Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:25](I)[CH3:26]>CN(C)C=O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([C@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:13][CH2:14]2)[CH2:25][CH3:26])=[O:7])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: O=C(N[C@H]1CC[C@H](c2ccccc2)CC1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccccc2)CC1

Procedure:
1 g of trans-N-(4-chlorobenzoyl)-4-phenylcyclohexylamine in 20 ml of dimethylformamide are mixed with 0.14 g of 55% sodium hydride and after 15 minutes 0.62 g of ethyliodide are added. After 1 hour at ambient temperature the reaction solution is evaporated down, the residue is taken up in water, extracted with ethyl acetate and the organic phase is dried and evaporated down. After purification by column chromatography (silica gel, petroleum ether/ethyl acetate=4:1 to 3:1, v:v), 0.73 g of the title compound are obtained, melting point 127°-129° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([OH:12])=[CH:11][C:4]=2[O:3]1.Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[OH-].[K+].CN(C)C=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[CH2:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:12][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[CH:11][C:4]=2[O:3]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CC1(C)CCc2ccc(O)cc2O1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC1(C)CCc2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2O1
Temperature: 110 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
2,3-Dihydro-2,2-dimethyl-7-hydroxy-4H-1-benzopyran (2.0 g) synthesized as in Referential Example 19, 1.8 g of p-chloronitrobenzene, 0.9 g of potassium hydroxide, 20 ml of N,N-dimethylformamide and 10 ml of toluene were put into a flask equipped with the DeanStark condenser, and were heated to 110° C. While removing evaporated water as an azeotrope with toluene, the reaction was carried out for 1 hour. After cooling, the reaction mixture was poured into water, and extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvents were evaporated. The residue was purified by column chromatography to give 2.8 g (yield 84%) of the desired product as a brown liquid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:5]=2[CH:6]=1.C([OH:16])C.[CH:17]([O-:19])=[O:18].[NH4+]>[Pd].C1COCC1>[C:4]([OH:3])(=[O:16])[C:17]([OH:19])=[O:18].[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:5]=2[CH:6]=1
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2o1
Reactant: O=C[O-]
Reactant: CCO
Agent: [Pd]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc2cc(N)ccc2o1
Product: O=C(O)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 35° C. mixture of 50 g of 2-methyl-5-nitrobenzofuran, ethanol (250 mL), THF (250 mL) and wet 10% Pd/C (4 g) was added ammonium formate (53.4 g, 0.85 mol) over 50 min. After an additional 4 h, the reaction was cooled to room temperature and filtered through Celite. The filtrate was concentrated and the residue was taken up in methyl t-butyl ether (415 mL). This mixture was filtered and a solution of oxalic acid (25.4 g) in methanol (80 mL) was added dropwise. The precipitate was stirred for 2 h, collected, washed with methanol/TBME and dried to provide 2-methyl-5-benzofuranamine oxalate.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])[CH:2]=[CH2:3].[NH2:14][C:15]1[C:16]([CH2:24][CH2:25][CH3:26])=[N:17][N:18]([CH3:23])[C:19]=1[C:20]([NH2:22])=[O:21]>ClCCl.N1C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:14][C:15]1[C:16]([CH2:24][CH2:25][CH3:26])=[N:17][N:18]([CH3:23])[C:19]=1[C:20]([NH2:22])=[O:21])=[O:8])[CH:2]=[CH2:3]
Reactant: CCCc1nn(C)c(C(N)=O)c1N
Reactant: C=CCOc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOc1ccccc1C(=O)Nc1c(CCC)nn(C)c1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
