Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH:8]([CH3:12])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[N:31]1[C:39]2[C:34](=[CH:35][C:36]([C:40]3[N:44]=[CH:43][N:42]([C:45]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[N:41]=3)=[CH:37][CH:38]=2)[C:33]([C:64]2[CH:65]=[C:66]([NH2:70])[CH:67]=[CH:68][CH:69]=2)=[N:32]1>ClCCl>[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[N:31]1[C:39]2[C:34](=[CH:35][C:36]([C:40]3[N:44]=[CH:43][N:42]([C:45]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[N:41]=3)=[CH:37][CH:38]=2)[C:33]([C:64]2[CH:65]=[C:66]([NH:70][C:9](=[O:11])[CH:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH3:12])[CH:67]=[CH:68][CH:69]=2)=[N:32]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CC(Oc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(Oc1ccccc1)C(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-phenoxypropanoic acid (0.045 g, 0.274 mmol) in 2.5 mL of dichloromethane was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) (0.057 g, 0.298 mmol). The reaction was stirred at room temperature for 10 min before 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) dissolved in 1 mL of dichloromethane, was added to the solution. The reaction was stirred at room temperature for 3 hours. The reaction mixture was then partitioned between water and dichloromethane. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 751 [M+H]+.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:21])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1>C(Cl)Cl>[Cl:4][CH:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:13]([C:10]1[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=1)=[O:21]
Reactant: O=C(Cc1ccccc1)c1ccc(F)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)C(Cl)c1ccccc1
Temperature: 12.5 °C

Procedure:
Sulfuryl chloride (66.6 g, 0.493 mol) is taken in a 4 necked RB flask equipped with mechanical strring rod, pressure equalization funnel and a CaCl2 guard tube. The contents of the flask are cooled to 10-15° C. A solution of 1-(4-Fluorophenyl)-2-phenyl ethanone (100 g, 0.467 mol) in 150 ml of methylene chloride is added to the above flask in about 30-45 min while maintaining the temperature between 10-15° C. After completion of addition, the reaction mass is then stirred for additional 2½ hours at 15-20° C. TLC examination of reaction mixture showed the absence of starting material. The reaction mixture is slowly poured over crushed ice (600 g) and further dilueted with methylene chloride (200 ml). The methylene chloride layer is separated and washed twice with 5% aqueous sodium bicarbonate (200 ml) followed by 5% aqueous sodium chloride(200 ml). The methylene chloride layer is dried over sodium sulphate. Methylene chloride is removed by distillation completely to obtain 2-Chloro-1-(4-fluorophenyl)-2-phenylethanone as a pale yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[S:19])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:3]=1[NH:20][CH2:21][C:22]([F:29])([F:28])[C:23](OCC)=[O:24].[BH4-].[Li+]>O1CCCC1>[NH2:1][C:2]1[C:3]([NH:20][CH2:21][C:22]([F:28])([F:29])[CH2:23][OH:24])=[C:4]([NH:8][C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[S:19])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(F)(F)CNc1c(N)cccc1NC(=S)Nc1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1cccc(NC(=S)Nc2ccc(Cl)cc2Cl)c1NCC(F)(F)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.1 %

Procedure:
To a solution of ethyl 3-[(2-amino-6-{[(2,4-dichlorophenyl)carbamothioyl]amino}phenyl)amino]-2,2-difluoropropanoate (694.5 mg, 1.50 mmol) in tetrahydrofuran (10 mL) was added lithium tetrahydroborate (65.3 mg, 3.00 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min. The reaction mixture was quenched with H2O. The mixture was extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-50% ethyl acetate/n-hexane gradient mixture to give a title compound (70.0 mg) and a mixture contained the title compound. The mixture was purified by preparative HPLC to give the title compound as the trifluoroacetic acid salt. The salt was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a colorless amorphous (273.3 mg). Total amount was 343.3 mg (0.815 mmol, 54%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH:19]([CH3:21])[CH3:20])[N:13]=2)[CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>CN1C(=O)CCC1.CCOC(C)=O>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:22][C@@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH:19]([CH3:21])[CH3:20])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Reactant: CC(C)c1nc(Nc2cc(Cl)nnc2C(N)=O)ccc1F
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)c1nc(Nc2cc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)ccc1F
Temperature: 140 °C
Yield: 25.3 %

