Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10](Cl)=[O:11].[C:13]([CH:15]1[CH2:17][NH:16]1)#[N:14]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([N:16]1[CH2:17][CH:15]1[C:13]#[N:14])=[O:11]
Reactant: O=C(Cl)c1cc2ccccc2o1
Reactant: N#CC1CN1
Product: N#CC1CN1C(=O)c1cc2ccccc2o1

Procedure:
This compound is obtained in a yield of 1.3 g., analogously to Example 75, from 1.8 g. benzofuran-2-carbonyl chloride and 0.68 g. 2-cyanoaziridine. It has a melting point of 92°-94° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:24]#N)[CH2:13][CH2:12][N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:9]1.S(=O)(=O)(O)O.[OH-:31].[NH4+].[CH2:33]([OH:35])[CH3:34]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:24]([O:35][CH2:33][CH3:34])=[O:31])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(C#N)(c3ccccc3F)CC2)cc1
Reactant: [OH-]
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: CCOC(=O)C1(c2ccccc2F)CCNCC1
Temperature: 150 °C
Reaction time: 4 h
Yield: 68.4 %

Procedure:
A mixture of 35.8 parts of 4-(2-fluorophenyl)-1-(4-methylphenylsulfonyl)-4-piperidinecarbonitrile and 50 parts of a sulfuric acid solution 75% is stirred for 4 hours at about 150° C. 192 Parts of ethanol are added dropwise. Upon completion, stirring is continued for 5 hours at reflux temperature. The reaction mixture is cooled and poured onto crushed ice. The whole is alkalized with ammonium hydroxide and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated, yielding 17.2 parts (68.4%) of ethyl 4-(2-fluorophenyl)-4-piperidinecarboxylate as a residue.
Reaction SMILES: C([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14]C=[CH:16][C:9]=3[S:8](=[O:18])(=[O:17])[C:7]=2[CH:19]=1)#N.[OH-:20].[Na+].[CH2:22]([OH:24])[CH3:23].Cl>O>[CH:13]1[C:10]2[CH:11]=[CH:12][C:6]3[CH:5]=[CH:4][CH:3]=[CH:19][C:7]=3[S:8](=[O:18])(=[O:17])[C:9]=2[CH:16]=[C:23]([C:22]([OH:20])=[O:24])[CH:14]=1
Reactant: CCO
Reactant: [OH-]
Reactant: N#Cc1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2

Procedure:
13.6 G. 3-cyanodibenzo[b,f]thiepin-5,5-dioxide are refluxed for 2.5 hours in a mixture of 20 cc. 10% aqueous sodium hydroxide solution and 20 cc. ethanol. The mixture is diluted with water and acidified with concentrated HCl. The acid precipitates as a white solid. The yield of acid, m.p. 268° C.-270° C., is 1.38 g. (94.6%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14].[CH3:19][NH:20][C:21]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:33]([C:35]3[N:36]=[CH:37][N:38]([C:40]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH:39]=3)=[O:34])[CH:29]=2)[CH:24]=1)=[O:22].[Cl-].[NH4+]>CCCCCC.C1COCC1>[OH:34][C:33]([C:28]1[CH:27]=[CH:26][C:25]2[C:30](=[CH:31][CH:32]=[C:23]([C:21]([NH:20][CH3:19])=[O:22])[CH:24]=2)[CH:29]=1)([C:35]1[N:36]=[CH:37][N:38]([C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:39]=1)[CH2:14][C:13]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCOC(=O)CC(O)(c1ccc2cc(C(=O)NC)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: -65 °C
Reaction time: 0.33 h
Yield: 128.7 %

