Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9](/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([C:23]2[CH:34]=[CH:33][C:26]([CH2:27]OS(C)(=O)=O)=[CH:25][CH:24]=2)=[O:22])=[CH:15][CH:14]=1)=[O:10].ClCC1C=CC(C(=O)/C=C/C2C=CC(/C=C/C(NOC3CCCCO3)=O)=CC=2)=CC=1.[N:65]1([C:71](=[O:73])[CH3:72])[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1>>[C:71]([N:65]1[CH2:70][CH2:69][N:68]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([C:21](=[O:22])/[CH:20]=[CH:19]/[C:16]3[CH:17]=[CH:18][C:13](/[CH:12]=[CH:11]/[C:9]([NH:8][OH:7])=[O:10])=[CH:14][CH:15]=3)=[CH:34][CH:33]=2)[CH2:67][CH2:66]1)(=[O:73])[CH3:72]
Reactant: CC(=O)N1CCNCC1
Reactant: CS(=O)(=O)OCc1ccc(C(=O)/C=C/c2ccc(/C=C/C(=O)NOC3CCCCO3)cc2)cc1
Agent: O=C(/C=C/c1ccc(/C=C/C(=O)c2ccc(CCl)cc2)cc1)NOC1CCCCO1
Product: CC(=O)N1CCN(Cc2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)NO)cc3)cc2)CC1

Procedure:
The product was obtained starting from a mixture of methanesulfonic acid 4-((E)-3-{4-[(E)-2-(tetrahydro-pyran-2-yloxycarbamoyl)-vinyl]-phenyl}-acryloyl)-benzyl ester and (E)-3-{4-[(E)-3-(4-chloromethyl-phenyl)-3-oxo-propenyl]-phenyl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (both obtained as described in Preparation 5) and 1-piperazin-1-yl-ethanone, following the experimental procedure described for Example 28. The title compound was obtained as its hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([O:9][CH3:10])[CH:3]=1.[CH3:11][N:12](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([C:11]#[N:12])=[CH:6][N:5]=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Cl)c(I)cn1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cc(Cl)c(C#N)cn1
Temperature: 120 °C
Yield: 54 %

Procedure:
A suspension of 4-chloro-5-iodo-2-methoxy-pyridine (30.5 g, 0.11 mol), zinc (II) cyanide (7.97 g, 68 mmol), Pd(PPh3)4 (6.56 g, 5.66 mmol) and DMF (450 mL) was degassed and then heated at 120° C. for 1 h before being concentrated in vacuo. The resultant residue was treated with water then extracted with DCM, the organic extract dried (MgSO4), filtered, then concentrated in vacuo. The resultant residue was crystallized from DCM to give the title compound (10.1 g, 54%). The mother liquors were concentrated in vacuo and the residue subjected to flash chromatography (SiO2 gradient 0 to 100% ethyl acetate in cyclohexane) then crystallization from cyclohexane to give the further title compound (5.16 g, 28%, 82% total). 1H NMR 400 MHz (CDCl3) δ: 8.45 (1H, s), 6.90 (1H, s), 4.01 (3H, s).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:10][C@H:11]([OH:30])[C@@H:12]([NH:20][C:21]([O:23][CH2:24][C:25]1[S:29][CH:28]=[N:27][CH:26]=1)=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][C@@H:9]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:10][C@H:11]([OH:30])[C@@H:12]([NH:20][C:21]([O:23][CH2:24][C:25]1[S:29][CH:28]=[N:27][CH:26]=1)=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reaction time: 1 h
Yield: 99.5 %

Procedure:
The product of Example 69A (6.43 g, 12.23 mmoles) was dissolved in 25 mL dioxane at room temperature under nitrogen atmosphere. To this stirred solution was added 20.25 mL of 4N HCl in dioxane, and after approximately 10 min thick precipitate formed. An additional 10 mL of dioxane was added to loosen up the slurry. This mixture was stirred for 1 h and then filtered. The filter cake of the product bis-HCl salt was washed with 20 mL dioxane, air dried, and then dissolved in 175 mL water. To this solution was added 175 mL ethyl acetate and the two phase mixture rapidly stirred. The pH of this mixture was adjusted to pH=10 by the dropwise addition of 3N NaOH to the rapidly stirred mixture. The organic layer was isolated, washed with brine (150 mL), and dried over Na2SO4. The solvent was removed to afford 5.18 g (99%) of the desired product as a clear oil. H1NMR (CDCl3) δ 8.81 (s, 1H), 7.87 (s, 1H), 7.35-7.05 (m, 10H), 5.33 (d, 1H, J=9.3 Hz), 5.28 (m,2H), 3.81 (m, 1H), 3.72 (m, 1H), 3.01 (m, 1H), 2.88 (m, 2.78 (dd, 1H, J=13.5, 5.1 Hz), 2.39 (dd, 1H, J=9.0, 4.5 Hz), 1.57-1.30 (m, 2H) 2H). ClMS m/z 426 (M+H)+.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[NH:13][C:12](=O)[CH:11]=[C:10]([C:15]3[C:23]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:26])=O.N1C=CC=CC=1>>[Cl:26][C:12]1[CH:11]=[C:10]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[N:9]=[C:8]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2c[nH]c3ncccc23)nc(NC2CCCCC2)[nH]1
Solvent: c1ccncc1
Product: Clc1cc(-c2c[nH]c3ncccc23)nc(NC2CCCCC2)n1
Yield: 25.5 %