Procedure:
To a solution of 6-chloro-4-(5-fluoro-6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (250 mg, 807 μmol) in NMP (3.2 mL) was added tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (174 mg, 807 μmol) and the mixture heated to 140° C. Over the next 36 h three additional portions of tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (174 mg, 807 μmol) were added at 12 h intervals. At 48 h the mixture was cooled, diluted with EtOAc, and washed with water and brine (2×). The organic layer was concentrated onto silica and purified by chromatography (70% to 100% EtOAc in hexanes) to give tert-butyl (3R,4R)-4-(6-carbamoyl-5-(5-fluoro-6-isopropylpyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (100 mg, 25%). 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 11.49 (s, 1H), 8.22 (s, 1H), 8.06 (br. s, 1H), 7.29 (t, J=9.4 Hz, 1H), 6.70 (dd, J=8.9, 3.0 Hz, 1H), 6.07 (br. s, 1H), 5.50 (br. s, 1H), 5.35 (br. s, 1H), 4.26 (br. s, 1H), 4.03 (m, 2H), 3.92 (d, J=11.4 Hz, 1H), 3.68 (d, J=11.5 Hz, 1H), 3.61 (t, J=11.8 Hz, 1H), 3.41 (m, 1H), 2.24 (d, J=11.2 Hz, 1H), 1.81 (m, 1H), 1.49 (s, 9H), 1.35 (d, J=6.9 Hz, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1
Yield: 98.8 %

Procedure:
A solution of 4-nitrophenol (10 g, 71.9 mmol), ethyl bromoacetate (13.5 g, 80.8 mmol) and potassium carbonate (12.0 g, 86.8 mmol) in N,N-dimethylformamide (100 mL) was stirred at room temperature for 18 hr. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed successively with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with diethyl ether-hexane to give the title compound (16.0 g, yield 99%) as colorless needle crystals.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH3:20])=[C:15]([CH:19]=2)[C:16]([OH:18])=O)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[NH2:52][C:53]1[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][N:54]=1>C(Cl)Cl>[NH2:52][C:53]1[N:54]=[CH:55][C:56]([NH:59][C:16](=[O:18])[C:15]2[CH:19]=[C:11]([CH:12]=[CH:13][C:14]=2[CH3:20])[C:9]([NH:8][CH2:7][CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:10])=[CH:57][CH:58]=1
Reactant: Nc1ccc(N)nc1
Reactant: Cc1ccc(C(=O)NCCC2CCCC2)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NCCC2CCCC2)cc1C(=O)Nc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a RBF was charged 5-((2-cyclopentylethyl)carbamoyl)-2-methylbenzoic acid (0.25 g, 0.91 mmol), DCM (3 ml), n,n-diisopropylethylamine (0.6 ml, 3.5 mmol), HOBt (0.14 g, 1.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.21 g, 1.1 mmol), and 2,5-diaminopyridine (0.1 g, 0.91 mmol) in that order. This mixture was stirred at RT under N2 for 18 h. The reaction was partitioned between DCM (30 ml) and brine (20 mL). The precipitate formed was collected, washed with water, dried in a vacuum oven overnight to give N3-(6-aminopyridin-3-yl)-N1-(2-cyclopentylethyl)-4-methylisophthalamide as a purple solid. MS (ESI, pos. ion) m/z: 367.2 (M+1).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][OH:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][O:31][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(CCO)cc1OC
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Product: COc1ccc(CCOC(=O)NC(=O)C(c2ccccc2)c2ccccc2)cc1OC

Procedure:
The title compound, white solid, m.p. 144° C. and MS: m/e=419.5 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and 2-(3,4-dimethoxy-phenyl)-ethanol.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]2[S:20][C:11]3[C:12]([CH2:18][CH3:19])=[N:13][N:14]([CH3:17])[C:15](=[O:16])[C:10]=3[C:9]=2[C:21](N2C[C@H](O)CO2)=[O:22])=[C:5]([CH3:29])[NH:4][N:3]=1.FC(F)(F)C(O)=[O:33]>>[CH3:29][C:5]1[C:6]([CH2:7][C:8]2[S:20][C:11]3[C:12]([CH2:18][CH3:19])=[N:13][N:14]([CH3:17])[C:15](=[O:16])[C:10]=3[C:9]=2[C:21]([OH:22])=[O:33])=[C:2]([CH3:1])[NH:3][N:4]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CCc1nn(C)c(=O)c2c(C(=O)N3C[C@H](O)CO3)c(Cc3c(C)n[nH]c3C)sc12
Product: CCc1nn(C)c(=O)c2c(C(=O)O)c(Cc3c(C)n[nH]c3C)sc12

