Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C1(P(=[CH:29][CH:30]=[O:31])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:29][CH:30]=[O:31]
Reactant: O=Cc1ccccc1Cl
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: O=CC=Cc1ccccc1Cl
Yield: 68.6 %

Procedure:
Following a procedure similar to that described in the first part of Preparation 17, 3.00 g of 2-chlorobenzaldehyde and 7.5 g of (triphenylphosphoranylidene)acetaldehyde were reacted in 100 ml of acetonitrile. The crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.44 g (yield 68%) of 3-(2-chlorophenyl)-2-propenal as a solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:10]1[CH:11]=[C:12]([N+:20]([O-:22])=[O:21])[C:13]([O:18][CH3:19])=[C:14]([CH2:16][OH:17])[CH:15]=1)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:17][CH2:16][C:14]1[CH:15]=[C:10]([C:6]([CH3:9])([CH3:7])[CH3:8])[CH:11]=[C:12]([N+:20]([O-:22])=[O:21])[C:13]=1[O:18][CH3:19])(=[O:4])=[O:3]
Reactant: COc1c(CO)cc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(COS(C)(=O)=O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.20 ml methanesulphonic acid chloride are added to an ice-cooled solution of 3.43 g (5-tert-butyl-2-methoxy-3-nitro-phenyl)-methanol and 2.40 ml triethylamine in 30 ml dichloromethane. The solution is stirred for 2 h while cooling with ice and then diluted with dichloromethane. The dilute solution is washed three times with water and once with saturated aqueous saline solution, dried (MgSO4) and evaporated to dryness.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].O>CN(C)C=O>[C:21]1(=[O:30])[N:20]([CH2:19][CH2:18][CH2:17][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][C:9]3=[O:12])=[CH:4][CH:3]=2)[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: O=C1CCCc2ccc(O)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCCc2ccc(OCCCN3C(=O)c4ccccc4C3=O)cc21
Reaction time: 0.05 h

Procedure:
7-Hydroxy-1-tetralone (33.3 g) is dissolved in dimethylformamide (325 ml) and the mixture is cooled in an ice bath. Sodium methoxide (11.07 g) is added to the mixture. After the mixture is stirred for 3 min., N-(3-bromopropyl) phthalimide (54.96 g) is added to the mixture; stirring is continued and the reaction mixture stirred overnight. The resulting mixture is poured into H2O (650 ml), stirred for 1 hour, filtered, washed with H2O and air dried. The resulting fluffy near-white solid (62.8 g) is crystallized from ethyl acetate to give the desired product, a fluffy white solid (M.P. 149°-150° C. )
Reaction SMILES: [CH3:1][C:2](=[O:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:19]=1[N:27]=[C:28]=[O:29])([CH3:17])[CH3:16].C([N-]C(C)C)(C)C.[Li+]>>[CH3:17][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:25])[CH3:26])[C:19]=1[NH:27][C:28](=[O:29])[CH2:1][C:2](=[O:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:16]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCCCCC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCCCCCCCCCC(=O)CC(=O)Nc1c(C(C)C)cccc1C(C)C
Yield: 64 %

Procedure:
The title compound was prepared from 2-tridecanone (10.0 g, 0.050 mol), 2,6-diisopropylphenyl isocyanate (10.16 g, 0.050 mol) and lithium diisopropylamide (0.050 mol) using the procedure described in Example 1. Purification by flash chromatography (silica gel, 15% EtOAc/hexane) yielded 13.14 g (0.032 mol, 65%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C:18]2[C:22]([Br:23])=[CH:21][N:20]([CH3:24])[N:19]=2)[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:23][C:22]1[C:18]([C:14]2[CH:13]=[C:12]([NH:11][C:6]([C:5]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:7])[CH:17]=[CH:16][CH:15]=2)=[N:19][N:20]([CH3:24])[CH:21]=1
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(Br)c(-c2cccc(NC(=O)c3ccc(Cl)cc3)c2)n1
Reaction time: 16 h
Yield: 73.6 %

