Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([C:8]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O:36][C:37]([NH:39][C@@H:40]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:41](O)=[O:42])=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:26]1([C:8]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14]([C:41](=[O:42])[C@@H:40]([NH:39][C:37]([O:36][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:38])[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Agent: Cl
Product: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)[C@@H](NC(=O)OC(C)(C)C)c3ccccc3)C[C@H]21
Yield: 11.1 %

Procedure:
By working in accordance with Example 4, starting from 2.25 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol hydrochloride and 1.25 g of (S)-2-tert-butoxycarbonylamino-2-phenylacetic acid, 0.35 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(S)-2-tert-butoxycarbonylamino-2-phenylacetyl]perhydroisoindol-4-ol is obtained in the form of a white foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([NH2:30])=[N:22]1.O.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[CH:8]1([C:6]2[N:5]=[C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]([F:20])([F:19])[F:18])[N:3]=[C:2]([NH:30][C:23]3[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[NH:21][N:22]=3)[CH:7]=2)[CH2:10][CH2:9]1
Reactant: Nc1n[nH]c2ccccc12
Reactant: FC(F)(F)c1ccccc1-c1nc(Cl)cc(C2CC2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: FC(F)(F)c1ccccc1-c1nc(Nc2n[nH]c3ccccc23)cc(C2CC2)n1
Temperature: 165 °C
Yield: 15.9 %

Procedure:
A mixture of 4-chloro-6-cyclopropyl-2-(2-trifluoromethyl-phenyl)-pyrimidine (0.08 g, 0.27 mmol) and 1H-indazol-3-ylamine (0.036 g, 0.41 mmol) was heated neat at 160-170° C. for 6 hours. The residue was cooled and dissolved in N-methylpyrrolidinone (2 mL), poured into water (30 mL) and sodium bicarbonate (5 mL) then filtered, washing with water and ether. The collected precipitate and the ether wash were combined and concentrated. Purification by flash chromatography [SiO2, methanol:dichloromethane (2:98)] provided the title compound (0.017 g, 15% yield) as a pale yellow solid. 1H-NMR (500 MHz, DMSO-d6) δ 12.6 (br s, 1H), 10.2 (br s, 1H), 8.00 (d, J=8.1 Hz, 2H), 7.81 (d, J=7.9 Hz, 1H), 7.71 (m, 3H), 7.65 (t, J=7.3 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.36 (t, J=7.5 Hz, 1H), 7.06 (t, J=7.5 Hz, 1H), 2.04 (m, 1H), 1.01 (m, 2H), 0.96 (m, 2H) ppm; LC-MS 396.10 (M+H); Rt (Method A) 3.122 minutes.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:2].CS(O[CH2:22][CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH2:22][CH2:23][C:24]2[N:25]=[C:26]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[O:27][C:28]=2[CH3:29])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:2]
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CCOS(C)(=O)=O
Reactant: CCOC(=O)CCc1ccc(O)cc1CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCc1ccc(OCCc2nc(-c3ccc(F)cc3)oc2C)cc1CC

Procedure:
The parent phenolic compound, ethyl 3-(2-ethyl-4-hydroxylphenyl)propionate (10.4 g, 50 mmol) and 120 ml acetonitrile were added into a 250 ml single neck flask, and stirred. Then the parent sulfonate compound, 2-[2-(4-fluorophenyl)-5-methyloxazol-4-yl]ethyl methanesulfonate (15 g, 50 mmol) and potassium carbonate (K2CO3) (100 mmol) were added. The mixture was heated for 16 hours under reflux. After the reaction was completed, the product was filtered. The filter cake was washed with ethyl acetate (3×50 ml) and then discarded. The filtrates were combined, and the solvent was distilled off under reduced pressure, to obtain crude ethyl 3-(2-ethyl-4-{2-[2-(4-fluorophenyl)-5-methyloxazol-4-yl]ethoxy}phenyl)propionate. The crude ethyl 3-(2-ethyl-4-{2-[2-(4-fluorophenyl)-5-methyloxazol-4-yl]ethoxy}phenyl)propionate, without purification, was dissolved with 120 ml ethanol. 10% NaOH (30 ml) was added at room temperature, and the stirring was maintained for 3 hours at room temperature. After the reaction was completed, the product was acidified by adding 10% dilute hydrochloric acid, to obtain a solid precipitate. It was filtered by suction filtration, to obtain crude 3-(2-ethyl-4-{2-[2-(4-fluorophenyl)-5-methyloxazol-4-yl]ethoxy}phenyl)propionic acid. The crude product was crystallized by ethyl acetate-petroleum ether, to obtain 12.3 g white solid, with a yield of 62% from the 2 steps.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1.N([O-])=O.[Na+].[OH-].[Na+].[ClH:17]>O>[Cl:17][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1
Reactant: Cl
Reactant: COc1cc(C)nc(N)n1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C)nc(Cl)n1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A solution of 25.4 g of 2amino-4-methyl-6-methoxypyrimidine in 150 ml concentrated hydrochloric acid was cooled to ca. 0° C. and treated with a solution of 25.3 g of sodium nitrite in 50 ml water, added over a period of 30-40 minutes. The thick orange reaction mixture was stirred at room temperature for 4-5 hours and then adjusted to pH 10 by addition of 12.5N sodium hydroxide solution. The precipitate was filtered and extracted thoroughly with approximately 600 ml of hot ether. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give 7.2 g of 2-chloro-4-methyl-6-methoxypyrimidine as a white, crystalline solid, m.p. 36°-38° C.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:4].CCN=C=N[CH2:25][CH2:26][CH2:27][N:28](C)C.C(N(CC)CC)C.C1(N)CC1>ClCCl>[CH:27]1([NH:28][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([C:9]#[C:8][CH2:7][CH2:6][CH2:5][C:3](=[O:4])[N:2]([CH3:1])[CH3:19])[CH:11]=2)[CH2:25][CH2:26]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CN(C)C(=O)CCCC#Cc1cccc(C(=O)O)c1
Agent: NC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CCCC#Cc1cccc(C(=O)NC2CC2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.5 %