Procedure:
Under nitrogen atmosphere, 52.9 mL (0.37 mol, 3 eq) of diisopropylamine was added to 1.3 liters of THF. 234 mL (0.37 mol, 3 eq) of a 1.6 M solution of n-butyllithium in hexane was added dropwise at −65° C. or lower over 23 minutes. After stirred at −65° C. for 20 minutes, 36.6 mL (0.37 mol, 3 eq) of ethyl acetate was added dropwise at −65° C. or lower over 10 minutes. After stirred at −65° C. for 45 minutes, a solution of 65 g (0.13 mol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide in 260 mL of THF was added dropwise at −65° C. or lower over 25 minutes. The mixture was stirred at −65° C. for 1 hour, and at −4˜−30° C. for 2 hours. After 370 mL of an aqueous saturated ammonium chloride solution was added dropwise at −20° C. or lower, the mixture was warmed to 30° C. After the layers were separated, the organic layer was washed with 370 mL of an aqueous saturated ammonium chloride solution two times. Concentration under reduced pressure afforded 102 g of ethyl 3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][C:3]=1[CH3:13].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:12][CH2:11][CH2:10][CH2:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([Br:1])=[C:3]([CH3:13])[CH:4]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(CCCO)cc(C)c1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(CCCOS(C)(=O)=O)cc(C)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a cooled (0° C.) solution of 3-(4-bromo-3,5-dimethylphenyl)propan-1-ol (250 mg) and triethylamine (160 μL) in dichloromethane (2 mL) is added methanesulfonyl chloride (850 μL). The mixture is stirred for 12 hours at room temperature. The mixture is partitioned between dichloromethane and saturated aqueous NaHCO3 solution and stirred vigorously for 30 minutes. The organic phase is separated, washed with brine and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→50:50) to give the title compound. Yield: 235 mg; LC (method 8): tR=0.44 min; Mass spectrum (ESI+): m/z=343 [M+Na]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15](=[O:24])[CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)[CH:9]=2)=[CH:5][C:4]=1[N+:27]([O-])=O>[Pd]>[NH2:27][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][C:3]=1[NH:2][CH3:1])[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15](=[O:24])[CH2:16][N:17]2[CH2:18][CH2:19][CH:20]([CH3:23])[CH2:21][CH2:22]2)[CH:9]=1
Reactant: CNc1ccc(Oc2ccnc(NC(=O)CN3CCC(C)CC3)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CNc1ccc(Oc2ccnc(NC(=O)CN3CCC(C)CC3)c2)cc1N

Procedure:
N-{4-[4-(methylamino)-3-nitrophenoxy](2-pyridyl)}-2-(4-methylpiperidyl)acetamide was hydrogenated in the presence of Pd/C for 4 hours. The catalyst was removed via filtration and filtrate was concentrated to give N-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-2-(4-methylpiperidyl)acetamide. MS: MH+=370.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]([C:28](O)=[O:29])[NH:26][CH:27]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]([C:28]([NH:1][C:2]3[CH:7]=[N:6][C:5]([O:8][CH2:9][CH2:10][N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)=[CH:4][CH:3]=3)=[O:29])[NH:26][CH:27]=2)=[CH:19][CH:18]=1
Reactant: Nc1ccc(OCCN2CCCC2)nc1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Product: O=C(Nc1ccc(OCCN2CCCC2)nc1)c1cc(-c2ccc(Cl)cc2)c[nH]1

Procedure:
5-Amino-2-((pyrrolidin-1-yl)ethoxy)pyridine was converted to the title compound (18 mg) by acylation with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid (21 mg) following the procedure described in step C of Example 1. MS (ESI) 411 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12](=O)[CH2:13][S:14]([CH3:16])=[O:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([N:22]=[C:12]([C:3]1[C:2]([OH:1])=[CH:11][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:13][S:14]([CH3:16])=[O:15])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCN
Reactant: CS(=O)CC(=O)c1cc2ccccc2cc1O
Product: CCCCN=C(CS(C)=O)c1cc2ccccc2cc1O
Yield: 55 %

