8 Hz, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26]>CN(C=O)C>[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1)(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=S(=O)(N[C@H]1CC[C@H](O)CC1)c1ccccc1Br
Reaction time: 2 h

Procedure:
To a 20 mL vial were added a stir-bar, trans-4-aminocyclohexanol (683 mg, 4.50 mmol), DMF (5 mL), and DIPEA (2.0 mL, 12 mmol). The mixture was then treated with 2-bromobenzene-1-sulfonyl chloride (1.00 g, 3.93 mmol) and the mixture stirred for 2 hours before subjecting the vial's content to FCC to give the title compound. (978 mg, 74%). MS (ESI): mass calcd. for C12H16BrNO3S 333.00, m/z found 334.0 [M+H]+; 1H NMR (600 MHz, CDCl3) δ 8.12 (dd, J=7.8, 1.7, 1H), 7.70 (dd, J=7.8, 1.2, 1H), 7.49-7.43 (m, 1H), 7.43-7.37 (m, 1H), 5.10 (d, J=7.5, 1H), 3.62-3.47 (m, 1H), 3.11-3.01 (m, 1H), 2.12 (s, 1H), 1.91-1.75 (m, 4H), 1.31-1.15 (m, 4H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[CH:17]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.[C:29](Cl)(=[O:37])[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O>[CH2:1]([NH:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:29](=[O:37])[O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:17]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCNC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
N1-ethyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (3.168 g, 10.69 mmol) synthesized in Production example 27-1 was dissolved in N,N-dimethylformamide (30 ml) under nitrogen atmosphere. Pyridine (1.25 ml, 15.40 mmol) and phenyl chlorocarbonate (1.61 ml, 12.83 mmol) were sequentially added dropwise while cooled with an ice water bath. The reaction mixture was heated to room temperature while stirred. After 1 hour, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the crystals were precipitated from ethyl acetate, filtered off, and dried under aeration to yield the title compound (1.530 g, 3.67 mmol, 34.4%) as white crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:16])=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:18]1[C:27]([N:28]=[C:29]=[S:30])=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:29]2[S:30][C:18]3[C:27]([N:28]=2)=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=3)=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncc(Br)cc1OCc1ccccc1
Reactant: COC(=O)c1cnc(Cl)c(N=C=S)c1
Solvent: CN(C)C=O
Product: COC(=O)c1cnc2sc(Nc3ncc(Br)cc3OCc3ccccc3)nc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
3-(Benzyloxy)-5-bromopyridin-2-amine (1.50 g, 5.37 mmol) was added to a mixture of methyl 6-chloro-5-isothiocyanatonicotinate (1.23 g, 5.37 mmol) in DMF (4 mL). The reaction mixture was stirred at 80° C. for an hour, then at 110° C. for 2 hours. The reaction mixture was cooled, partitioned between dichloromethane (200 mL) and water (200 mL) and 2N NaOH (15 mL). The organic layer was washed with water and brine, dried, and concentrated. The residue was dissolved in warm dichloromethane (70 mL), and to this was added warm hexanes (40° C.) (250 mL). The solution was cooled to ambient temperature and the resulting solids were collected by filtration to afford methyl 2-(3-(benzyloxy)-5-bromopyridin-2-ylamino)thiazolo[5,4-b]pyridine-6-carboxylate (1.77 g, 69.9% yield) as a white powder. 1H NMR (CDCl3) δ 3.98 (s, 3H), 5.15 (s, 2H), 7.35 (s, 1H), 7.46 (m, 5H), 8.10 (s, 1H), 8.42 (s, 1H), 8.76 (bs, 1H), 9.02 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)=[N:11][OH:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[CH2:25][C:26]1[N:31]=[C:30]([N:32]2[C:40](=[O:41])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]2=[O:42])[CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:10](=[N:11][O:12][CH2:25][C:26]2[N:31]=[C:30]([N:32]3[C:33](=[O:42])[C:34]4[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:40]3=[O:41])[CH:29]=[CH:28][CH:27]=2)[C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(=NO)c2ncc(C(F)(F)F)cc2Cl)cc1Br
Reactant: O=C1c2ccccc2C(=O)N1c1cccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=NOCc2cccc(N3C(=O)c4ccccc4C3=O)n2)c2ncc(C(F)(F)F)cc2Cl)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of 1-(3-bromo-4-methoxyphenyl)-1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-N-hydroxymethanimine (4.30 g, 10.4 mmol) and 2-[6-(bromomethyl)pyridin-2-yl]-1H-isoindole-1,3(2H)-dione (3.66 g, 11.5 mmol) in acetonitrile (40 mL) were added cesium carbonate (7.18 g, 22.0 mmol) and potassium iodide (174 mg, 1.05 mmol). After stirring overnight at room temperature, the reaction mixture was diluter with water (100 mL) and ethyl acetate (50 mL). After phase separation and further extraction of the aqueous phase with ethyl acetate (2×30 mL), the combined organic layers were dried over MgSO4 and concentrated in vacuo to afford 2-(6-{[({(3-bromo-4-methoxyphenyl)[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methylene}amino)oxy]methyl}pyridin-2-yl)-1H-isoindole-1,3(2H)-dione as an oil [7.10 g, yield 94%; HPLC/MS: m/z=646 (M+H); log P(HCOOH)=4.78].
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C=C.N1C(=O)CC(=O)NC1=O>ClCCl.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>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1
Reactant: C=CCOc1ccc([C@H]2CC[C@H](OCC(=O)OC(C)(C)C)CC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C1CC(=O)NC(=O)N1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Reaction time: 16 h