Procedure:
To a solution of 3-(5-dimethylcarbamoyl-pent-1-ynyl)-benzoic acid (0.100 g, 0.38 mmol) in dry dichloromethane (1.5 mL) under a nitrogen atmosphere at room temperature, EDCI (0.0728 g, 0.38 mmol) was added followed by triethylamine (0.162 mL, 1.14 mmol), the resulting mixture was stirred at room temperature for further 5 minutes. Cyclopropylamine (0.027 g, 0.38 mmol) was then added and the mixture stirred at room temperature for 16 hrs. The reaction mixture was washed with a mixture of saturated brine and saturated sodium bicarbonate (1:1; 2×150 mL) followed by saturated brine solution (100 mL). The organic layer was separated and dried over magnesium sulfate and the solvent evaporated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM:MeOH, 95% to 5% methanol gradient) to afford N-cyclopropyl-3-(5-dimethylcarbamoyl-pent-1-ynyl)benzamide (25) (0.10 g, 0.34 mmol, 91% yield).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[CH2:15][CH2:16][F:17].C(N(CC)C(C)C)(C)C>C(#N)C>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:15][CH2:16][F:17])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: FCCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(CCF)CC1
Yield: 98.5 %

Procedure:
Heat a mixture of 1-boc-piperazine (4.08 g, 21.9 mmol), 1-bromo-2-fluoroethane (16.68 g, 0.131 mol) and N,N-diisopropyl ethyl amine (17.0 g, 0.131 mol) in acetonitrile (40 mL) to 50° C. for 16 hours and then heat to reflux for 7 additional hours. Cool the reaction to room temperature and remove the solvent in vacuo. Treat the residue with 1 N NaOH (25 mL) and extract twice with ethyl acetate. Dry the organic layer with Na2SO4 and purify the crude product on silica with a 0 to 10% Methanol in CH2Cl2 gradient to afford 5.01 g (99%) of 4-(2-fluoro-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (Rf 0.36 (9/1 CH2Cl2/Methanol, I2 stain).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.CCN(C(C)C)C(C)C>Cl.CCCCO>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: C1COCCN1
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2cc(N3CCOCC3)ncn2)cc1
Temperature: 200 °C
Yield: 89 %

Procedure:
50 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 17 mg of morpholine and 64 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 30 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc. N-(4-Methoxyphenyl)-6-morpholinopyrimidin-4-amine in the form of a colorless solid was obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: Clc1ccncc1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: Cl
Product: CS(=O)(=O)c1ccc(Oc2ccncc2)cc1
Temperature: 150 °C
Reaction time: 4 h
Yield: 19.1 %

