Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][C:20](O)=[O:21])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][C:20]([N:25]3[CH2:30][CH2:29][S:28][CH2:27][CH2:26]3)=[O:21])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CSCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(CC(=O)O)c2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2cccc(CC(=O)N3CCSCC3)c2)=C(C)C1=O
Yield: 40.7 %

Procedure:
3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenylacetic acid (90 mg, 0.27 mmol) obtained in Example 57 and thiomorpholine (0.040 ml, 0.41 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (47 mg, 0.11 mmol, yield 41%).
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[C:23]([CH2:24][O:25][CH3:26])=[CH:22][CH:21]([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[NH:20][CH2:19]1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1>C(#N)C>[CH2:1]([O:4][NH:5][C@H:18]1[C:23]([CH2:24][O:25][CH3:26])=[CH:22][CH:21]([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31])[NH:20][CH2:19]1)[CH:2]=[CH2:3]
Reactant: C=CCON([C@@H]1CNC(CO[Si](C)(C)C(C)(C)C)C=C1COC)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC#N
Product: C=CCON[C@@H]1CNC(CO[Si](C)(C)C(C)(C)C)C=C1COC
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a stirred suspension of Intermediate 120 (5 g, 9.47 mmol) and K2CO3 (7.86 g, 56.85 mmol) in acetonitrile (100 mL), PhSH (3.90 mL, 37.90 mmol) was added. The reaction was stirred at rt overnight. It was filtered and concentrated, then diluted with DCM and filtered through disposal filter. The filtrate was concentrated and purified by silica gel column (0-100% Hex/EA, 80 g ISCO) to afford the title compound (2.04 g, 63%) as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:38])([CH3:37])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([C:16]1[N:20]3[CH:21]=[CH:22][C:23]([CH2:25][N:26]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:24][C:19]3=[N:18][N:17]=1)[CH:12]=[CH:11]2.NN>CCO>[NH2:26][CH2:25][C:23]1[CH:22]=[CH:21][N:20]2[C:16]([C:13]3[CH:12]=[CH:11][C:10]4[C:15](=[C:6]([O:5][CH2:4][C:3]([CH3:38])([CH3:37])[CH2:2][OH:1])[CH:7]=[CH:8][CH:9]=4)[N:14]=3)=[N:17][N:18]=[C:19]2[CH:24]=1
Reactant: CC(C)(CO)COc1cccc2ccc(-c3nnc4cc(CN5C(=O)c6ccccc6C5=O)ccn34)nc12
Agent: NN
Solvent: CCO
Product: CC(C)(CO)COc1cccc2ccc(-c3nnc4cc(CN)ccn34)nc12
Reaction time: 0.5 h
Yield: 9.6 %

Procedure:
To a solution of 2-((3-(8-(3-hydroxy-2,2-dimethylpropoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methyl)isoindoline-1,3-dione (0.056 g, 0.11 mmol) in EtOH (2 mL) was added hydrazine (0.018 g, 0.55 mmol), and the reaction was stirred for 30 minutes. The reaction was concentrated, and the crude material was purified by flash column chromatography (eluting with a 20:1:0.1 mixture of DCM/MeOH/NH4OH) to afford the desired product (4 mg). MS ESI (+) m/z 378 (M+1) detected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5][OH:6].[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C>ClCCl>[CH3:11][S:12]([O:6][CH2:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[C:8]([Cl:10])[CH:7]=1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(Cl)cc(Cl)c1

Procedure:
To a solution of 3.5 g of 3,5-dichlorobenzyl alcohol (Aldrich) in 75 mL of dichloromethane at 0° C. was added 1.8 mL of methane sulfonylchloride followed by 3.5 mL of triethylamine added dropwise. After 2 hours the solution was diluted to 150 mL with dichloromethane, washed with 3N HCl, saturated aqueous NaHCO3 dried with Na2SO4 and the solvents removed to yield the desired 3,5-dichlorobenzyl methanesulfonate as a yellow oil that was used without purification.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:24][O:25][CH2:26][CH2:27][NH2:28].C(N(CC)CC)C>C(Cl)Cl>[CH3:24][O:25][CH2:26][CH2:27][NH:28][C:14](=[O:15])[CH:13]([O:12][C:11]1[CH:18]=[CH:19][C:8]([O:7][C:6]2[CH:20]=[CH:21][C:3]([C:2]([F:23])([F:22])[F:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)[CH3:17]
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Reactant: COCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCNC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 2 h
Yield: 77.7 %