Procedure:
3.6 g of tert-butyl trans-[4-(4-allyloxyphenyl)cyclohexyloxy]acetate are dissolved in 70 mL of dichloromethane, to which are added with stirring 4.87 g of barbituric acid (31.17 mmol, 3 eq.) and then 1.20 g of tetrakis(triphenylphosphine)palladium (1.04 mmol, 0.1 eq.). The reaction medium is refluxed for 3 hours. After 16 hours at room temperature, the reaction medium is diluted with dichloromethane and washed with brine. The aqueous phase is extracted with dichloromethane. The organic phases are combined, washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue is chromatographed on silica gel, eluting with a gradient of ethyl acetate in heptane ranging from 2% to 20%. 3.2 g of tert-butyl trans-[4-(4-hydroxyphenyl)cyclohexyloxy]acetate are obtained.
Reaction SMILES: [C:1](=[N:4][NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[CH3:15])([CH3:3])[CH3:2].Cl[O:18][N:19]=[CH:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1.C(Cl)(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>O>[CH3:28][C:23]1[CH:22]=[C:21]([C:20]2[N:4]([NH:5][C:6](=[O:16])[C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=3[CH3:15])[C:1]([CH3:3])([CH3:2])[O:18][N:19]=2)[CH:26]=[C:25]([CH3:27])[CH:24]=1
Reactant: COc1cccc(C(=O)NN=C(C)C)c1C
Reactant: Cc1cc(C)cc(C=NOCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cccc(C(=O)NN2C(c3cc(C)cc(C)c3)=NOC2(C)C)c1C
Reaction time: 24 h
Yield: 37.5 %

Procedure:
3-Methoxy-2-methyl-benzoic acid isopropylidene-hydrazide (1.71 g, 7.77 mmol) and 3,5-dimethyl-benzaldehyde chlorooxime (2.29 g, 12.4 mmol), both as CHCl3 solutions (total volume 40 mL), were added to a 250 mL round bottom flask equipped with a magnetic stirrer. An aqueous K2CO3 solution (5 g in 30 mL) was added, the vessel was placed in a 50° C. water bath, and the reaction was stirred vigorously for 24 hours. The reaction was monitored by 1H NMR. Chloroform (100 mL) and water (50 mL) were added, and the mixture was shaken in a separatory funnel. The organic phase was separated, dried, and the solvent was removed in vacuo. Column chromatography on silica gel using a gradient of 10-30% ethyl acetate in hexane yielded 1.07 g of N-[3-(3,5-dimethyl-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-3-methoxy-2-methyl-benzamide (32%). An analytical sample was obtained by crystallization from CH2Cl2/hexane under refrigeration. 1H NMR (300 MHz, CDCl3)δ(ppm): 7.4 (s, 2H), 7.1 (t, 1H), 7.07 (s, 1H), 6.85 (d, 1H), 6.65 (d, 1H), 3.78 (s, 3H), 2.30 (s, 6H), 2.07 (s, 3H), 1.65 (s, 6H).
Reaction SMILES: [C:1]([C:4]1[C:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:22])[CH3:21])[CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:23])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+]>CO.C(#N)C>[NH2:30][CH:1]([C:4]1[C:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:22])[CH3:21])[CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:23])[CH:5]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)N[C@H]1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(=O)N[C@H]1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)C1
Temperature: 65 °C