A solution of 2-allyloxybenzoyl chloride (3.93 g, 0.02 mol) in dichloromethane (20 ml) was added dropwise to a stirred, partial solution of 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide (3.64 g, 0.02 mol) in pyridine (50 ml), and the resulting mixture stirred at room temperature overnight in a dry atmosphere. The solvent was evaporated under vacuum and the residue partitioned between dichloromethane (50 ml) and saturated aqueous sodium carbonate solution (50 ml). The organic layer was separated and the aqueous layer exhaustively extracted with further dichloromethane. The combined organic solutions were washed with 2M HCl (3×30 ml), then brine (1×30 ml), and dried (Na2SO4). After filtration and evaporation under vacuum of the filtrate, the crude product was crystallised from ethyl acetate to give the title compound (4.525 g, 66%), m.p. 132°-134° C. Found: C,63.49; H, 6.42; N, 16.33. C18H22N4O3 requires C,63.14; H, 6.48; N, 16.36%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[C:31]1([S:41](Cl)(=[O:43])=[O:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:41]([C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)(=[O:43])=[O:42])=[C:3]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH:4]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Product: O=S(=O)(Nc1cc(N2CCNCC2)ccc1NS(=O)(=O)c1cccc2ccccc12)c1ccccc1

Procedure:
N-{4-(1-Piperazinyl)-2-[(phenylsulfonyl)amino]phenyl}-1-naphthalenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 1-naphthalenesulfonylchloride (54 mg, 0.239 mmol) according to general method 3 to give 40 mg of a purple solid. MS (posES-FIA) m/z=Found: 523.2; Calcd 523.14; 1H NMR δ 8.83–8.59 (m, 1H), 8.10 (d, 1H), 8.02–7.97 (m, 1H), 7.90 (d, 1H), 7.74–7.38 (m, 8H), 6.69–6.65 (m, 1H), 6.39-6.34 (m, 2H), 3.3
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[C:6]([F:10])=[CH:5][C:3]=1[NH2:4].[CH3:11][S:12](Cl)(=[O:14])=[O:13].N1C=CC=CC=1.Cl>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:8]=[C:7]([I:9])[C:6]([F:10])=[CH:5][C:3]=1[NH:4][S:12]([CH3:11])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(F)c(I)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(F)c(I)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.7 %

Procedure:
To a solution of 2,5-difluoro-4-iodoaniline (5.3 g, 19.4 mmol, Can. J. Chem., 2000(78), 1081-1088) in DCM(50 ml) was added methanesulfonyl chloride (1.65 ml, 21.3 mmol) and pyridine (4.7 ml, 58.2 mmol) at 0° C. The mixture was stirred for 24 hours at room temperature. The mixture was partitionedbetween EtOAc and 2 M HCl aqueous solution. The organic layer was separated and washed with 2 M aqueous HCl solution and brine, dried over sodium sulfate and concentrated in vacuo. The crude puroduct was purified by silica gel column chromatography eluting with gradually from hexane/EtOAc (4:1) to hexane/EtOAc (3:1) to give the title compound (5.6 g, 87%) as purple solids.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9]N(C)C(=O)C.C(O)CCC.OP(O)(O)=O>C1(C)C=CC=CC=1>[N:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][CH:9]=1
Reactant: Nc1ccccc1N
Reactant: CC(=O)N(C)C
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: c1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The dried product (5.57 g) obtained from step 1 was charged along with 3.1 grams 1,2-phenylenediamine, 120 mL N,N-dimethyl acetamide, 30 mL n-butanol, 10 grams o-phosphoric acid (85%), and 40 mL toluene in a four neck 250 mL reaction kettle equipped with an overhead stirrer, thermocouple, gas inlets adapter and condenser. The mixture was stirred at 250 rpm at room temperature for 15 minutes and heated to 150° C. under argon atmosphere to remove all the toluene. The reaction was continued for 6 hours and the product was cooled to room temperature.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[C:15]([C:19]4([CH3:26])[NH:24][C:23](=S)[CH2:22][O:21][CH2:20]4)[CH:16]=[CH:17][CH:18]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH4+:27].[OH-].C(OO)(C)(C)C>CO>[NH2:27][C:23]1[CH2:22][O:21][CH2:20][C:19]([C:15]2[CH:14]=[C:13]([NH:12][C:6]3[C:5]4[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[CH:18]=[CH:17][CH:16]=2)([CH3:26])[N:24]=1
Reactant: [NH4+]
Reactant: Cn1nc(Nc2cccc(C3(C)COCC(=S)N3)c2)c2ccc(Br)cc21
Agent: CC(C)(C)OO
Agent: [OH-]
Solvent: CO
Product: Cn1nc(Nc2cccc(C3(C)COCC(N)=N3)c2)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 5-[3-(6-bromo-1-methyl-1H-indazol-3-ylamino)-phenyl]-5-methyl-morpholine-3-thione (21 mg, 0.049 mmol) in MeOH (1.5 ml) were added NH4OH (0.303 ml of a 25% aq. soln., 273 mg, 1.947 mmol) and tBuOOH (0.101 ml of a 70% aq. soln., 94 mg, 0.730 mmol) and the reaction mixture was allowed to stir at rt for 20 h, quenched with sat. aq. NaHCO3 soln. and diluted with EtOAc. The layers were separated and the aq. layer was twice reextracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated to leave the crude title compound that was purified by RP-HPLC (Waters SunFire C18 column, 5 μM, 19×150 mm, gradient 10 to 90% ACN+0.1% TFA).