Procedure:
To 4-chlorobenzoyl chloride (15 mg, 0.08 mmol) in CH2Cl2 (1 mL) was added dropwise a solution of 3-(3-aminophenyl)4-bromo-1-methylpyrazole (21 mg, 0.08 mmol) and triethylamine (12 μL, 0.08 mmol) in CH2Cl2 (0.5 mL). The mixture was stirred for 16 h and concentrated. Chromatography on flash silica (50% EtOAc/hexane) gave the title compound as a colourless solid (23 mg, 72%), m.p. 184.4-184.8° C. (EtOAc/hexane).
Reaction SMILES: [C:1]12([C:11]3[CH:24]=[CH:23][C:14]([O:15][C:16]([CH3:22])([CH3:21])[C:17]([O:19]C)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.[OH-].[Li+].Cl>O.C1COCC1>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][C:16]([CH3:21])([CH3:22])[C:17]([OH:19])=[O:18])=[CH:23][CH:24]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: COC(=O)C(C)(C)Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of methyl 2-(4-(adamantan-1-yl)phenoxy)-2-methylpropanoate (1.0 g, 3.00 mmol), prepared from step 1, in H2O/THF (1:1.20 mL) was added lithium hydroxide monohydrate (0.51 g, 12.00 mmol), and stirred at room temperature overnight. The reaction mixture was adjusted to acidic solution with 1 N aqueous HCl and extracted with dichloromethane. The organic layer was washed with H2O and brine, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give 2-(4-(adamantan-1-yl)phenoxy)-2-methylpropanoic acid as a white solid (0.92 g, 96.1% yield).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[NH3:11]>>[NH2:11][CH2:3][C@@H:2]([OH:1])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: N
Reactant: C1CN(C[C@H]2CO2)CCO1
Product: NC[C@@H](O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.6 %

Procedure:
(S)-4-oxiranylmethyl-morpholine 78b (5.52 g, 38.6 mmol) was added slowly with 395 ml of aqueous ammonia (25%, 5.8 mol) in an ice-water bath while maintaining the temperature below 0° C. Upon the completion of the addition, the reaction mixture was naturally warmed to room temperature, and stirred for another 18 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction was stopped. The reaction solution was concentrated under reduced pressure to remove the reaction solvent and to obtain the title compound (R)-1-Amino-3-morpholin-4-yl-propan-2-ol 78c (6.1 g, yield 99%) as a light yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[C:8]1([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)=[N:16][N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:33]1[C:38]([I:39])=[CH:37][N:36]=[CH:35][N:34]=1>CS(C)=O.O>[I:39][C:38]1[C:33]([O:31][C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:14]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)=[N:15][N:16]=3)=[CH:30][CH:29]=2)=[N:34][CH:35]=[N:36][CH:37]=1
Reactant: Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Reactant: Clc1ncncc1I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Ic1cncnc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a brown mixture of cesium carbonate (2.79 g, 8.58 mmol) and 4-(4-phenylphthalazin-1-ylamino)phenol hydrochloride (1.00 g, 2.86 mmol) in 10 mL DMSO was added 4-chloro-5-iodopyrimidine (0.687 g, 2.86 mmol). The reaction was allowed to stir at RT for 1 h. The reaction was heated to and maintained at 70° C. overnight. The reaction was cooled and diluted with water. The solid was filtered and dried in vacuo to give N-(4-(5-iodopyrimidin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine as a gray solid. MS m/z=518 [M+H]+. Calc'd for C24H16IN5O: 517.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:13][N:12]=1>CC(O)CC>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:13][N:12]=2)=[CH:5][CH:4]=1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Reactant: COc1ccc(N)cn1
Solvent: CCC(C)O
Product: COc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cn1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A RBF was charged with 6-methoxypyridin-3-amine (155 mg, 1.25 mmol), 1-chloro-4-phenylphthalazine (300 mg, 1.25 mmol), and 2-butanol (4 mL). The vessel was sealed and the mixture was stirred overnight at 90° C. LC/MS shows completion of reaction. Reaction cooled to RT and purified by silica gel chromatography (1-5% MeOH/DCM) to afford N-(6-methoxypyridin-3-yl)-4-phenylphthalazin-1-amine as tan solid. MS [M+H]=329.1. Calc'd for C20H6N4O: 328.4.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[CH2:22](C1CC2C(=CC=CC=2)C1N)[CH3:23]>>[CH2:1]([C:3]1[C:4]([NH:11][CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH:13]2[CH2:22][CH3:23])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: CCC1Cc2ccccc2C1N
Product: CCc1cnc(CC)c(NC2c3ccccc3CC2CC)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 2-ethylindan-1-amine and making non-critical variations provided the title compound as a yellow oil. MS (ESI+) for m/z 296.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=2)=[N:6][CH:7]=1.CN1[C:30]([CH2:31][O:32]C2C=CC(C(O)=O)=CN=2)=[C:29]([C:42]2[CH:47]=CC=CN=2)[N:28]=N1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:28][CH:29]3[CH2:30][CH2:31][O:32][CH2:47][CH2:42]3)=[O:22])=[CH:18][N:17]=2)=[N:6][CH:7]=1
Reactant: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)cn1
Reactant: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)cn1
Product: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 78 %