Procedure:
While cooling with ice, 17.2 g (0.05 mole) of α-[4-(p-trifluoromethylphenoxy)-phenoxy]-propionyl chloride are added dropwise to a mixture of 4.1 g (0.055 mole) of 2-methoxyethylamine, 7.5 ml (0.055 mole) of triethylamine and 50 ml of methylene chloride, and the temperature is allowed to rise to 20° C. The reaction mixture is stirred for 2 hours, then concentrated. The residue is filtered in ether over a small column of silica gel. Concentration of the filtrate affords 14.9 g (77.6%) of α-[4-(p-trifluoromethylphenoxy)-phenoxy]-propionic acid (2-methoxy)-ethylamide with a melting point of 73°-75° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@H:11]3[C@@H:15]4[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]4[C@@H:13]([CH2:21][OH:22])[O:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:32][C@@H:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34]1>C(O)CCC>[C@@H:33]1([NH:32][C:2]2[C:3]3[CH:10]=[CH:9][N:8]([C@H:11]4[C@@H:15]5[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]5[C@@H:13]([CH2:21][OH:22])[O:12]4)[C:4]=3[N:5]=[CH:6][N:7]=2)[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1ccc2c(Cl)ncnc21
Reactant: N[C@H]1CCc2ccccc21
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1ccc2c(N[C@H]3CCc4ccccc43)ncnc21

Procedure:
A solution of [(3aR,4R,6R,6aR)-6-(4-Chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-methanol (574 mg, 1.76 mmol), diisopropylethylamine (1.2 mL, 7.04 mmol) and (S)-(+)-1-aminoindane (680 μL, 5.27 mmol) in n-butanol 3.3 mL) was divided into two portions and each portion was microwave irradiated at 190° C. for 900 s. The solvent was removed in vacuo and the combined crude portions were purified by silica gel chromatography (0 to 5% MeOH/CH2Cl2) to afford 460 mg (62% over two steps) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([CH3:18])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:17])[NH:15][CH3:16])[CH:9]=1)[CH3:6])[CH3:2].Cl[CH2:21][C:22]1[C:23]([CH2:39][CH2:40][O:41][CH3:42])=[N:24][C:25]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)=[N:26][C:27]=1[CH3:28]>>[CH2:1]([O:3][C:4](=[O:19])[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:17])[N:15]([CH2:21][C:22]2[C:23]([CH2:39][CH2:40][O:41][CH3:42])=[N:24][C:25]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:34]=3)=[N:26][C:27]=2[CH3:28])[CH3:16])[CH:9]=1)([CH3:18])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC)c1
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C)c1CCl
Product: CCOC(=O)C(C)(C)Oc1cccc(C(=O)N(C)Cc2c(C)nc(-c3ccc(C(F)(F)F)cc3)nc2CCOC)c1

Procedure:
In analogy to the procedures described in examples 59C] and 26C], 2-methyl-2-(3-methylcarbamoyl-phenoxy)-propionic acid ethyl ester (example 59B]) was reacted 5-chloromethyl-4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 118G]) to give 2-(3-{[4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethyl]-methyl-carbamoyl}-phenoxy)-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=2O)=[O:10])=[CH:4][CH:3]=1>C(O)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:10])[C:11]3[C:12](=[C:13]([F:18])[C:14]([F:17])=[CH:15][CH:16]=3)[O:24][C:20]=2[CH:21]([CH3:23])[CH3:22])=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)C(C(=O)c1ccc(F)c(F)c1O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)c1oc2c(F)c(F)ccc2c(=O)c1-c1ccc(Cl)cc1
Temperature: 140 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(4-chlorophenyl)-1-(3,4-difluoro-2-hydroxy-phenyl)-4-methyl-pentane-1,3-dione (3.65 g, 10.3 mmol) in acetic acid (36 ml) and concentrated HCl solution (2 ml) is stirred at 140° C. for 3 h. The reaction mixture is cooled to room temperature, poured onto ice-water and extracted with methylene chloride. The organic layer is washed with saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo to afford the title compound as a brown solid.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[OH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[CH:10]=[C:9]([OH:22])[CH:8]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[OH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[CH:10]=[C:9]([O:22][CH2:1][CH:3]2[CH2:4][O:5]2)[CH:8]=1
Reactant: ClCC1CO1
Reactant: O=c1c2ccccc2sc2cc(O)cc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1c2ccccc2sc2cc(OCC3CO3)cc(O)c12
Temperature: 57.5 °C
Yield: 18.6 %