Reaction SMILES: [NH3:1].Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[CH:13]3)[CH:4]=1>CO>[NH2:1][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[CH:13]3)[CH:4]=1
Reactant: N
Reactant: Clc1cc(Nc2ccc3[nH]ccc3c2)ncn1
Solvent: CO
Product: Nc1cc(Nc2ccc3[nH]ccc3c2)ncn1
Temperature: 130 °C
Yield: 69 %

Procedure:
A 7N ammonia in methanol (60 ml) was added to 6-chloro-4-(1H-5-indolylamino)pyrimidine (2.455 g, 10 mmol); and the reaction mixture was heated in a sealed tube at 130° C. for 90 hours. The solvent was distilled off under reduced pressure; the residue was purified by silica gel column chromatography (eluent; ethyl acetate:tetrahydrofuran=1:1); diethyl ether was added to crystallize; and the crystals were filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (1.563 g, 6.9 mmol, 69%) as pale brown crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(P(=O)(OCC)OCC)#N.CN1CCOCC1.[NH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]1[C:44]2[CH:45]=[C:46]([S:49]([NH:52][CH2:53][C:54]3[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=3)(=[O:51])=[O:50])[CH:47]=[CH:48][C:43]=2[S:42][N:41]=1>C(Cl)Cl.Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([NH:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]3[C:44]4[CH:45]=[C:46]([S:49](=[O:50])(=[O:51])[NH:52][CH2:53][C:54]5[CH:55]=[CH:56][C:57]([O:60][CH3:61])=[CH:58][CH:59]=5)[CH:47]=[CH:48][C:43]=4[S:42][N:41]=3)=[O:17])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: COc1ccc(CNS(=O)(=O)c2ccc3snc(NCCCN)c3c2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(CNS(=O)(=O)c2ccc3snc(NCCCNC(=O)c4ccc(-c5ccc(OC)cc5)cc4)c3c2)cc1
Reaction time: 0.25 h
Yield: 21.1 %

Procedure:
To a solution of 4′-methoxybiphenyl-4-carboxylic acid (34 mg, 0.1 mmol) in methylene chloride (1 mL), diethyl cyanophosphonate (23 μL, 0.2 mmol) and 4-methylmorpholine (34 μL, 0.3 mmol) were added at room temperature and allowed to stir for 15 min. A solution of 3-(3-aminopropylamino)-N-(4-methoxybenzyl)benzo[d]isothiazole-5-sulfonamide (57 mg, 0.1 mmol) in methylene chloride (1 mL) was then added and the resulting reaction mixture was allowed to stir for 7 h. Upon diluting the reaction mixture with methylene chloride (20 mL) and 10% HCl aqueous solution, a precipitate was observed, filtered and air-dried to provide 4′-methoxy-N-(3-(5-(N-(4-methoxybenzyl)sulfamoyl)-benzo[d]isothiazol-3-ylamino)propyl)biphenyl-4-carboxamide (13 mg). 1H NMR (300 MHz, DMSO-d6): 9.01 (br s, 1H), 8.58 (t, 1H), 8.47 (d, 1H), 7.88-7.91 (m, 3H), 7.70 (d, 2H), 7.66 (d, 2H), 7.50 (dd, 1H), 7.34 (d, 1H), 7.13 (d, 2H), 7.03 (d, 2H), 6.78 (d, 2H), 3.88 (d, 2H), 3.80 (s, 3H), 3.67 (s, 3H), 3.42-3.48 (m, 2H), 3.31 (m, 2H), 2.00-2.09 ppm (m, 2H). MW=616 confirmed by LC-MS, tr=13.65 min (Method Y) MH+=617.