Procedure:
As described for example 26b, 6-[5-(5-fluoro-pyridin-2-yl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (82 mg, 0.25 mmol), instead of 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid, was converted to the title compound (80 mg, 78%) which was obtained as a white solid. MS: m/e=413.4 [M+H]+.
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.CN([CH:28]=[O:29])C>ClC(Cl)C.Cl>[C:1]1([N:7]2[C:8]3[CH:9]=[CH:10][C:11]([CH:28]=[O:29])=[CH:12][C:13]=3[C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: c1ccc(-n2c3ccccc3c3ccccc32)cc1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: O=Cc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To 0.49 g of N-phenylcarbazole in 2 mL of dichloroethane is added 0.19 mL of phosphorus oxychloride and 0.5 mL of DMF. The resulting mixture is stirred at 40° C. overnight. After stirring, 1 mL of 1 M HCl is added. After 5 additional minutes, the mixture is diluted with 1 M HCl and extracted with ethyl acetate. The crude product is purified by column chromatography on silica gel to give 60 mg of Compound 7.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[N+:6]([O-])[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:3]1[C:2]([Cl:1])=[C:7]([Cl:8])[N:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(Cl)c(Cl)[n+]1[O-]
Product: COC(=O)c1cc(Cl)c(Cl)c(Cl)n1
Yield: 83 %

Procedure:
A solution of methyl 5,6-dichloropyridine-2-carboxylate-N-oxide (22.0 g, 0.100 mol) and phosphorus oxychloride (15.70 mL, 0.169 mol) was heated at 70° C. for 36 hours. The solvent was removed and the residue carefully taken up into diethyl ether and water. The organic layer was washed with saturated sodium bicarbonate solution, water, brine, dried and concentrated to give methyl 4,5,6-trichloropyridine-2-carboxylate (20.0 g, 0.083 mol). 1H NMR (CDCl3): δ 8.16 (s, 1H), 4.02 (s, 3H).
Reaction SMILES: [CH3:1][Li].[Cl:3][C:4]1[CH:5]=[C:6]2[C:36](=[CH:37][CH:38]=1)[C:14]1[N:15]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:16]([C:18]3[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]#[N:21])=[N:17][C:13]=1[C:12]1[CH:11]=[CH:10][C:9]([CH2:39][C:40](=[O:42])[CH3:41])=[CH:8][C:7]2=1>C(OCC)C.Cl[Ti](Cl)(Cl)Cl>[Cl:3][C:4]1[CH:5]=[C:6]2[C:36](=[CH:37][CH:38]=1)[C:14]1[N:15]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[C:16]([C:18]3[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]#[N:21])=[N:17][C:13]=1[C:12]1[CH:11]=[CH:10][C:9]([CH2:39][C:40]([OH:42])([CH3:1])[CH3:41])=[CH:8][C:7]2=1
Reactant: CC(=O)Cc1ccc2c(c1)c1cc(Cl)ccc1c1c2nc(-c2c(C#N)cccc2C#N)n1COCC[Si](C)(C)C
Reactant: [Li]C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Product: CC(C)(O)Cc1ccc2c(c1)c1cc(Cl)ccc1c1c2nc(-c2c(C#N)cccc2C#N)n1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a round bottomed flask at −78° C. charged with TiCl4 (1 M in CH2Cl2, 20 mL), was added methyllithium (1.6 M in diethyl ether, 12.5 mL). The resulting deep red solution was stirred at −78° C. for 15 minutes and then added via cannula to a 0° C. solution of 2-(9-chloro-6-(2-oxopropyl)-1-{[2-(trimethylsilyl)ethoxy]methyl)-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile (2.8 g, 5.0 mmol) from Step 2 above, in diethyl ether (10 mL). The resulting mixture was stirred at 0° C. for 3 h, then quenched with saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate. The organic layer washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography on silica (50% ethyl acetate in hexanes) to provide 2-(9-chloro-6-(2 -hydroxy-2-methylpropyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile (1.94 g),
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH2:13])=[S:12])([CH3:3])[CH3:2].Br[CH:15]([CH:19]([CH3:21])[CH3:20])[C:16](O)=[O:17]>>[CH:19]([CH:15]1[S:12][C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])=[N:13][C:16]1=[O:17])([CH3:21])[CH3:20]
Reactant: CC(C)C(Br)C(=O)O
Reactant: CC(C)c1ccccc1NC(N)=S
Product: CC(C)c1ccccc1NC1=NC(=O)C(C(C)C)S1