Procedure:
A mixture of 4-methylsulfonylphenol (2.93g, 17 mmol) and 4-chloropyridine hydrochloride (2.93 g, 19.5 mmol) was heated at 150° C., resulting in a gradual melt, which was stirred at 150° C. for 4 h, then partitioned between ethyl acetate and 1N NaOH. The organic extract was dried over MgSO4, filtered, and concentrated to 1.3 g of a yellow solid. The solid was recrystallized from ethyl acetate-ether to give 0.81 g of the title compound as a white solid.
Reaction SMILES: CC1(C)C[O:36][C:5]2([CH2:9][C@@H:8]([CH2:10][C@H:11]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:12](N([C@H](C)[C@H](O)C3C=CC=CC=3)C)=[O:13])[CH2:7][CH2:6]2)OC1.S(=O)(=O)(O)[OH:40]>O1CCOCC1.O>[O:36]=[C:5]1[CH2:6][CH2:7][C@H:8]([CH2:10][C@H:11]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:12]([OH:40])=[O:13])[CH2:9]1
Reactant: C[C@H]([C@H](O)c1ccccc1)N(C)C(=O)[C@H](C[C@H]1CCC2(C1)OCC(C)(C)CO2)c1cccc(C(F)(F)F)c1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: O=C1CC[C@H](C[C@@H](C(=O)O)c2cccc(C(F)(F)F)c2)C1
Temperature: 110 °C
Yield: 73 %

Procedure:
A solution of (R)-3-((R)-8,8-dimethyl-6,10-dioxa-spiro[4.5]dec-2-yl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-2-(3-trifluoromethyl-phenyl)-propionamide (250 mg, 0.47 mmol) in dioxane (2.5 mL) was treated with a 9 N aqueous sulfuric acid solution (1.5 mL). The resulting solution was then heated at 110° C. for 16 h. The reaction was then cooled and diluted with water (50 mL) and extracted with a chloroform/methanol solution (3:2, 2×25 mL) and then concentrated. The resulting residue was then dissolved in acetonitrile and concentrated with silica gel (2 g) and purified on Biotage Flash chromatography system (40S column, silica gel, 60% ethyl acetate/hexanes) to afford (R)-3-((R)-3-oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionic acid (102 mg, 73%) as a pale yellow oil: [α]22589=−86.1° (c=0.18, methanol); ES-HRMS m/e calcd for C15H15O3F3 (M+Na)+ 323.0865, observed 323.0865; 1H NMR (400 MHz, CDCl3) δ 1.55 (m, 1H, CH), 1.82-2.47 (m, 8H, 4×CH2), 3.73 (t, J=7.8 Hz, 1H, ArCHCO), 7.47-7.61 (m, 4H, Ar).
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].S(O)(O)(=O)=O.Cl[C:27]1[NH:28][CH2:29][CH2:30][N:31]=1>CC(O)C>[CH:1]([NH:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:27]3[NH:31][CH2:30][CH2:29][N:28]=3)=[CH:18][CH:19]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: ClC1=NCCN1
Reactant: CC(C)NC(=O)N1CCC(Cc2ccc(N)cc2)CC1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)NC(=O)N1CCC(Cc2ccc(NC3=NCCN3)cc2)CC1
Yield: 59.2 %

Procedure:
A mixture of 4-(1-isopropylaminocarbonylpiperidin-4-ylmethyl)-phenylamine (0.64 g, 2.31 mmol) and 2-chloro-2-imidazoline sulfate (0.70 g, 3.47 mmol) in 2-propanol (20 mL) was heated under reflux for 30 minutes. The reaction mixture was concentrated in vacua. The residue was diluted with water, basified with 10% sodium hydroxide solution and extracted into dichloromethane. The organic layer was washed with water and brine, dried (Na2SO4), and concentrated in vacua. The crude product was chromatographed on neutral aluminum oxide, eluting with 5% methanol/dichloromethane, and crystallized from ethyl acetate containing some ethanol, to give 2-[4-(1-isopropylaminocarbonylpiperidin-4-ylmethyl)-phenyl]amino-imidazoline (0.47 g, 59%) as a white solid, m.p. 191-192° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[Li]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:13]1[S:12][CH:16]=[CH:15][N:14]=1)([OH:11])[CH3:10]
Reactant: CC(=O)c1cc(Br)ccc1N
Reactant: [Li]c1nccs1
Product: CC(O)(c1nccs1)c1cc(Br)ccc1N