Procedure:
A solution of 3'-hydroxy-2-(methylsulfinyl)-2'-acetonaphthone (10 g, 0.040 mole) in n-butylamine (50 ml) was stirred at room temperature for 24 hrs. The reaction mixture was poured into petroleum ether (400 ml) and the product, which precipitated, was filtered off. Recrystallization from absolute ethanol gave light brown crystals (7.0 g, 55%), mp 162°-164°.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[O:10][C:11](=O)OC1C=C(Br)C=CC=1OC.[OH-].[Na+]>CO>[Br:9][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[C:3]([OH:2])=[CH:8][CH:7]=1
Reactant: COc1ccc(Br)cc1OC(=O)Oc1cc(Br)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(Br)ccc1O
Temperature: 25 °C
Yield: 195.4 %

Procedure:
A suspension of (20.7 g, 47.9 mmol, 1.0 eq) bis(2-methoxy-5-bromophenyl)carbonate in 250 ml methanol and 60 ml (120 mmol, 2.5 eq) of 2N NaOH was refluxed for 2 hours. The reaction mixture was cooled to room temperature, concentrated to a volume of ca 100 ml, and poured 1 L of H2O. The pH was adjusted to 2 using 1N HCl. The acidic mixture was transferred to a separatory funnel, and extracted three times with ether. The ether extracts were combined and washed once with H2 O, once with brine, and then dried over anhydrous sodium sulfate. Filtration, concentration and drying afforded 19.0 g of a white solid, which was recrystallized from petroleum ether to yield 17.63 g, 91% yield, of white prisms.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][C:25](=[O:33])[C:26]1[C:31](Br)=[CH:30][CH:29]=[N:28][CH:27]=1.C([O-])(O)=O.[Na+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][O:24][C:25]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[C:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH:12]=1)=[O:33]
Reactant: COC(=O)c1cnccc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cnccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 72 °C
Reaction time: 0.17 h
Yield: 72.3 %

Procedure:
A solution of PdCl2(PPh3)2 (1.3 g, 1.9 mmol, 0.05 eq.) in THF (250 mL) was stirred for 10 minutes under nitrogen. 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (11.7 g, 37.8 mmol, 1.0 eq.) was added and the resulting solution was stirred for another 10 minutes. 4-Bromonicotinic acid methyl ester (8.2 g, 38.0 mmol, 1.0 eq.) in THF (100 mL) and NaHCO3 (16.1 g, 151.9 mmol, 4.0 eq.) in H2O (76 mL) were added, and the resulting solution was stirred for 6 hours while the temperature was maintained at 72° C. in an oil bath. The mixture was cooled to room temperature and the reaction was then quenched with water (50 mL). The resulting solution was extracted with EtOAc (150 mL). The organic layer was washed with saturated aqueous NaCl (3×200 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:5) to yield 3,6-dihydro-2H-[4,4]bipyridinyl-1,3′-dicarboxylic acid 1-t-butyl ester 3′-methyl ester (8.7 g) as a white solid. ES m/z: [M+H]+319.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C@@H:6]1[C@H:11](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:9][N:8]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:7]1>CN(C=O)C.O.C(Cl)Cl>[N:1]([C@H:11]1[CH2:10][CH2:9][N:8]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:7][C@@H:6]1[F:5])=[N+:2]=[N-:3]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](N=[N+]=[N-])[C@@H](F)C1
Temperature: 100 °C

