Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[O:16][C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[N:14][C:13]=1[CH2:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)=O)C>O1CCCC1>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[O:16][C:12]([CH2:10][OH:9])=[C:13]([CH2:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[N:14]=2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1oc(-c2ccc(OC)cc2)nc1COC1CCCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(COC3CCCCO3)c(CO)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.6 %

Procedure:
To a cooled suspension of 2.73 g lithium aluminium hydride in 180 ml tetrahydrofuran a solution of 12.3 g 2-(4-methoxy-phenyl)-4-(tetrahydro-pyran-2-yloxymethyl)-oxazole-5-carboxylic acid ethyl ester in 120 ml tetrahydrofuran were added at 0° C. The ice bath was removed and the reaction mixture stirred at room temperature for one hour. The reaction mixture was cooled in an ice bath again and 100 ml ethyl acetate were added followed by the addition of 300 ml methyl-tert-butyl ether. Then a solution of 10.92 g sodium hydroxide in 12.3 ml water was added. Solid precipitate was filtered off through a plug of celite. The filtrate was dried over MgSO4 and then the solvent was removed in vacuo to obtain 11.8 g [2-(4-methoxy-phenyl)-4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-5-yl]-methanol as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[C:5]([N+:20]([O-])=O)[CH:4]=1.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:20][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)c(N)c1
Yield: 75.9 %

Procedure:
To a mixture of 4-methoxy-2-nitro-N-(4-chlorophenyl)benzenesulfonamide (37.2 g) and ammonium chloride (75.4 g) in a mixture of methanol (400 ml) and water (400 ml) was added iron (76.4 g) in small portions over a period of one and half hours at 100° C. The reaction mixture was refluxed for 8 hours and the hot mixture was filtrated. The filtrated cake was washed with hot methanol. The combined filtrates were evaporated under reduced pressure and the residue was extracted three times with ethyl acetate. The extracts were washed with water, dried, and concentrated to give crude product, which was purified by silica gel column-chromatography (elution by methylene chloride) to yield 2-amino-4-methoxy-N-(4-chlorophenyl) benzenesulfonamide (25.77 g).
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:8][C:7](=[O:24])[N:6]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[N:5]=1)(=O)[NH2:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C1COCC1>[C:1]([C:4]1[C:9]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:8][C:7](=[O:24])[N:6]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[N:5]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(Cl)c(Cl)c3)nc2C(N)=O)CC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(Cl)c(Cl)c3)nc2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a stirring solution of tert-butyl 4-(3-carbamoyl-1-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate (example 16) (9 mg, 0.019 mmol) in THF (1 mL) at room temperature under argon was added TEA (5.65 mg, 0.056 mmol), and was followed by addition of TFAA (11.73 mg, 0.056 mmol). The resulting reaction mixture was stirred at room temperature overnight. Solvent was removed in vacuo. The crude product was purified by preparative HPLC (C18 column; 10-100% methanol in water without TFA) to give tert-butyl 4-(3-cyano-1-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate (6 mg, white solid, 69.2%). 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (s, 9H) 1.74-1.94 (m, 2H) 1.92-2.12 (m, 2H) 3.32-3.55 (m, 2H) 3.58-3.81 (m, 2H) 4.42-4.72 (m, 1H) 6.26 (s, 1H) 7.45 (dd, J=8.79, 2.20 Hz, 1H) 7.55 (d, 1H) 7.72 (d, J=2.20 Hz, 1H). MS (ESI) 409 (M+H-tBu).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[O:20][CH3:21])[N:7]([CH:22]([CH2:28][CH3:29])[C:23](OCC)=[O:24])[C:6]=2[C:5]([CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:4][CH:3]=1.[BH4-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[O:20][CH3:21])[N:7]([CH:22]([CH2:28][CH3:29])[CH2:23][OH:24])[C:6]=2[C:5]([CH:30]([CH2:31][CH3:32])[CH2:33][CH3:34])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CC)n1c(Nc2c(C)cc(Cl)cc2OC)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3c(C)cc(Cl)cc3OC)n(C(CC)CO)c12
Temperature: 25 °C
Reaction time: 84 h
Yield: 67 %