Procedure:
A mixture of N-[(3S)-1-(7-acetyl-5-chloroquinolin-8-yl)pyrrolidin-3-yl]acetamide (22 mg, 0.066 mmol) and ammonium acetate (51.1 mg, 0.663 mmol) in methanol (0.37 mL) and acetonitrile (0.38 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling, sodium cyanoborohydride (8.33 mg, 0.133 mmol) was added to the resultant mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature, quenched with saturated sodium bicarbonate, and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness (17 mg, 77%). The residue was used directly in the next step. LCMS calculated for C17H22ClN4O(M+H)+: m/z=333.1; found: 333.1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([OH:15])[CH2:10][CH2:11][C:12]([O-:14])=[O:13].[Na+].[H-].[Na+].F[C:20]1[CH:27]=[C:26]([O:28][CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:25]=[CH:24][C:21]=1[C:22]#[N:23]>O1CCCC1>[C:22]([C:21]1[CH:24]=[CH:25][C:26]([O:28][CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:27][C:20]=1[O:15][CH:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])#[N:23]
Reactant: Cc1cccc(C(O)CCC(=O)[O-])c1C
Reactant: N#Cc1ccc(OCc2cccnc2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(C(CCC(=O)O)Oc2cc(OCc3cccnc3)ccc2C#N)c1C
Temperature: 57.5 °C
Yield: 47 %

Procedure:
A solution of sodium (RS)-4-(2,3-dimethylphenyl)-4-hydroxybutanoate (1 g) is added to a stirred suspension of sodium hydride (0.5 g, 60% dispersion in mineral oil) in tetrahydrofuran (50 mL) under nitrogen. The mixture is stirred at room temperature for 3 hours when 2-fluoro-4-(3-pyridylmethoxy)benzonitrile (1 g) is added in one portion. The reaction mixture is heated at 55-60° C. for 18 hours and evaporated. The residue is dissolved in water (100 mL), the solution acidified to pH 1 with 1 N hydrochloric acid. The precipitated solid Is filtered, washed with water, ethyl acetate and ether, dried, and recrystallised from ethyl acetate to give (RS)-4-[2-cyano-5-(3-pyridylmethoxy)-phenoxy]-4-(2,3-dimethylphenyl)butanoic acid (0.85 g) as a white solid, m.p. 187-189° C. [Elemental analysis:- C,71.76; H,6.59; N,5.67%. Calculated:- C,72.10; H,6.73; N,5.81%]
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([CH:15]3[CH2:17][CH:16]3[C:18](O)=O)[CH:9]=2)[N:3]=1.[CH3:21][NH:22][C:23]1[C:28]([NH2:29])=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.N1C2C(=NC=CC=2)N(O)N=1.C(N(C(C)C)CC)(C)C>O1CCCC1.C(O)(=O)C>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([CH:15]3[CH2:17][CH:16]3[C:18]3[N:22]([CH3:21])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[N:29]=3)[CH:9]=2)[N:3]=1
Reactant: CNc1ccccc1N
Reactant: Cc1nc(C2CC2C(=O)O)cc(-n2nc(C)nc2C)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: Cc1nc(C2CC2c2nc3ccccc3n2C)cc(-n2nc(C)nc2C)n1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A slurry of 2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropanecarboxylic acid (2-5, 1.50 g, 5.49 mmol, 1.0 eq.), n-methyl-2-phenylenediamine (1.006 g, 8.23 mmol, 1.0 eq.), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (1.473 g, 7.68 mmol, 1.3 eq.), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (1.046 g, 7.68 mmol) and diisopropylethyl amine (2.88 mL, 16.47 mmol) in tetrahydrofuran (20 mL) was allowed to stir for 16 hours. The solvent was removed by roto-evaporation to afford a dark brown oil. The oil was dissolved in acetic acid (3 mL) and heated at 90° C. for 30 minutes. The solvent was removed by roto-evaporation and the resulting yellow oil was purified by reverse phase liquid chromatography (H2OCH3CN gradient w/ 0.1% NR4OH present) to afford 2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (2-6) as a white powder. 1H NMR (500 MHz, CDCl3) δ 7.69 (m, 2H), 7.28 (m, 3H), 3.82 (s, 3H), 2.90 (s, 3H), 2.83 (m, 2H), 2.68 (s, 3H), 2.41 (s, 3H), 2.19 (m, 2H). HRMS m/z (M+H) 360.1937 found, 360.1931 required.
Reaction SMILES: CON(C)[C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1(P(=[CH:44][C:45]([O:47][CH3:48])=[O:46])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C1(C)C=CC=CC=1>[CH3:48][O:47][C:45](=[O:46])[CH:44]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCNc1cc(F)ccc1C(=O)N(C)OC
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCNc1cc(F)ccc1C=CC(=O)OC
Temperature: -35 °C
Reaction time: 0.67 h
Yield: 30.3 %