Procedure:
Prepared from 1-(2-amino-5-bromo-phenyl)-ethanone and 2-thiazolyl lithium generally according to the procedure described in example 1. 1H-NMR (DMSO-d6) δ 7.70 (d, J=3.3 Hz, 1H), 7.64 (d, J=3.2 Hz, 1H), 7.28 (d, J=2.4 Hz, 1H), 7.10 (dd, J=8.5, 2.4 Hz, 1H), 6.92 (s, 1H), 6.55 (d, J=8.5 Hz, 1H), 5.50 (s, 2H), 1.90 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][S:8](=[O:11])(=[O:10])[N:7]([CH3:12])[C:6]=2[CH:13]=1.CN1[C:19](=O)[CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[Cs+].[Cs+].BrCC1CC1>C(OCC)(=O)C.O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[S:8](=[O:11])(=[O:10])[N:7]([CH3:12])[C:6]=2[CH:13]=1
Reactant: CN1c2cc(Br)ccc2NS1(=O)=O
Reactant: CN1CCCC1=O
Agent: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN1c2cc(Br)ccc2N(CC2CC2)S1(=O)=O
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a round bottom flask was added 6-bromo-1-methyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (1-3) (5.32 g, 20.2 mmol), anhydrous NMP (10 mL), anhydrous 1,4 Dioxane (100 mL), cesium carbonate (13.2 g, 40.4 mmol), followed by (bromomethyl)cyclopropane (3.00 g, 22.2 mmol). The reaction mixture was then heated to 100° C. while stirring in a hot oil bath for 18 hours. The crude reaction mixture was then cooled to room temperature, then suspended in ethyl acetate and washed with a saturated solution of sodium bicarbonate, followed by water, then brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0-40% EtOAc/Hex) to give 5-bromo-1-(cyclopropylmethyl)-3-methyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (1-4) as a tan solid. HRMS (M+H)+: observed=316.9953, calculated=316.9954.
Reaction SMILES: C([C@H:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[OH:13])(O)=O.[N:14]([O-])=O.[Na+]>OS(O)(=O)=O>[NH2:14][C@H:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[OH:13]
Reactant: O=N[O-]
Reactant: O=C(O)[C@H]1c2ccccc2C[C@H]1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N[C@H]1c2ccccc2C[C@H]1O
Temperature: 2.5 °C

Procedure:
The hydrazide of (1S,2R)-1-carboxy-2-hydroxyindane (0.5 gram) is reacted with a solution of 0.5 grams of sodium nitrite in 10 ml of 5% H2SO4. The reaction mixture is maintained for 1 hour at 0-5° C., followed extraction of the reaction mixture with ethyl acetate, followed by basification of the resulting aqueous solution with NaOH, extraction with methyl t-butyl ether, drying of the extracts over MgSO4, filtration, and the removal of solvent by rotary evaporation. The product (1S,2R)-1-amino-2-indanol is isolated as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](O)([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1.[CH3:29][S:30][CH2:31][CH2:32][NH2:33]>CO.C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:16])([NH:33][CH2:32][CH2:31][S:30][CH3:29])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1
Reactant: CSCCN
Reactant: CC1(C)CC=C(c2cc(C(C)(C)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Solvent: CO
Solvent: ClCCl
Product: CSCCNC(C)(C)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCC(C)(C)CC2)c1
Yield: 50.3 %

Procedure:
The title compound was prepared by the procedure of Example 14, step (e) using 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide (as prepared in Example 14, step (d), 120 mg, 0.317 mmol) and 2-methylsulfanyl-ethylamine (69.0 μL, 0.951 mmol). Silica gel chromatography (1-4% MeOH/DCM) afforded the title compound (72 mg, 50%) as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.26 (d, 1H, J=8.6 Hz), 7.94 (s, 1H), 7.39 (dd, 1H, J=8.6, 2.3 Hz), 7.32 (d, 1H, J=2.3 Hz), 5.75 (m, 1H), 2.51-2.61 (m, 4H), 2.29-2.36 (m, 2H), 2.05-2.12 (m, 2H), 1.91 (s, 3H), 1.60 (t, 2H, J=6.3 Hz), 1.54 (s, 6H), 1.09 (s, 6H). Mass spectrum (ESI-neg, m/z): Calcd. for C25H33N5OS, 450.4 (M−H). found 450.2.
Reaction SMILES: [CH3:1][N:2]([CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([C:30]([O:32]C)=O)[C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:41][OH:42].Cl>O1CCCC1.CO>[OH:42][NH:41][C:30](=[O:32])[CH:25]([CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][N:2]([CH3:1])[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:4])[CH:13]=2)=[CH:23][CH:22]=1)[C:26]([OH:28])=[O:27]
Reactant: NO
Reactant: COC(=O)C(Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1)C(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN(Cc1cccc(-c2ccc(CC(C(=O)O)C(=O)NO)cc2)c1)C(=O)c1ccccc1
Temperature: 60 °C
Yield: 69.4 %