Procedure:
To a solution of ethyl {4-chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl}butanoate (100 mg, 0.197 mmol) in tetrahydrofuran (1.5 mL) was added lithium tetrahydroborate (13 mg, 0.597 mmol), and the mixture was stirred at room temperature for 84 hr. An additional lithium tetrahydroborate (26 mg, 1.19 mmol) was added, followed by stirring at 50° C. for 24 hr. The mixture was diluted with water and extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound (61 mg, 0.132 mmol, 20%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=[O:15])[CH2:7][CH2:8][CH:9](O)[C:10]([Cl:13])([Cl:12])[Cl:11])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=[O:15])[CH2:7][CH:8]=[CH:9][C:10]([Cl:12])([Cl:13])[Cl:11])=[CH:4][CH:3]=1
Reactant: O=C(CCC(O)C(Cl)(Cl)Cl)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(CC=CC(Cl)(Cl)Cl)c1ccc(Cl)cc1
Reaction time: 60 h

Procedure:
1-p-Chlorophenacyl-2-hydroxy-3,3,3-trichloropropane (450 mg) was dissolved in benzene and p-toluene sulphonic acid monohydrate (40 mg) added. The solution was refluxed with a Dean and Stark apparatus and any reaction followed by tlc. After 5 hours refluxing tlc revealed that only starting material was present. The solution was treated with a second portion of p-toluene sulphonic acid (100 mg) and further refluxed for 5 hours. The solution was allowed to stand over 60 hours and evaporated to dryness. tlc Analysis (10% Et.AC./petrol) revealed a new product (Rf 0.8) with no starting material remaining. The solution was taken up in ethyl acetate and passed down a short alumina column (to remove pTSA). Elution with 25% Et.Ac./petrol yielded the product. Yield 200 mg.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([CH3:19])[C:9]=1[C:10]([NH2:12])=[O:11].[CH3:20][N:21]([CH3:35])[CH2:22][CH2:23][O:24][C:25]1[C:32]([CH3:33])=[CH:31][C:28]([C:29]#N)=[CH:27][C:26]=1[CH3:34]>C1COCC1>[CH3:20][N:21]([CH3:35])[CH2:22][CH2:23][O:24][C:25]1[C:32]([CH3:33])=[CH:31][C:28]([C:29]2[NH:12][C:10](=[O:11])[C:9]3[C:13]([CH:19]=2)=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=3[O:7][CH3:6])=[CH:27][C:26]=1[CH3:34]
Reactant: COc1cc(C)c(C(N)=O)c(OC)c1
Reactant: Cc1cc(C#N)cc(C)c1OCCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN(C)C)c(C)c3)cc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 8.9 %