Procedure:
Synthesis was performed from N-(2-isopropylphenyl)thiourea and 2-bromo-3-methylbutyric acid according to Method C1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][N:3]=1.[OH-].[NH4+:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:9])[NH2:13])=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: [NH4+]
Agent: [OH-]
Product: NS(=O)(=O)c1ccc(Cl)nc1

Procedure:
2-Chloro-5-chlorosulfonylpyridine (2.84 g, 0.0134 mole) was added to concentrated ammonium hydroxide (50 ml) and the mixture was boiled. After adding more concentrated ammonium hydroxide (50 ml), and extending boiling until the reaction volume was approximately 50 ml, the reaction mixture was cooled in an ice bath to cause precipitation of the product. The solid was collected by filtration, washed with water and air dried; yield, 2.17 g (84 percent), m.p. 153° to 155° C. A melting point of 155° to 156° C. was observed after recrystallization from water.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[S:21][CH:22]=1>CN(C)C=O>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[S:21][CH:22]=[C:18]([CH2:17][N:3]3[C:4](=[O:15])[C:5]4[C@@H:6]5[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]5)[C:10]=4[N:2]3[CH3:1])[N:19]=2)=[CH:28][CH:27]=1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1csc(-c3ccc(Cl)cc3)n1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 43.9 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 4-chloromethyl-2-(4-chlorophenyl)-thiazole (Maybridge plc, Tintagel, Cornwall, UK; 153 mg, 0.63 mmol) in dimethylformamide (5 mL) was heated at 100° C. for 2 days. The solvent was evaporated and ethyl acetate (50 mL) was added. The solution was washed with water (twice) and brine, dried (magnesium sulfate), filtered, evaporated and purified by chromatography, eluting with 2-3% methanol/dichloromethane to give (4S,7R)-2-[2-(4-Chloro-phenyl)-thiazol-4-ylmethyl]-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (89 mg, 44%) as an off-white foam. APCI(+)-MS (M+H) 414.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1.Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N+:34]([O-:36])=[O:35]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N+:34]([O-:36])=[O:35])[CH2:15][CH2:16]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccccc1OCCCCl
Product: COc1ccc(C(OC2CCN(CCCOc3ccccc3[N+](=O)[O-])CC2)c2ccccc2)cc1

Procedure:
The procedure of Example 24 (a) was repeated except for using 4-[(4-methoxyphenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane instead of 4-[(2-chlorophenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane to give oily 4-[(4-methoxyphenyl)-phenylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[O:18]=[C:19]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([C:41]3[N:46]=[CH:45][CH:44]=[CH:43][N:42]=3)=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)[CH2:20][N:21]1[CH2:25][CH2:24][CH:23]([C:26](O)=[O:27])[CH2:22]1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:26]([CH:23]4[CH2:24][CH2:25][N:21]([CH2:20][C:19](=[O:18])[N:29]5[CH2:30][CH2:31][N:32]([C:35]6[CH:40]=[CH:39][C:38]([C:41]7[N:42]=[CH:43][CH:44]=[CH:45][N:46]=7)=[CH:37][CH:36]=6)[CH2:33][CH2:34]5)[CH2:22]4)=[O:27])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: O=C(O)C1CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1)C1CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Reaction time: 18 h
Yield: 24.3 %