Procedure:
Epichlorohydrin (0.24 mL, 3.05 mmol) was added dropwise to a mixture of 1,3-dihydroxy-9H-thioxanthen-9-one (137 mg, 0.61 mmol) and K2CO3 (169 mg, 1.22 mmol) in anhydrous acetone (15 mL) in a dry round-bottom flask, followed by stirring under reflux at a temperature of 55 to 60° C. for one day. Solid of the reaction mixture was filtered and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: CH2Cl2) to give the title compound (34 mg, 18.6%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stream of nitrogen gas was bubbled through a stirred suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.96 g, 0.0208 mole), 1,1'-carbonyldiimidazole (3.37 g, 0.0208 mole), and anhydrous tetrahydrofuran (100 ml) at room temperature for 3 hrs. To the resulting solution was added dropwise a solution of morpholine (1.81 g, 0.0208 mole) in tetrahydrofuran (10 ml). The reaction mixture was stirred overnight at room temperature. The tetrahydrofuran was evaporated and the crystalline residue suspended in water and filtered, giving 5.35 g (72%). Recrystallization from 95% ethanol gave 4.9 g of white flakes, mp 213°-216° C.
Reaction SMILES: [C:1]([Cl:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].[Br:21]Br>>[Br:21][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:1]([Cl:20])=[O:19]
Reactant: CC(C)CCCCCCCCCCCCCCC(=O)Cl
Reactant: BrBr
Product: CC(C)CCCCCCCCCCCCCC(Br)C(=O)Cl

Procedure:
Isooctadecanoyl chloride prepared as described in Example 5 (20.2 g) was stirred and heated to 100° and illuminated with a tungsten lamp (100 watts) whilst bromine (10.7 g) was added dropwise during 1.5 hours. Heating and stirring under illumination were continued and further additions of bromine were made until after 10 hours and the addition of a further 6 g of bromine, 95% of the starting material was shown by gas chromatography to be completely reacted. Excess bromine and hydrobromic acid were removed by applying vacuum (20 mm of mercury) to the heated liquid. The 2-bromoisooctadecanoyl chloride thus obtained was cooled and treated with 1,2,4-triazole (9.0 g) and drowned into water and extracted with petroleum ether (b.p. 60°-80° ). The organic solution was separated and washed with aqueous hydrochloric acid (2M) and water, and the solvent was distilled leaving 1-(2'-bromoiso- octadecanoyl)-1,2,4-triazole (25.3 g) as a pale brown oil. The nuclear magnetic resonance spectrum of the product as a solution in deuterated chloroform was compared with that of the product of Example 5, confirming that absorption at delta 3.4 ppm from tetramethylsilane, associated with a proton in the 2'-position of the side chain, had vanished. This compound was evaluated as an extractant for copper by the procedure of Example 1 and the results are presented in Table 1. The results show that the compound is a slightly "weaker" ligand than the products of Examples 1-7, and that it transfers only a small amount of acid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([N:13]([CH2:15][CH:16]=C)[CH3:14])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:18]=[O+][O-]>CO>[C:1]([C:5]1[O:9][N:8]=[C:7]([N:10]2[CH:16]([OH:18])[CH2:15][N:13]([CH3:14])[C:11]2=[O:12])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=[O+][O-]
Reactant: C=CCN(C)C(=O)Nc1cc(C(C)(C)C)on1
Solvent: CO
Product: CN1CC(O)N(c2cc(C(C)(C)C)on2)C1=O
Reaction time: 1.33 h