Procedure:
A mixture of 130 mg (0.3 mmol) of dimethyl 2-(3′{[methyl-(1-phenylmethanoyl)amino]methyl}biphenyl-4-ylmethyl)malonate (prepared in Example 15(b)), 2 ml of methanol, 2 ml of tetrahydrofuran, 480 mg of sodium carbonate (4.5 mmol) and 200 mg (1.5 mmol) of hydroxylamine hydrochloride is heated at 60° C. for 18 hours. The reaction medium is neutralized to pH 6-7 with hydrochloric acid solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica, eluted with a mixture of heptane and ethyl acetate (75/25). 90 mg (72%) of the desired product, with a melting point of 60° C., are obtained.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH2:10]([N:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][NH2:16])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:3][C:2]1[N:1]=[C:8]([NH:16][CH2:15][CH2:14][CH2:13][N:12]([CH2:17][CH3:18])[CH2:10][CH3:11])[N:7]=[C:5]([NH:16][CH2:15][CH2:14][CH2:13][N:12]([CH2:17][CH3:18])[CH2:10][CH3:11])[N:4]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCN(CC)CCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCN(CC)CCCNc1nc(Cl)nc(NCCCN(CC)CC)n1
Temperature: 3 °C
Reaction time: 8 h

Procedure:
Following the procedure described in Japanese Patent Publication 39272/74, 50.0 ml of water was cooled to 3° C. and slowly 18.4 g (0.1 mole) of cyanuric chloride was added while maintaining 3°-5° C. by means of an external ice-water bath. Slowly 26.0 g (0.2 mole) of 3-(diethylamino)propylamine was added while maintaining 3°-12° C. by means of an ice-water bath. The resulting solution was stirred at ambient temperature for approximately eight hours and allowed to stand overnight. Slowly a 10 percent aqueous potassium carbonate solution was added to the reaction solution until it was slightly alkaline. The solid which precipitated was collected by filtration. The water wet filter cake was resuspended in water and dissolved by the addition of hydrochloric acid. Slowly 10 percent aqueous potassium carbonate was added until the mixture was slightly alkaline. The resulting solid was collected by filtration, washed with water and dried in vacuo to obtain 2-chloro-4,6-bis[3-(diethylamino)-propyl]amino-1,3,5-triazine, a water-insoluble, white colored solid which melted at 119° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:34]([C:36]1[C:44]2[C:43]([C:45]([O:47][CH3:48])=[O:46])=[CH:42][CH:41]=[CH:40][C:39]=2[N:38]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)[N:37]=1)=O>O1CCCC1>[CH3:57][O:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][N:38]2[C:39]3[CH:40]=[CH:41][CH:42]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[C:44]=3[C:36]([CH:34]=[CH:2][O:3][CH3:4])=[N:37]2)=[CH:51][CH:52]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cccc2c1c(C=O)nn2Cc1ccc(OC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC=Cc1nn(Cc2ccc(OC)cc2)c2cccc(C(=O)OC)c12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a −78° C. cooled suspension of (methoxymethyl)triphenylphosphonium chloride (119 g, 347 mmol) in tetrahydrofuran (1000 mL) was carefully added a solution of lithium bis(trimethylsilyl)amide (1.0M in THF, 347 mL, 347 mmol). The resulting dark red mixture was stirred at −40° C. for 30 min. To this was added a solution of methyl 3-formyl-1-(4-methoxybenzyl)-1H-indazole-4-carboxylate (45 g, 139 mmol) in tetrahydrofuran slowly and the mixture was stirred for 30 min. The reaction was quenched with sat. aqueous sodium chloride (500 mL) and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (4×300 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude oil was purified by column chromatography (silica gel, 5 to 30% ethyl acetate in hexanes) to afford methyl 1-(4-methoxybenzyl)-3-(2-methoxyvinyl)-1H-indazole-4-carboxylate (40.3 g, 82%) as a yellow oil. A mixture of tetrahydrofuran (950 mL) and 6N hydrochloric acid (30 mL) was added to methyl 1-(4-methoxybenzyl)-3-(2-methoxyvinyl)-1H-indazole-4-carboxylate (40.3 g, 114.5 mmol) and the resulting biphasic mixture was heated to reflux for 2.5 h. The mixture was cooled to room temperature and diluted with ethyl acetate (1500 mL). The organic layer was separated and washed with brine (4×500 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford methyl 1-(4-methoxybenzyl)-3-(2-oxoethyl)-1H-indazole-4-carboxylate (30 g, 77%) as a yellow solid: 1H NMR δ (300 MHz, DMSO-d3) 9.78 (s, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.49 (dd, J=7.2, 0.6 Hz, 1H), 7.48 (dd, J=8.7, 7.5 Hz, 1H), 7.22-7.19 (m, 2H), 6.88-6.85 (m, 2H), 5.61 (s, 2H), 4.26 (s, 2H), 3.84 (s, 3H), 3.69 (s, 3H); MS (ESI+) m/z 339 (M+H).