Procedure:
3-(4-Fluoro-phenyl)-1H-indazol-5-ylamine (0.11 gm, 0.5 mmol) and 1-{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid (compound 12 from Step 9, 0.125 gm, 0.25 mmol) were dissolved in 4 ml of DMF. O-(7-azabenzotriazol-1-yl-)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (0.24 gm, 0.63 mmol) and triethylamine (0.1 ml, 0.76 mmol) were added to the reaction mixture and the mixture stirred for 18 hrs. The reaction mixture was added to bring and extracted with dichloromethane. After drying over magnesium sulfate and filtered, the mixture was evaporated and chromatographed to obtain 36.7 mg of title product.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[NH2:19][CH2:20][CH2:21][CH2:22][C:23]1[C:24]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[N:25][C:26]([NH2:30])=[N:27][C:28]=1[CH3:29].[C:37]1([CH2:47][C:48](O)=[O:49])[CH:42]=[CH:41][C:40]([CH2:43][C:44]([OH:46])=[O:45])=[CH:39][CH:38]=1>C1COCC1.CCOC(C)=O>[NH2:30][C:26]1[N:27]=[C:28]([CH3:29])[C:23]([CH2:22][CH2:21][CH2:20][NH:19][C:48](=[O:49])[CH2:47][C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44]([OH:46])=[O:45])=[CH:39][CH:38]=2)=[C:24]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[N:25]=1
Reactant: CCCCCNc1nc(N)nc(C)c1CCCN
Reactant: O=C(O)Cc1ccc(CC(=O)O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCNc1nc(N)nc(C)c1CCCNC(=O)Cc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of T3P (1.591 ml, 1.57M in THF) was added to a mixture of the product from example 1 step (v) (0.2 g), TEA (0.333 ml) and 2,2′-(1,4-phenylene)diacetic acid (0.463 g) in THF (15 mL) and the mixture stirred at rt overnight. The reaction was diluted with EtOAc, washed with water, dried and evaporated under reduced pressure. Used crude in next step.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11]1[O:15][N:14]=[C:13]([NH2:16])[N:12]=1)([CH3:10])[CH3:9])(C)(C)C.[ClH:18].O1CCOCC1>C(O)C>[ClH:18].[NH2:7][C:8]([C:11]1[O:15][N:14]=[C:13]([NH2:16])[N:12]=1)([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1nc(N)no1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)(N)c1nc(N)no1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of [1-(3-amino-[1,2,4]oxadiazol-5-yl)-1-methyl-ethyl]carbamic acid tert-butyl ester (100 mg, 0.41 mmol) in ethanol (2 mL) was added HCl in dioxane (4 M, 0.41 ml, 1.65 mmol) and the reaction mixture was stirred 16 hours at room temperature. The reaction mixture was concentrated in vacuo and dried by applying high vacuum at 40° C. for 4 hours to give the title compound as white solid (75 mg, quant.); LC-MS (UV peak area/ESI) nd, 143.0928 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([NH:12][CH:13]2[CH:18]3[CH:14]2[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17]3)=[N:10][CH:11]=1)=[O:5])[CH3:2].[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27].C(Cl)Cl>>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[CH:14]12[CH:13]([NH:12][C:9]3[N:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][N:10]=3)[CH:18]1[CH2:17][NH:16][CH2:15]2
Reactant: CCOC(=O)c1cnc(NC2C3CN(C(=O)OC(C)(C)C)CC32)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cnc(NC2C3CNCC32)nc1

Procedure:
A solution of tert-butyl 6-{[5-(ethoxycarbonyl)pyrimidin-2-yl]amino}-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.15 g) was allowed to stand in 20% TFA/DCM (10 ml) at r.t. for 1 h. The reaction mixture was concentrated to dryness giving the title product as the TFA salt (0.17 g). LCMS purity 76%, m/z 249 [M+H]+. The product was used in the next stage without purification.