Procedure:
n-Butyl lithium (4.2 mL, 10.54 mmol, 2.5 M solution in hexane) was added slowly to a solution of 2,4-dimethoxy-6-methyl benzamide (958 mg, 4.58 mmol) in THF (30 mL) under nitrogen with cooling (ice-salt bath), maintaining the temperature below 20° C. After completion of the addition, the mixture was stirred for 1 h at 0° C., then cooled to −50° C. and a solution of 4-(2-dimethylaminoethoxy)-3,5-dimethyl benzonitrile (1.1 g, 5.04 mmol) (the B-ring building block) in THF (10 mL) was added quickly. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stirred for 16 h at room temperature. A saturated NH4Cl solution was added with cooling and the layers were separated. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to give crude product. The crude product was purified by chromatography to give 3-(4-(2-(dimethylamino)ethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (162 mg, 8%) as a hydrochloride. Selected data: MS (ES) m/z: 397.06; MP 261-263° C. at decomposition (HCl).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:12][C:13]([OH:15])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH2:22])[S:20][CH:21]=1>>[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH:22][C:13](=[O:15])[CH2:12][C:3]2[C:2]([F:1])=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][CH:7]=[N:8]3)[S:20][CH:21]=1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: O=C(O)Cc1c(F)ccc2ncccc12
Product: O=C(Cc1c(F)ccc2ncccc12)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
N-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(6-fluoroquinolin-5-yl)acetamide was prepared from 2-(6-fluoroquinolin-5-yl)acetic acid (42 mg, 0.203 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (25 mg, 0.102 mmol) according to protocol A. Retention time (min)=2.499, method [7], MS(ESI) 432.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 8.99 (dd, J=4.2, 1.1 Hz, 1H), 8.86 (d, J=7.9 Hz, 1H), 8.23 (dd, J=8.9, 4.5 Hz, 1H), 8.08 (s, 1H), 7.85 (dd, J=9.4, 9.2 Hz, 1H), 7.81 (dd, J=9.2, 4.5 Hz, 1H), 7.07 (s, 1H), 4.48 (s, 2H).
Reaction SMILES: [CH2:1]([C@H:8]([NH:39]C(=O)OC(C)(C)C)[C@@H:9]([OH:38])[CH2:10][N:11]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[CH:28][CH:27]=1)[NH:12][C:13](=[O:24])[C@@H:14]([NH:19][C:20]([O:22][CH3:23])=[O:21])[C@@H:15]([CH3:18])[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[NH2:39][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([OH:38])[CH2:10][N:11]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[CH:30][CH:31]=1)[NH:12][C:13]([C@@H:14]([NH:19][C:20](=[O:21])[O:22][CH3:23])[C@@H:15]([CH3:18])[CH2:16][CH3:17])=[O:24]
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
A solution of Example 7C (0/37 g, 0.59 mmol) in THF (4 mL) was treated with 4N HCl (1 mL), stirred at 60° C. for 3 hrs and cooled to room temperature. The solvents were evaporated, and the crude residue was partitioned between ethyl acetate and 10% sodium bicarbonate. The organic layer was separated and washed with brine, dried over sodium sulfate, filtered and the solvents were evaporated to give 0.28 g (89%) of the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:21])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11].[NH2:22][C:23]1[C:27]([NH2:28])=[N:26][O:25][N:24]=1.C(N(CC)CC)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH2:28][C:27]1[C:23]([NH:22][C:10](=[O:11])[C:9]2[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:18])[F:19])=[N:16][C:8]=2[CH2:7][N:3]2[CH2:4][CH2:5][CH2:6][S:2]2(=[O:1])=[O:21])=[N:24][O:25][N:26]=1
Reactant: Nc1nonc1N
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1CN1CCCS1(=O)=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1nonc1NC(=O)c1ccc(C(F)(F)F)nc1CN1CCCS1(=O)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
150 mg (0.46 mmol) of 2-[(1,1-dioxido-1,2-thiazolidin-2-yl)methyl]-6-(trifluoromethyl)nicotinic acid and 46 mg (0.46 mmol) of 3,4-diamino-1,2,5-oxadiazole are dissolved at RT in 10 ml of CH2Cl2, and 0.32 ml (2.31 mmol) of triethylamine, 11 mg (0.09 mmol) of DMAP and 442 mg (0.69 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF) are added. The reaction mixture is stirred at RT for 20 h and then washed twice with 5 ml each time of water. The organic phase is dried over Na2SO4 and concentrated. The residue is purified by column chromatography (silica gel, heptane/ethyl acetate). Yield: 42 mg (22%).
Reaction SMILES: [O:1]1[CH2:28][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>CN(C=O)C>[CH2:29]([N:31]([CH2:28][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27])[CH2:32][CH3:33])[CH3:30]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CO1
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)CC(O)COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3)c2cc1OC
Temperature: 70 °C
Yield: 45.2 %

Procedure:
A mixture of 7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg, 0.27 mmol), (prepared as described for the starting material in Example 162), and diethylamine (100 μl, 0.8 mmol) in DMF (4 ml) was heated at 70° C. for 24 hours. The solvent was removed by evaporation and the residue was purified by silica column chromatography eluting with dichloromethane/methanol/0.880 aqueous ammonia (100/8/1). The relevant fractions were evaporated to dryness then the residue treated with a little dichloromethane and dried under high vacuum to give 7-(3-(N,N-diethylamino)-2-hydroxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (55 mg, 46%) as a white foam.
Reaction SMILES: C1C2SC3C(=CC=CC=3)SC=2C=CC=1S(Cl)(=O)=O.[CH:19]1[C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[S:33](Cl)(=[O:35])=[O:34].C(OC(=O)[C@H](C(C)C)N)(C)(C)C.C([O:53][C:54](=[O:67])[C@H:55]([CH2:57][C:58]1[C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[NH:60][CH:59]=1)[NH2:56])(C)(C)C>>[NH:60]1[C:61]2[C:66](=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:58]([CH2:57][C@H:55]([NH:56][S:33]([C:20]2[CH:21]=[CH:22][C:23]3[O:24][C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[S:31][C:32]=3[CH:19]=2)(=[O:35])=[O:34])[C:54]([OH:67])=[O:53])=[CH:59]1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1O2
Agent: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1S2
Product: O=C(O)[C@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1O2