Procedure:
Prepared from the product of example 3, part g) (1.0 g) in trifluoroacetic acid (10 ml) under reflux for 20 hrs. The resulting mixture was evaporated under reduced pressure, azeotroping with dichloromethane (×3). The residue was triturated with water and then with ether, and the solid was collected and dried to give the subtitle compound as a solid (580 mg).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Cl[CH2:16][C:17]([O:19]CC)=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:12]([C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:16][C:17]([OH:19])=[O:18])=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[OH:1])(=[O:14])[CH3:13]
Reactant: CCOC(=O)CCl
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCC(=O)O)ccc(C(C)=O)c1O

Procedure:
A mixture of 24.25 g of 1-(2,4-dihydroxy-3-propylphenyl) ethanone, 16.0 ml of ethyl chloroacetate and 26 g of anhydrous potassium carbonate in 375 ml of anhydrous acetone was stirred at reflux for 17 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was crystallized from ethanol to give 27.2 g of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid, the titled compound, mp 61°-64°, (78% yield) in two crops.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:10]=2[CH:11]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[O:22])=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[C:4]([NH:12][C:21]([NH:20][CH2:19][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:26])[F:25])=[CH:24][CH:23]=2)=[O:22])[CH:3]=1
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: Nc1cc(F)cc2cnccc12
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cc(F)cc2cnccc12

Procedure:
Prepared from 7-fluoroisoquinolin-5-amine (Description 90) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 364 (M+H)+.
Reaction SMILES: Cl.N1C=CC=CC=1.C([O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21](=[S:22])[N:20]([CH3:23])[N:19]=[C:18]2[C:24]([F:27])([F:26])[F:25])=[CH:13][CH:12]=1)C>O>[F:26][C:24]([F:25])([F:27])[C:18]1[N:17]([C:14]2[CH:13]=[CH:12][C:11]([OH:10])=[CH:16][CH:15]=2)[C:21](=[S:22])[N:20]([CH3:23])[N:19]=1
Reactant: CCOc1ccc(-n2c(C(F)(F)F)nn(C)c2=S)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Cn1nc(C(F)(F)F)n(-c2ccc(O)cc2)c1=S
Temperature: 215 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A mixture of 12.6 g (0.109 mole) of pyridine hydrochloride and 11.0 g (0.0363 mole) of 4-(4-ethoxyphenyl)-3-trifluoromethyl-4,5-dihydro-1-methyl-1,2,4-triazol-5(1H)-thione was heated at 215° C. and stirred for one hour. The mixture was cooled and dissolved in water. The aqueous solution was extracted with a mixture of tetrahydrofuran:diethyl ether (50:50). The organic phase was extracted with an aqueous, 10% sodium hydroxide solution. The basic extract was acidified, forming a precipitate. This solid was collected by filtration and dried to yield 7.1 g of 3-trifluoromethyl-4,5-dihydro-4-(4-hydroxyphenyl)-1-methyl-1,2,4-triazol-5(1H)-thione, mp 150°-152° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].[NH2:17][CH2:18][C:19]1[O:20][CH:21]=[CH:22][CH:23]=1>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:17][CH2:18][C:19]4[O:20][CH:21]=[CH:22][CH:23]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Reactant: NCc1ccco1
Solvent: CS(C)=O
Product: CCn1ncc2c(NCc3ccco3)c3ccccc3nc21
Yield: 34.2 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (1.0 g, 0.0043 mol), DMSO (3 mL) and 2-aminomethylfuran (0.8 mL, 0.009 mol) was heated at 90° for 3 hours. The reaction mixture was then partitioned between CH2Cl2 (50 mL) and water (50 mL). The aqueous layer was separated and then extracted with CH2Cl2 (25 mL) and then the CH2Cl2 layers were combined, washed with water dried over Na2SO4 and reduced to a volume of about 3-5 mL. The solution was passed through a silica gel column eluting with ethyl acetate to afford the product which was recrystallized from ether/CH2Cl2 to afford 430 mg of 1-ethyl-N-(2-furanylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as a yellow solid, m.p. 156-158° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([CH:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]4[C:26]=3[C:25]3[C@@H:24]([CH2:27][C:28]#[N:29])[CH2:23][CH2:22][C:21]=3[S:20]4)[CH2:10][CH2:9]2)[CH2:3]1.[OH:30][Li].O.OO>CO>[O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([CH:8]2[CH2:9][CH2:10][CH:11]([O:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]4[C:26]=3[C:25]3[C@@H:24]([CH2:27][C:28]([NH2:29])=[O:30])[CH2:23][CH2:22][C:21]=3[S:20]4)[CH2:12][CH2:13]2)[CH2:3]1
Reactant: N#CC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCNC(=O)C5)CC4)c3c21
Reactant: [Li]O
Agent: OO
Solvent: O
Solvent: CO
Product: NC(=O)C[C@H]1CCc2sc3ncnc(OC4CCC(N5CCNC(=O)C5)CC4)c3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.6 %