Procedure:
Sodium azide (0.48 g, 0.0073 mol) was added to a solution of tert-butyl (3S,4R)-3-fluoro-4-(tosyloxy)piperidine-1-carboxylate, 4.3-1, Peak-1 (0.7 g, 0.00187 mol) dissolved in DMF (15 mL). The reaction mixture was heated at 100° C. for 4 h. The mixture was cooled and diluted with water and methylene chloride. After separation, the organic layer was dried over Na2SO4, filtered and concentrated in vacuum to provide the desired product, 4.4 (0.4 g). The obtained product was taken for the next reaction without any purification.
Reaction SMILES: [CH2:1]1[C:10](=[O:11])[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.C(N(CC)CC)C.[CH3:19][Si:20](Cl)([CH3:22])[CH3:21]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:19][Si:20]([CH3:22])([CH3:21])[O:11][C:10]1[CH2:1][CH2:2][C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:9]=1
Reactant: O=C1CCc2ccccc2C1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)OC1=Cc2ccccc2CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Charge an oven dried, nitrogen flushed 100-mL round bottomed flask equipped with a stirring bar with β-tetralone (4.977 grams, 0.0340 moles), triethylamine (6.970 grams, 0.0689 moles), 4-dimethylamino pyridine (0.219 grams,0.0018 moles), trimethylsilyl chloride (7.704 grams, 0.0709 moles) and 30 mL methylene chloride. Stir at RT for 20 hours, filter, wash the solid with 1×20 mL methylene chloride, wash the combined organic layers with 1×5 mL saturated sodium bicarbonate solution, 1×5 mL water, dry over magnesium sulfate, concentrate on a Buchi rotavapor and distill (96°-99° C., 1 Torr) to yield the product as a viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:12][C:13](SC)=[C:14]([S:17]([CH3:20])(=[O:19])=[O:18])[C:15]#[N:16])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:23][CH:24]([NH2:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]([NH:29][CH:24]([CH3:23])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:14]([S:17]([CH3:20])(=[O:19])=[O:18])[C:15]#[N:16])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CSC(Nc1cc(F)cc(C(F)(F)F)c1)=C(C#N)S(C)(=O)=O
Reactant: CC(N)C(C)(C)C
Product: CC(NC(Nc1cc(F)cc(C(F)(F)F)c1)=C(C#N)S(C)(=O)=O)C(C)(C)C
Yield: 49 %

Procedure:
3-(3-Fluoro-5-trifluoromethylphenylamino)-2-methylsulfonyl-3-methylsulfanyl-propenenitrile (0.176 g, 0.5 mmol) was stirred in 1,2,2-trimethylpropylamine (1 ml) for 17 h at 75° C. under nitrogen. Work-up as described in EXAMPLE 17, 2) without chromatography gave 98 mg (49%) of the title compound. Mp 183-185° C. 1H NMR (200 MHz, CDCl3): δ=0.87 (s, 9H), 1.03 (d, 3H), 3.05 (m, 1H), 3.13 (s, 3H) 7.02 (br d, 1H), 7.15 (m, 2H); EI SP/MS: 407 (M+).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[C:18]([O:30][CH3:31])=[CH:19][C:20](C#N)=[C:21]([N:23]=[CH:24][N:25]([CH3:27])C)[CH:22]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:32][C:33]1[CH:37]=[C:36]([CH2:38][C:39]([OH:41])=[O:40])[NH:35][N:34]=1>C(O)(=O)C>[C:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[C:21]3[C:20]([C:27]([NH:32][C:33]4[CH:37]=[C:36]([CH2:38][C:39]([OH:41])=[O:40])[NH:35][N:34]=4)=[N:25][CH:24]=[N:23]3)=[CH:19][C:18]=2[O:30][CH3:31])[CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1OCCC1CCN(CCOC(C)(C)C)CC1
Reactant: Nc1cc(CC(=O)O)[nH]n1
Solvent: CC(=O)O
Product: COc1cc2c(Nc3cc(CC(=O)O)[nH]n3)ncnc2cc1OCCC1CCN(CCOC(C)(C)C)CC1
Yield: 67.1 %