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)[CH2:9][NH:10][C:11]2[N:19]=[C:18](Cl)[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:21]2[CH2:25][C@H:24]([N:26]3[N:30]=[N:29][C:28]([CH2:31][CH3:32])=[N:27]3)[C@@H:23]([OH:33])[C@H:22]2[OH:34])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C1(C(C2C=CC=CC=2)CNC2N=C(NCCN3CCCCC3)N=C3C=2N=CN3[C@@H]2C[C@H](N3C=C(CO)C=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.[C:96]([O:100][C:101](=[O:108])[NH:102][C@@H:103]1[CH2:107][CH2:106][NH:105][CH2:104]1)([CH3:99])([CH3:98])[CH3:97]>>[C:96]([O:100][C:101](=[O:108])[NH:102][C@@H:103]1[CH2:107][CH2:106][N:105]([C:18]2[N:17]=[C:16]3[C:12]([N:13]=[CH:14][N:15]3[C@@H:21]3[CH2:25][C@H:24]([N:26]4[N:30]=[N:29][C:28]([CH2:31][CH3:32])=[N:27]4)[C@@H:23]([OH:33])[C@H:22]3[OH:34])=[C:11]([NH:10][CH2:9][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[C:35]3[CH:36]=[CH:37][C:38]([OH:41])=[CH:39][CH:40]=3)[N:19]=2)[CH2:104]1)([CH3:99])([CH3:97])[CH3:98]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Agent: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(N5CC[C@@H](NC(=O)OC(C)(C)C)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-{6-[2,2-bis-(4-hydroxy-phenyl)-ethylamino]-2-chloro-purin-9-yl}-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Intermediate BF1) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoro-acetate (Example 46) by replacing trans-1,4-diaminocyclohexane with (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester.
Reaction SMILES: CS[CH:3]1[C:11]2[C:6](=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:18]>[Ni].O.O1CCCC1>[C:12]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[NH:5][C:4](=[O:18])[CH2:3]3)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CSC1C(=O)Nc2c(-c3ccccc3)cccc21
Agent: [Ni]
Solvent: O
Solvent: C1CCOC1
Product: O=C1Cc2cccc(-c3ccccc3)c2N1

Procedure:
A stirred solution of 21.5 g. (0.084 mole) of 3-methylthio-7-phenylindolin-2-one in 400 ml. of tetrahydrofuran was treated portionwise with 110 g. of a commercial Raney nickel/water slurry over a 3 hr. period. The mixture was filtered through Celite and the filtrate was concentrated to a gummy residue. The residue was recrystallized from cyclohexane-benzene to yield 7.6 g. (43%) of product as tan needles, m.p. 167°-169° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:8]([CH3:10])=[O:9])[C:4]([O:6][CH3:7])=[O:5].S(Cl)([Cl:14])(=O)=O>C(Cl)Cl>[Cl:14][CH2:10][C:8](=[O:9])[C:3](=[N:2][OH:1])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)C(=NO)C(C)=O
Solvent: ClCCl
Product: COC(=O)C(=NO)C(=O)CCl
Temperature: 25 °C
Reaction time: 72 h
Yield: 85.9 %

Procedure:
In 50 ml of methylene chloride is dissolved 19 g of methyl 2-hydroxyiminoacetoacetate and under ice-cooling and stirring 19.6 g of sulfuryl chloride is added dropwise. The mixture is stirred at room temperature for 3 days, after which the methylene chloride is distilled off under reduced pressure. The residue is dissolved in 200 ml of ether and washed seven times with 100 ml portions of water. The ether layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 20.2 g of methyl 4-chloro-2-hydroxyiminoacetoacetate as a light-yellow oil.