Procedure:
To a solution of 2-[(3R)-12-[[4-(3-oxopiperazin-1-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetonitrile (330 mg, 0.80 mmol, 1.00 equiv) in methanol (10 mL) was added LiOH.H2O (101 mg, 2.40 mmol, 3.00 equiv) and H2O2 (30%, 0.5 mL) at 0° C. The resulting solution was stirred for 2 h at room temperature and quenched with Na2SO3 (aq.), extracted with DCM (80 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1) to give 50 mg (15%) of 2-[(3R)-12-[[4-(3-oxopiperazin-1-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetamide as a white solid. [Note: The product was found to decompose during column purification].
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:13])([CH3:12])[CH2:4][CH2:3]1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[Cl:19][CH2:20][C:21]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5]([CH3:13])([CH3:12])[CH2:4][CH2:3][C:2]2([CH3:14])[CH3:1])=[O:22]
Reactant: O=C(Cl)CCl
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(C(=O)CCl)ccc21
Reaction time: 8 h

Procedure:
A solution of 68 g (0.36 mole) of 1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene in 200 ml of methylene chloride was added dropwise at 0°-5° C. to a solution of 72 g (0.55 mole) of anhydrous aluminum chloride and 40.7 g (0.36 mole) of chloroacetyl chloride in 270 ml of dry methylene chloride. Stirring was then carried out overnight at room temperature. The mixture was poured onto ice/water and extracted with methylene chloride, and the organic phase was washed several times with water, dried over sodium sulfate and evaporated down. 92.2 g of 6-chloroacetyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene remained as an oil. The structure was determined by H-NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25]O)=[CH:23][N:24]=2)[CH:3]=1.[Br-:27].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.C(=O)([O-])O.[Na+]>ClCCl>[Br:27][CH2:25][C:22]1[O:21][C:20]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:10]=[C:9]3[C:5]=2[CH:6]=[N:7][N:8]3[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[N:24][CH:23]=1
Reactant: [Br-]
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3ncc(CO)o3)cc(Cl)cc21
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: O=S(=O)(c1ccccc1)n1ncc2c(-c3ncc(CBr)o3)cc(Cl)cc21
Temperature: 3 °C
Reaction time: 0.17 h