Procedure:
N′-(5-{2-[1-(2-tert-butoxyethyl)piperidin-4-yl]ethoxy}-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide (654 mg, 1.5 mmol) in acetic acid (1.35 ml) was heated with (3-amino-1H-pyrazol-5-yl)acetic acid (214 mg, 1.52 mmol) at reflux for 45 minutes. Acetic acid was evaporated and the residue taken up in a mixture of dichloromethane:methanol. Excess diisopropylethylamine was added, and the solvent evaporated in vacuo. Dichloromethane was added to the solid, which was filtered and dried to yield {3-[(7-{2-[1-(2-tert-butoxyethyl)piperidin-4-yl]ethoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetic acid as a white powder (530 mg, 66% yield):
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.C[O:26][C:27](=[O:39])[C@H:28]([NH2:38])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:38][C@H:28]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[C:27]([OH:26])=[O:39])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@H](N)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: O=C(N[C@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoic acid was-coupled to (R)-2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=10.97 min. MS (ESI−): mass-calcd. for C22H15Cl3N4O5S2, 585.87; m/z found, 583/585 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.36 (s, 1H), 8.36 (dd, J=7.0, 0.8, 1H), 8.21 (dd, J=8.8, 0.6, 1H), 7.74-7.70 (m, 2H), 7.34 (d, J=8.2, 1H), 7.21 (d, J=1.9, 1H), 7.15 (d, J=8.4, 1H), 6.97 (dd, J=8.2, 2.0, 1H), 6.93 (dd, J=8.4, 2.0, 1H), 6.44 (d, J=7.0, 1H), 4.98 (q, J=5.7, 1H), 3.32-3.15 (m, 2H).
Reaction SMILES: C[C@@H]1C[C@H]1[C:5]([N:7]=[N+]=[N-])=[O:6].[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:18]1([CH3:24])[CH:23]=[CH:22]C=CC=1>CN(C=O)C.CCOCC.[Cu]Cl>[CH3:24][C@@H:18]1[CH2:23][C@H:22]1[NH:7][C:5](=[O:6])[O:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccccc1
Reactant: C[C@@H]1C[C@H]1C(=O)N=[N+]=[N-]
Reactant: OCc1ccccc1
Agent: Cl[Cu]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C[C@@H]1C[C@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 57 %

Procedure:
A solution of (1R,2R)-2-methylcyclopropanecarbonyl azide (1.80 g, 14.4 mmol) in toluene (100 mL) was heated to 90° C. for 1 h. After gas evolution had subsided, the solution was cannulated into a flask containing a slurry of benzyl alcohol (4.5 mL, 43.2 mmol) and copper(I) chloride (750 mg, 7.5 mmol) in DMF (100 mL). The reaction was maintained at room temperature for 1 h, then diluted with Et2O (200 mL) then washed with brine, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography over silica gel (20-30% EtOAc/hexane eluent) to provide benzyl ((1R,2R)-2-methylcyclopropyl)-carbamate (1.68 g, 57% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.27-7.46 (m, 5 H), 5.11 (br. s., 2H), 4.80-4.99 (m, 1H), 2.28 (d, J=3.0 Hz, 1H), 1.07 (d, J=5.5 Hz, 3H), 0.82-0.97 (m, 1H), 0.67 (ddd, J=9.0, 5.3, 3.8 Hz, 1H), 0.51 (q, J=5.9 Hz, 1H).
Reaction SMILES: C(N(CC)[C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH2:16][C@H:17]([NH:19][CH2:20][C@H:21]([OH:28])[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH3:18])C.[OH-].[K+].C([OH:36])C.C(O)(=O)C>O>[OH:28][C@H:21]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH2:20][NH:19][C@H:17]([CH3:18])[CH2:16][C:12]1[C:11]2[C:15](=[C:7]([O:6][CH2:5][C:4]([OH:29])=[O:36])[CH:8]=[CH:9][CH:10]=2)[NH:14][CH:13]=1
Reactant: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)NC[C@H](O)c3cccnc3)c[nH]c12
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: C[C@H](Cc1c[nH]c2c(OCC(=O)O)cccc12)NC[C@H](O)c1cccnc1