Procedure:
A 4.74 g. portion of 1-(5-t-butylisoxazol-3-yl)-3-allyl-3-methylurea was dissolved in 50 ml. of methanol, and was cooled to -12°. Ozone-containing air was bubbled through the mixture with good stirring for 80 minutes. The temperature rose as high as 0° during the ozone addition, and the mixture foamed and left solids on the flask walls above the liquid. It was necessary to wash the solid down with 20 ml. of additional methanol. Ten ml. of additional methanol was used to wash the gas frit when it began to plug from precipitated product. After the addition was complete, nitrogen was bubbled through the solution for 5 minutes, and then 1.5 ml. of dimethyl sulfide was added and the mixture was warmed to 20° and diluted with 80 ml. of water. The methanol was removed under vacuum at 40°, and the remaining mixture was filtered and the solids were washed with 50 ml. of water and dried under vacuum at 50° to obtain 2.68 g. of the desired product, m.p. 173°-176°. It was further identified by nmr analysis which showed it to be substantially identical to the product of Example 1.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:20][CH2:21][C:22](Br)=[O:23].Cl>ClCCl>[Br:20][CH2:21][C:22]([C:8]1[CH:9]=[CH:10][C:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:6][CH:7]=1)=[O:23]
Reactant: O=C(Br)CBr
Reactant: OCCCCCCCCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CBr)c1ccc(CCCCCCCCO)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Aluminium chloride (200 mg, 1.50 mmol, 3.0 eq.) was suspended in dry dichloromethane (8 mL) and cooled to 0° C. 8-phenyl-1-octanol (0.11 mL, 0.50 mmol) and bromo acetylbromide (53 μL, 0.60 mmol, 1.2 eq.) were added dropwise. After 20 min the mixture was warmed to r.t. and stirred overnight. The reaction was stopped by pouring the solution into a mixture of ice water (25 mL) and concentrated hydrochloric acid (10 mL). The phases were separated and the aqueous layer was extracted with dichloromethane (2×10 mL). The combined organic phases were washed with saturated sodium bicarbonate solution (1×10 mL) and brine (1×10 mL) and dried over MgSO4. The solvent was evaporated and the residue was purified by column chromatography (silica gel, 12×4 cm, cyclohexane/ethyl acetate, 8:1). The product was isolated as colourless oil. Yield: 120 mg (73%).
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([N+:23]([O-])=O)[CH:17]=3)(=[O:15])=[O:14])=[CH:9][NH:10]2)=[CH:6][CH:5]=1.C(OC(=O)C)C>C(O)C.[Fe]>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH2:23])[CH:17]=3)(=[O:15])=[O:14])=[CH:9][NH:10]2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)c2c[nH]c3cc(Cl)ccc23)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)c2c[nH]c3cc(Cl)ccc23)cc1N
Temperature: 92.5 °C
Reaction time: 0.08 h

Procedure:
To a 250 mL round bottomed flask, added Iron powder (1.56 grams, 27.9 mmol), 10 mL demineralized water and heated to 90-95° C. At this temperature, 4 mL of concentrated hydrochloric acid was added drop wise. The mass was further heated at 90-95° C. for 1 hour. Then cooled the mass to 60° C. and added absolute ethanol (25 mL). A solution of 6-chloro-3-(4-methyl-3-nitro benzenesulfonyl)-1H-indole (obtained from above step) (2.8 grams, 7.9 mmol) in 10 mL absolute ethanol was added lot wise over a period of 15 minutes. Then the mass was refluxed for 3 hours at 80° C. The mass was cooled to 25° C., added ethylacetate (200 mL) and stirred for 5 minutes. The reaction mass was then filtered through buckner funnel, washed with ethylacetate (3×50 mL). Aqueous layer separated from the filtrate and the organic layer was washed with brine solution (1×50 mL), dried over anhydrous sodium sulfate and solvent was concentrated to obtain oily mass. The technical product was further purified by column chromatography to obtain the title product, the eluent being 70% ethylacetate and 30% n-hexane. Yield: 1.47 grams
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([OH:12])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:13])[CH:3]=1.[CH3:14][S:15]([O-:17])=[O:16].[Na+].N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[F:13][C:4]1[CH:3]=[C:2]([S:15]([CH3:14])(=[O:17])=[O:16])[CH:11]=[C:10]([OH:12])[C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1c(O)cc(Br)cc1F
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COC(=O)c1c(O)cc(S(C)(=O)=O)cc1F
Temperature: 95 °C
Yield: 10.1 %

Procedure:
Methyl 4-bromo-2-fluoro-6-hydroxybenzoate (1.7 g, 5.6 mmol), sodium methanesulfinate (95%) (0.91 g, 8.5 mmol), CuI (0.64 g, 3.4 mmol), L-proline (0.78 g, 6.8 mmol) and K2CO3 (0.47 g, 3.4 mmol) was dissolved in DMSO (dry) (10 ml). Nitrogen was bubbled through the solution for 15 min. The mixture was stirred and heated at 95° C. for 6 h under nitrogen. After cooling to RT, the mixture was filtered on a plug of silica and eluted with ETOAc. The filtrate was washed with 1M citric acid. The waterlayer was extracted once with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. Purification on flash column chromatography (isooctane/EtOAc) gave the crude title compound (0.14 g). MS m/z (rel. intensity, 70 eV) 248 (M+, 36), 216 (bp), 173 (19), 125 (20), 81 (24).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([O:35][CH3:36])=[O:34])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([NH:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[CH3:39]C(O)=O.C([BH3-])#N.[Na+].[OH-].[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([O:35][CH3:36])=[O:34])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([N:27]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[CH3:39])[CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(NCCN(C)C)COc1cc(F)ccc1-3
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(N(C)CCN(C)C)COc1cc(F)ccc1-3
Reaction time: 0.08 h