Procedure:
(2-(6-Chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methanol (1.0 eq., 1 wt, 34.0 g) and triphenylphosphine dibromide (1.3 eq., 1.32 wt, 45.0 g) are stirred in dichloromethane (15 vols, 510 ml) at 20 (±3° C.) under a nitrogen atmosphere for 1 hr. The reaction is then checked by HPLC for completion. Once complete methanol (0.8 vols, 27.2 ml) is added to the reaction, with vigorous stirring 8% w/w sodium hydrogen carbonate solution (10 vols, 340 ml) is added drop wise over 15 minutes (check aqueous pH>7). The mixture is heated to 30° C. (±3° C.) and stirred together for 10 minutes, then separated, the aqueous is back extracted with dichloromethane (5 vols, 170 ml) and the combined dichloromethane layers are washed with water (5 vols, 170 ml). The dichloromethane solution is then evaporated under reduced pressure to a volume of approximately 4 vols. To the solution is added methanol (15 vols, 510 ml) and the solution evaporated under reduced pressure at 260 mbar, 20° C. to remove the remaining dichloromethane down to ˜15 vols. The suspension is then stirred at 20° C. for at least 6 hrs. The solid is filtered, washed with methanol (2×1 vols, 2×34 ml), sucked dry for 20 minutes, then dried under high vacuum at 30° C. (±3° C.) to constant probe temperature to afford 5-(bromomethyl)-2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazole as a beige solid.
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[C:25]([O:27][CH3:28])=[O:26])[C:19](O)=[O:20].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O>CN(C=O)C>[I:15][C:16]1[CH:17]=[C:18]([C:19](=[O:20])[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:22]=[CH:23][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1ccc(C(=O)O)cc1I
Reactant: Nc1ccccc1Oc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)Nc2ccccc2Oc2ccccc2)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a stirring solution of 2-phenoxyaniline 99 (0.813 g, 4.39 mmol) and 3-iodo-4-(methoxycarbonyl)benzoic acid 100 (1.28 g, 4.18 mmol) in DMF (15 mL) was added BOP (1.942 g, 4.39 mmol) and TEA (1.166 mL, 8.36 mmol), the reaction mixture was stirred at room temperature for 1 h then poured into water. The desired product was extracted with ethyl acetate and the combined organic layers were washed with water, brine, dried over Na2SO4, filtered and solvent evaporated to provide methyl 2-iodo-4-(2-phenoxyphenylcarbamoyl)benzoate 101 (1.382 g, 70% yield) as a red foam after purification by flash chromatography (0 to 40% ethyl acetate in hexane).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N+:13]([O-])=O)[CH:10]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.CCOCC.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[CH2:1]([N:8]1[CH2:9][CH:10]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH:11]([NH2:13])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccc(F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC1CN(Cc2ccccc2)CC1c1ccc(F)cc1
Temperature: 68 °C
Yield: 22.6 %

Procedure:
Titanium (IV) chloride (179.4 g, 0.94 mol) was added drop wise to a suspension of zinc powder (123.6 g, 1.89 mol) in THF (1200 ml). This solution was heated at 68° C. for one hour, then cooled to RT before rac-(3R,4S)-1-benzyl-3-(4-fluoro-phenyl)-4-nitro-pyrrolidine (94 g, 0.31 mol) in THF (400 ml) was added. The reaction mixture was then stirred at reflux over night. The reaction was cooled to RT, diluted with 3000 ml of Et2O, washed with an aqueous solution of NaHCO3 and the organic phases were dried over Na2SO4. Flash chromatography (SiO2, CH2Cl2/MeOH, 9:1) yielded 18.9 g (22%) of rac-(3S,4R)-1-benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-ylamine as a brown oil.
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:7][N:6]=1)([O-])=O.[NH:20]([C:24]1[S:25][CH:26]=[C:27]([CH2:29][S:30][CH2:31][CH2:32]N)[N:28]=1)[C:21]([NH2:23])=[NH:22]>N1C=CC=CC=1>[NH:20]([C:24]1[S:25][CH:26]=[C:27]([CH2:29][S:30][CH2:31][CH2:32][NH:4][C:5]2[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[CH:7][N:6]=2)[N:28]=1)[C:21]([NH2:23])=[NH:22]
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCSCc3csc(NC(=N)N)n3)[nH]c2=O)cn1

Procedure:
2-Nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone (5.21 g) and 2-(2-guanidino-4-thiazolylmethylthio)ethylamine (2.98 g) were heated under reflux in dry pyridine for 9 hours. The mixture was evaporated and the residue was washed with water to give 2-[2-(2-guanidino-4-thiazolylmethylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone which was treated with hydrogen chloride in ethanol-ether to give the trihydrochloride (0.92 g). This was converted into the free base by dissolving the material in water, adjusting the mixture to pH 9 with sodium bicarbonate, and extracting the mixture with chloroform and evaporating the extracts to dryness. A sample of the free base recrystallised from aqueous 2-propanol had m.p. 161°-164°.