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[F:13][C:14]([F:22])([F:21])[CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(C(C)C)C(C)C)C.[Cl:32][C:33]1[CH:38]=[C:37]([N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[CH:36]=[CH:35][C:34]=1[CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>O.ClCCl>[Cl:32][C:33]1[CH:38]=[C:37]([N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[CH:36]=[CH:35][C:34]=1[CH2:44][N:45]1[CH2:46][CH2:47][N:48]([C:2]([O:20][CH:15]([C:16]([F:19])([F:18])[F:17])[C:14]([F:22])([F:21])[F:13])=[O:4])[CH2:49][CH2:50]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: Clc1cc(N2CCCC2)ccc1CN1CCNCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OC(C(F)(F)F)C(F)(F)F)N1CCN(Cc2ccc(N3CCCC3)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
A 100 mL round-bottom flask was charged with triphosgene (119 mg, 0.400 mmol, 0.70 equiv), dichloromethane (15 mL). 1,1,1,3,3,3-Hexafluoropropan-2-ol (193 mg, 1.15 mmol, 2.00 equiv) and N-ethyl-N-isopropylpropan-2-amine (592 mg, 4.58 mmol, 8.00 equiv) were added at 0° C. The mixture was stirred for 2 h at room temperature. 1-[[2-chloro-4-(pyrrolidin-1-yl)phenyl]methyl]piperazine (160 mg, 0.570 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with H2O (10 mL), extracted with dichloromethane (3×10 mL). The organic layers were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (300 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% Phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% CH3CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 106 mg (39% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-chloro-4-(pyrrolidin-1-yl)phenyl]methyl]piperazine-1-carboxylate as yellow oil. 1H NMR 300 MHz (CDCl3) δ 7.18 (d, J=8.4 Hz, 1H), 6.54 (s, 1H), 6.40-6.44 (m, 1H), 5.71-5.80 (m, 1H), 3.54-3.56 (m, 6H), 3.23-3.33 (m, 4H), 2.47-2.52 (m, 4H), 1.96-2.04 (m, 4H). LCMS (ESI, m/z): 474 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[C:3]=1[N+:13]([O-])=O.C([O-])=O.[NH4+]>O1CCCC1.O.[Fe]>[NH2:13][C:3]1[C:4]([CH3:12])=[C:5]([CH:10]=[CH:11][C:2]=1[NH2:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(N)c([N+](=O)[O-])c1C
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N)c(N)c1C
Yield: 97.8 %

Procedure:
To a solution of methyl 4-amino-2-methyl-3-nitrobenzoate (1.10 g, 5.22 mmol) in tetrahydrofuran (75 mL) and water (25 mL) was added ammonium formate (6.6 g, 104 mmol) and iron powder (2.92 g, 52.2 mmol). This mixture was refluxed for 12 hours then filtered and the filter cake rinsed with ethyl acetate. The filtrate layers were separated and the organic layer was dried (magnesium sulfate), filtered and concentrated to give 0.92 g (98% yield) of crude methyl 3,4-diamino-2-methylbenzoate, which was used without further purification. 1H NMR (400 MHz, d6-DMSO): 7.05 (d; 1H), 6.40 (d, 1H), 3.69 (s, 3H), 2.29 (s, 3H). MS (EI) for C9H12N2O2: 181 (MH+).