Procedure:
When in the procedure of Example 1, Step (b), thianthrene-2-sulfonyl chloride is replaced by phenoxathiine-2-sulfonyl chloride and (L)-valine-t-butyl ester is replaced with (L)-tryptophan-t-butyl ester, (S)-3-(1H-indol-3-yl)-2-(phenoxathiine-2-sulfonylamino)-propionic acid is obtained; mp 120-130° C.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C@@H:10]1([NH2:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1>>[C:1]1([CH2:7][CH2:8][NH:20][C@@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCc1ccccc1
Reactant: N[C@H]1CCCc2ccccc21
Product: c1ccc(CCN[C@H]2CCCc3ccccc32)cc1

Procedure:
Phenylacetaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: C([O-])(=O)C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:25]1[CH:26]=[CH:27][C:28]([C:31]([OH:34])([CH3:33])[CH3:32])=[N:29][CH:30]=1.[CH3:35][Si:36]([CH3:76])([CH3:75])[CH2:37][CH2:38][O:39][CH2:40][N:41]([CH2:67][O:68][CH2:69][CH2:70][Si:71]([CH3:74])([CH3:73])[CH3:72])[C:42]1[N:47]2[N:48]=[CH:49][C:50](I)=[C:46]2[N:45]=[C:44]([CH:52]2[CH2:58][CH:57]3[N:59]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH:54]([CH2:55][CH2:56]3)[CH2:53]2)[CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:74][Si:71]([CH3:72])([CH3:73])[CH2:70][CH2:69][O:68][CH2:67][N:41]([CH2:40][O:39][CH2:38][CH2:37][Si:36]([CH3:35])([CH3:76])[CH3:75])[C:42]1[N:47]2[N:48]=[CH:49][C:50]([C:25]3[CH:30]=[N:29][C:28]([C:31]([OH:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)=[C:46]2[N:45]=[C:44]([CH:52]2[CH2:58][CH:57]3[N:59]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH:54]([CH2:55][CH2:56]3)[CH2:53]2)[CH:43]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n1)C2
Reactant: CC(C)(O)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(C(C)(C)O)nc4)c3n1)C2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 56.2 %

Procedure:
Potassium acetate (1.383 g, 14.09 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (168 mg, 0.230 mmol), bis(pinacolato)diboron (1.40 g, 5.49 mmol), and 2-(5-bromopyridin-2-yl)propan-2-ol (1.099 g, 5.086 mmol) were combined in a microwave tube equipped with a stir bar. The headspace was exchanged for dry nitrogen (×3), and 1,4-dioxane (10 mL) was added. The vessel was lowered into a 90° C. oil bath, and stirred rapidly for 2.5 h. The mixture was cooled to room temperature and tert-butyl 3-[7-(bis{[2-(trimethylsilyl)ethoxy]methyl}amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate (1.774 g, 2.431 mmol) in 1,4-dioxane (6 mL, 80 mmol), and aqueous sodium carbonate (2.0 M, 3.3 mL, 6.6 mmol) were added. The organic layer became homogeneous, and the aq. becomes milky. The reaction was again lowered into the 90° C. bath, and stirred vigorously for 16 h, at which point HPLC shows the reaction to be complete. The mixture was cooled and partitioned between ethyl acetate (200 mL) and water (50 mL). The organics were washed with water (50 mL), brine (50 mL), dried with MgSO4, filtered through celite, and concentrated. The crude material was purified by flash chromatography (20-100% ethyl acetate in hexanes). The title compound (1.01 g) was isolated as a brown oil.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].[CH:10](=[O:14])[CH2:11][CH2:12][CH3:13]>C(O)C>[CH2:1]([CH:2]1[CH:2]2[C:1](=[O:7])[CH:6]([CH2:5][CH2:4][CH2:3]2)[C:10]2([OH:14])[CH:3]1[CH2:4][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH3:5]
Reactant: CCCC=O
Reactant: O=C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCC1C2CCCC(C2=O)C2(O)CCCCC12
Temperature: 72.5 °C
Reaction time: 15 h