Procedure:
To a solution of crude methyl 14-cyclohexyl-7-{[2-(dimethylamino)ethyl]amino}-3-fluoro-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (from Step 5) in DCM (0.05 M) was added formaldehyde (3.0 eq) and HOAc (5.5 eq), followed by sodium cyanoborohydride (3 eq). NaOH (20 eq, 1 N) was added after 2 h, and after stirring for 5 min the mixture was taken into EtOAc and washed with water and brine. Drying over Na2SO4 and concentration i. vac. gave the crude product which was used without further purification; MS (ES+) m/z 508 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][N:5]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][CH:8]=2)[C:4](=[O:18])[CH2:3]1.[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1>>[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:30][CH2:31][N:32]([C:11]([C:10]4[CH:9]=[CH:8][C:7]([N:5]5[CH2:6][C:2]([CH3:1])([CH3:19])[CH2:3][C:4]5=[O:18])=[CH:17][CH:16]=4)=[O:13])[CH2:33][CH2:34]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: CCOC(=O)c1ccc(N2CC(C)(C)CC2=O)cc1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CC(C)(C)CC3=O)cc2)CC1
Yield: 14.8 %

Procedure:
Using ethyl 4-(4,4-dimethyl-2-oxopyrrolidin-1-yl)benzoate (131 mg) described in Preparation Example 49 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (109 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 109, the title compound (32 mg) was obtained.
Reaction SMILES: O1CCCCC1[N:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:10][C:9]([C:19]([NH:21][C:22]2[N:26](C3CCCCO3)[N:25]=[C:24]([C:33](=O)[NH:34][C:35]3[CH:39]=[C:38]([C:40]4[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=4)[N:37](C4CCCCO4)[N:36]=3)[CH:23]=2)=O)=[N:8]1.CO.Cl>C1COCC1>[C:43]1([CH3:46])[CH:42]=[CH:41][C:40]([C:38]2[NH:37][N:36]=[C:35]([NH:34][CH2:33][C:24]3[CH:23]=[C:22]([NH:21][CH2:19][C:9]4[CH:10]=[C:11]([C:12]5[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=5)[NH:7][N:8]=4)[NH:26][N:25]=3)[CH:39]=2)=[CH:45][CH:44]=1
Reactant: Cc1ccc(-c2cc(NC(=O)c3cc(NC(=O)c4cc(-c5ccc(C)cc5)n(C5CCCCO5)n4)n(C4CCCCO4)n3)nn2C2CCCCO2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2cc(CNc3cc(CNc4cc(-c5ccc(C)cc5)[nH]n4)n[nH]3)n[nH]2)cc1
Temperature: 0 °C

Procedure:
1-(Tetrahydro-2H-pyran-2-yl)-N-(1-(tetrahydro-2H-pyran-2-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-5-p-tolyl-1H-pyrazol-3-ylcarbamoyl)-1H-pyrazol-5-yl)-5-p-tolyl-1H-pyrazole-3-carboxamide (28 mg, 0.04 mmol) was suspended in anhydrous THF (500 μL) and borane dimethylsulfide complex (26 μL, 0.27 mmol) was added dropwise. The reaction mixture was stirred under reflux for 16 hrs. The reaction mixture was then cooled down to 0° C. and MeOH (50 μL) was added and the mixture was stirred for 10 min. Concentrated hydrochloric acid (12 N) was added until pH<2 was obtained The resulting mixture was stirred at 50° C. for 16 hrs. The mixture was cooled to room temperature and the solvent was evaporated. The residue was resuspended in THF and the precipitate was filtrated and washed with cold THF. 5-p-Tolyl-N-((5-((5-p-tolyl-1H-pyrazol-3-yl)methylamino)-1H-pyrazol-3-yl)methyl)-1H-pyrazol-3-amine was obtained as a white solid.