Procedure:
A solution of N,N-diethyl-2-{3-[(2R)-2-((2R)-2-hydroxy-2-pyridin-3-ylethylamino)propyl]-1H-indol-7-yloxy}acetamide (30 mg, 0.071 mmol) and potassium hydroxide (120 mg, 2.1 mmol) in water (1 mL)/ethanol (1 mL) is stirred at 60° C. for 6 hours. After cooling, to the mixture is added acetic acid (0.112 mL), and the mixture is concentrated. The residue is purified by preparative reversed phase HPLC (octadecylsilyl, trade name: Combiprep, ODS-A (YMC), inner diameter: 50×20 mm, particle size: 5 μm, pore size: 120 angstrom (hereinafter, this column is used in preparative reversed phase HPLC column), 0.05% trifluoroacetic acid/water-0.035% trifluoroacetic acid/acetonitrile) to give the desired {3-[(2R)-2-((2R)-2-hydroxy 2-pyridin-3-yl-ethylamino)propyl]-1H-indol-7-yloxy}acetic acid.2 trifluoroacetate (24 mg, yield: 57%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([NH2:8])[CH2:5][CH2:6][CH3:7].Cl[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]=[C:17]=[O:18].C(Cl)[Cl:20]>>[Cl:20][C:14]1[CH:13]=[CH:12][C:11]([NH:16][C:17]([NH:8][CH:4]([CH2:5][CH2:6][CH3:7])[CH2:3][CH2:2][CH3:1])=[O:18])=[CH:10][CH:15]=1
Reactant: O=C=Nc1ccccc1Cl
Reactant: ClCCl
Reactant: CCCC(N)CCC
Product: CCCC(CCC)NC(=O)Nc1ccc(Cl)cc1
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of heptan-4-amine (0.18 mL, 1 mmol) in CH2Cl2 (5 mL) was added 1-chloro-2-isocyanatobenzene (0.12 mL, 1 mmol) at room temperature. The reaction mixture was stirred for 2 h. A white solid was precipitated out. The reaction mixture was filtered. The solid was washed with CH2Cl2 to afford 1-(4-chlorophenyl)-3-(heptan-4-yl)urea (180 mg, 67%) as a white solid. mp: 135-136° C. 1H NMR (500 MHz, CDCl3): δ 0.93 (t, 6H), 1.45 (m, 6H), 1.53 (m, 2H), 3.80 (br s, 1H), 4.33 (d, 1H), 6.00 (s, 1H), 6.95 (td, 1H), 7.23 (dt, 1H), 7.33 (dd, 1H), 8.13 (dd, 1H). MS (M+H, 269).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])=[O:28])[CH:24]=2)[N:19](C2CCCCO2)[N:18]=1>C(Cl)Cl>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])=[O:28])[CH:24]=2)[NH:19][N:18]=1
Reactant: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)Nc1ccc(F)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
TFA (0.1 mL, 1.587 mmol) was added to a solution of 1-(3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-3-(2,4-difluorophenyl)urea (15 mg, 0.030 mmol) in CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound in a 60% yield. 1H NMR (400 MHz, CD3OD): δ 8.38 (s, 1H), 8.05-7.99 (m, 1H), 764 (m, 3H), 7.56 (d, 1H, J=9.2 Hz), 7.26 (m, 2H), 7.01 (m, 1H), 6.92 (m, 1H); ESI-MS [M+H]+: 405.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:16])[N:11]([CH3:15])[C:12](=[O:14])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:17]1[CH2:22][CH2:21][CH:20]=[CH:19][CH:18]=1>C(Cl)(Cl)Cl.C(OCC)(=O)C.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:19]4[CH2:20][CH2:21][CH:22]([CH:17]=[CH:18]4)[CH:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]3=[O:16])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN1C(=O)C=C(c2ccc(F)c(F)c2)C1=O
Reactant: C1=CCCC=C1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CN1C(=O)C2C3C=CC(CC3)C2(c2ccc(F)c(F)c2)C1=O
Temperature: 25 °C

Procedure:
A 5.0 g amount of 3-(3,4-difluorophenyl)-1-methyl-1H-pyrrole-2,5-dione was dissolved in 25 ml of chloroform with warming. The solution was cooled to room temperature and 2.0 g of cyclohexadiene was added. After prolonged standing another 11/2 ml of diene was added with a small amount of butylated hydroxytoluene. The solution was heated at reflux for 24 hours. The reaction mixture was subjected to high pressure liquid chromatography using a silica gel column and 20% ethyl acetate in hexane as eluent giving 4.9 g of 3a-(3,4-difluorophenyl)-3a,4,7,7a-tetrahydro-2-methyl-4,7-ethano-1H-isoindole-1,3(2H)-dione as a white solid, mp 125°-127° C.