Reaction SMILES: [F:1]C1C=CC=CC=1CN1C=C(C2C3C(=NC=C(C4C=C(NS(C)(=O)=O)C=CC=4)C=3)NC=2)C=N1.F[C:35]1[CH:80]=[CH:79][C:78]([F:81])=[CH:77][C:36]=1[CH2:37][N:38]1[C:42]([CH3:43])=[C:41]([C:44]2[C:52]3[C:47](=[N:48][CH:49]=[C:50]([C:53]4[CH:54]=[CH:55][C:56]([O:64][CH3:65])=[C:57]([S:59]([NH:62][CH3:63])(=[O:61])=[O:60])[CH:58]=4)[CH:51]=3)[N:46](S(C3C=CC(C)=CC=3)(=O)=O)[CH:45]=2)[C:40]([CH3:76])=[N:39]1.[OH-].[Li+]>C1COCC1.CO.O>[F:81][C:78]1[CH:77]=[C:36]([CH:35]=[C:80]([F:1])[CH:79]=1)[CH2:37][N:38]1[C:42]([CH3:43])=[C:41]([C:44]2[C:52]3[C:47](=[N:48][CH:49]=[C:50]([C:53]4[CH:54]=[CH:55][C:56]([O:64][CH3:65])=[C:57]([S:59]([NH:62][CH3:63])(=[O:60])=[O:61])[CH:58]=4)[CH:51]=3)[NH:46][CH:45]=2)[C:40]([CH3:76])=[N:39]1
Reactant: CNS(=O)(=O)c1cc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cc(F)ccc4F)c2C)cn3S(=O)(=O)c2ccc(C)cc2)ccc1OC
Reactant: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cnn(Cc5ccccc5F)c4)c3c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CNS(=O)(=O)c1cc(-c2cnc3[nH]cc(-c4c(C)nn(Cc5cc(F)cc(F)c5)c4C)c3c2)ccc1OC
Yield: 11.4 %

Procedure:
Using similar reaction conditions as described in step-iii of example 1, 5-(3-(1-(2,5-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxy-N-methylbenzenesulfonamide (180 mg, 0.2604 mmol) was hydrolyzed by lithium hydroxide (109 mg, 2.604 mmol), THF/Methanol/water (24/12/6 ml) to yield 16 mg (11.4% yield) of the titled compound after purification by preparative TLC (SiO2-1000 micron eluted by 3% MeOH in CHCl3). 1H NMR (CD3OD, 300 MHz): δ 8.382 (m, 1H), 7.940-7.935 (d, 1H), 7.816-7.779 (m, 2H), 7.342 (s, 1H), 7.241-7.213 (d, 1H), 6.68-6.64 (m, 1H), 5.275 (s, 2H), 3.914 (s, 3H), 2.441 (s, 3H), 2.128-2.101 (d, 6H). MS: m/z=538.1 (M+1); HPLC: 95.69% in method B.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[CH:22]1([C:27]2[O:31][N:30]=[C:29]([C:32]3[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:39])[C:28]=2[CH2:40]O)[CH2:26][CH2:25][CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH:22]1([C:27]2[O:31][N:30]=[C:29]([C:32]3[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:39])[C:28]=2[CH2:40][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]4)=[CH:4][CH:3]=2)[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Reactant: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CCCC4)cc3)ccc2n1
Temperature: 90 °C
Yield: 36.8 %

Procedure:
To a solution of methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (0.10 mg, 0.36 mmol), [5-cyclopentyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methanol (0.11 mg, 0.36 mmol) and triphenylphosphine (0.10 mg, 0.39 mmol) in dichloromethane (2.5 mL) was added diisopropyl azodicarboxylate (0.071 mL, 0.39 mmol) slowly. The solution was heated in a microwave reactor at 90° C. for 10 minutes and then was adsorbed onto silica gel and purified by chromatography (silica gel, 0-45% ethyl acetate in hexanes gradient elution) to afford methyl 6-[4-({[5-cyclopentyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (76 mg, 37%). 1H-NMR (400 MHz, DMSO d6) δ 8.55 (d, J=8 Hz, 1H), 8.28 (s, 1H), 8.18-8.10 (m, 3H), 7.73 (d, J=9 Hz, 2H), 7.63-7.51 (m, 3H), 6.96 (d, J=9 Hz, 2H), 4.98 (s, 2H), 3.93 (s, 3H), 3.58-3.50 (m, 1H), 2.11-2.03 (m, 2H), 1.84-1.64 (m, 6H).