Procedure:
To a solution of N-methoxy-N-methyl-4-fluoro-2-n-butylamino-benzamide (0.5 g, 1.97 mmol) in THF (8 mL) was added dropwise LiAlH4 (1 M in THF, 1.0 mL) at −45° C. The mixture was stirred for 40 minutes at −35° C. and then quenched by adding saturated aqueous KHSO4 solution. The mixture was diluted with EtOAc, washed with 3 N HCl, and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was reacted with methyl (triphenylphosphoranylidene)acetate (725 mg, 2.17 mmol) in toluene (4 mL) overnight at 100° C. The mixture was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.15 g, 30%) after purification by column chromatography (EtOAc:hexane=1:10).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:22]([O-])=O)=[C:9]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[O:12])[CH:10]=1)[CH:2]=[CH2:3]>C(O)(=O)C.[Fe]>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:22])=[C:9]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([CH:19]([CH3:20])[CH3:21])=[CH:17][CH:18]=2)=[O:12])[CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc([N+](=O)[O-])c(C(=O)c2ccc(C(C)C)cc2)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: C=CCOc1ccc(N)c(C(=O)c2ccc(C(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an ice chilled solution of 16 g (5-allyloxy-2-nitro-phenyl)-(4-isopropyl-phenyl)-methanone in 65 ml acetic acid are added 21.8 g iron powder. A precipitate that is formed is brought into solution by addition of additional acetic acid. After stirring for 16 h at r.t. the reaction mixture is filtered and basified by addition of aqueous potassium hydroxide solution. Extraction with dichloromethane yields (5-allyloxy-2-amino-phenyl)-(4-isopropyl-phenyl)-methanone.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: BrCC1CCCCC1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(CC3CCCCC3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.72 g) and (bromomethyl)cyclohexane (0.25 mL) as starting materials, 5-benzyloxy-N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.86 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.63 g) was obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[C:17]1[C:18]([CH3:23])=[N:19][CH:20]=[CH:21][CH:22]=1)[C:11]([OH:13])=O.[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([C:31](=[N:33]O)[NH2:32])[CH:30]=1.CCN(C(C)C)C(C)C>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([C:31]2[N:32]=[C:11]([C:10]3[CH:14]=[CH:15][C:16]([C:17]4[C:18]([CH3:23])=[N:19][CH:20]=[CH:21][CH:22]=4)=[C:8]([CH3:7])[CH:9]=3)[O:13][N:33]=2)[CH:30]=1
Reactant: Cc1cc(C(=O)O)ccc1-c1cccnc1C
Reactant: COc1ccc(F)cc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2ccc(-c3cccnc3C)c(C)c2)n1

Procedure:
Oxalyl chloride (84 mg; 0.66 mmol; 3 eq.), Intermediate 37 (50 mg; 0.22 mmol; 1 eq.), Intermediate 23 (41 mg; 0.22 mmol, 1 eq.) and DIEA (85 mg; 0.66 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 90/10 then 85/15) afforded the title compound as a white solid.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:23])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:17]=[CH:18][C:19](=S)[NH:20][N:21]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:25][NH2:26]>>[C:1]([NH:5][CH2:6][CH:7]([OH:23])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:21]=[N:20][C:19]([NH:25][NH2:26])=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NCC(O)COc1ccccc1-c1ccc(=S)[nH]n1
Reactant: NN
Solvent: O
Product: CC(C)(C)NCC(O)COc1ccccc1-c1ccc(NN)nn1

Procedure:
A stirred mixture of 6-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3(2H)-pyridazinethione (2 g, 0.006 mole) and hydrazine hydrate (50 ml) was heated under reflux in an atmosphere of nitrogen for 90 minutes. Excess of hydrazine hydrate was removed under reduced pressure and 3-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-6-hydrazinopyridazine was isolated as an oil which was characterised as the hemisulphate hemihydrate (2.34 g, 98%, m.p. 180°-185°). Recrystallisation from aqueous ethanol gave a crystalline material of m.p. 200°-203° (decomposition).