Procedure:
Into a three-neck 500 mL round bottom flask equipped with magnetic stirrer and an oil bath under nitrogen was added 250 parts of cyclohexanone. The oil bath temperature was maintained at 70-75° C. with stirring. A solution of 2.5 parts of potassium hydroxide dissolved in 25 mL of absolute ethyl alcohol was added to the reaction flask in one portion. Thirty parts of butyraldehyde was dissolved in 35 mL of absolute ethyl alcohol and added dropwise to the reaction flask over a period of 6 hours. The reaction mixture was stirred at 70-75° C. for the 15 hours. After the reaction mixture was cooled to room temperature and refrigerated for 15 hours. The inside surface of the flask was scratched with a glass rod to precipitate out the white material and the flask was refrigerated for additional 4-5 hours. The white solid material was filtered and washed with 50 mL of cold water and then with 50 mL cold ether. The recovered solid was dried at room temperature and the yield was 35 parts. The solid showed a single spot on silica gel TLC plate eluted with 10% ethyl acetate/hexane. The structure of the material was confirmed on the basis of 1H NMR. This reaction proceded as follows:
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[C:20]([C:21]([F:24])([F:23])[F:22])=[C:19]([C:25]([OH:27])=O)[CH:18]=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:50][CH2:51][C:52]([N:54]1[CH2:59][CH2:58][N:57]([C:60](=[O:72])[C:61]2[CH:66]=[C:65]([F:67])[CH:64]=[CH:63][C:62]=2[C:68]([F:71])([F:70])[F:69])[CH2:56][CH2:55]1)=[O:53]>CN(C=O)C.O>[F:67][C:65]1[CH:64]=[CH:63][C:62]([C:68]([F:70])([F:69])[F:71])=[C:61]([CH:66]=1)[C:60]([N:57]1[CH2:58][CH2:59][N:54]([C:52](=[O:53])[CH2:51][NH:50][C:25]([C:19]2[CH:18]=[N:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:20]=2[C:21]([F:22])([F:23])[F:24])=[O:27])[CH2:55][CH2:56]1)=[O:72]
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Reactant: O=C(O)c1cnn(-c2ccccc2)c1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1cnn(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 27.9 %

Procedure:
DIPEA (141 mg, 0.19 mL, 1.1 mmol) was added to a stirred solution of 1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (70 mg, 0.27 mmol) in DMF (5 mL). HOBT (40 mg, 0.29 mmol) and EDCI (131 mg, 0.68 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (111 mg, 0.3 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using 60-120 silica gel and 70% EtOAC in hexane as eluent) to afford 43 mg (27.56% yield) of 1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LCMS Purity: 86.39%. 1H NMR (CDCl3): δ 8.0 (s, 1H), 7.8 (t, 1H), 7.56-7.4 (m, 5H), 7.26 (s, 1H), 7.1 (d, 2H), 4.36-4.2 (m, 2H), 4.06-3.84 (m, 1H), 3.8-3.64 (m, 2H), 3.62-3.48 (m, 2H), 3.44 (t, 1H), 3.3-3.2 (m, 2H).
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[O:8][CH:7](C(Cl)(Cl)Cl)[C:6]=2[CH:19]=1.C(Cl)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:14][C:11]([CH:9]1[O:8][CH2:7][C:6]2[CH:19]=[CH:2][CH:3]=[CH:4][C:5]=2[O:10]1)([Cl:13])[Cl:12]
Reactant: Oc1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Solvent: Cc1ccccc1
Solvent: O=C(Cl)c1ccccc1
Product: ClC(Cl)(Cl)C1OCc2ccccc2O1
Temperature: 25 °C

Procedure:
A mixture of 6-hydroxy-2,4-bis(trichloromethyl)benzo[1,3]dioxin (1.0 g.), benzoyl chloride (0.35 ml.) and toluene (20 ml.) was warmed on the steam bath for 1 hour. The resulting solution was cooled to ambient temperature and evaporated to dryness under reduced pressure to give an oily residue. The residue was triturated with ethanol (5 ml.) to give a white solid, which was crystallised from ethanol to give 6-benzoyloxy-2,4-bis(trichloromethylbenzo[1,3]dioxin, m.p. 167°-169° C.