Procedure:
A mixture of Example 49d (100 mg, 0.323 mmol), phosphoryl trichloride (1 ml, 10.92 mmol) and pyridine (0.05 ml, 0.618 mmol) was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and purified by HPLC on a Phenomenex Luna C8(2) 5 μm 100 Å AXIA column (30 mm×75 mm), eluting with a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B), at a flow rate of 50 mL/min (0-0.5 min 10% A, 0.5-7.0 min linear gradient 10-95% A, 7.0-10.0 min 95% A, 10.0-12.0 min linear gradient 95-10% A) to give the title product (27 mg, 25.5% yield). MS (ESI) m/e 328 (M+H)+; 1H NMR (400 MHz, DMSO-d6) ppm 1.15-1.48 (m, 5H) 1.58-1.69 (m, 1H) 1.73-1.83 (m, J=9.31, 3.51 Hz, 2H) 1.94-2.03 (m, 2H) 3.76-3.90 (m, 1H) 6.93-7.04 (m, 1H) 7.07 (s, 1H) 7.17 (dd, J=7.93, 4.58 Hz, 1H) 8.28 (d, J=3.36 Hz, 1H) 8.34 (s, 1H) 8.79 (d, J=7.63 Hz, 1H) 12.01 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[O:24][C:18]2[CH:19]([CH3:23])[NH:20][CH2:21][CH2:22][C:17]=2[CH:16]=1>>[Br:14][C:15]1[O:24][C:18]2[CH:19]([CH3:23])[N:20]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH2:21][CH2:22][C:17]=2[CH:16]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cc(Br)oc21
Product: CC1c2oc(Br)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2-bromo-7-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridine to provide the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[NH2:16]>>[CH3:23][O:22][C:18]1[CH:17]=[C:15]([NH:16][C:7]([C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[NH:8])[CH:14]=[C:13]([O:12][CH3:11])[C:19]=1[O:20][CH3:21]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CSc1ccc(C#N)cc1
Product: COc1cc(NC(=N)c2ccc(SC)cc2)cc(OC)c1OC

Procedure:
The title compound was prepared from 4-methylthiobenzonitrile (4.1 g, 27 mmol) and 3,4,5-trimethoxyaniline (5 g, 27 mmol) by following the procedure described in preparation 10 (7.8 g, yield 86.32%). 1H-NMR (CDCl3):δ 2.51 (s, 3H), 3.8 (s, 9H), 4.9 (bs, 2H, D2O exchangeable), 6.23 (s, 2H), 7.24-7.30 (m, 2H), 7.78-7.8 (d, 2H). MS m/z:333.5 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[CH:3]=1.C(N(CC)CC)C.[CH3:16][CH2:17][CH2:18][C:19](Cl)=[O:20].OP([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:19]([NH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[CH:3]=1)(=[O:20])[CH2:18][CH2:17][CH3:16]
Reactant: CCCC(=O)Cl
Reactant: Cc1cc(N)n(C)n1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)Nc1cc(C)nn1C
Reaction time: 1 h
Yield: 114.2 %

Procedure:
A stirred solution under nitrogen of 5-amino-1,3-dimethylpyrazole (7.09 g, 63.8 mmol) and triethylamine (10 mL) in sieve-dried methylene chloride (100 mL) was chilled in an ice-bath and n-butyryl chloride (7.3 mL, 70.3 mmol) was added dropwise. After 1 hour, the reaction mixture was shaken with 50 mL of 1M K2HPO4 solution and the aqueous phase was further extracted with CH2Cl2 (2×70 mL). The organic phase was dried over MgSO4, filtered and then evaporated to dryness to give 13.2 g of an orange-yellow oil. This was purified by chromatography on SiO2 (300 g), developing with EtOAc/hexane (45:55) to give the Step A compound (10.53 g; 91%) as an oil. 1H NMR (200 MHz, CDCl3), δ 6.00 (s, 1H), 3.65 (s, 3H), 2.37 (t, 2H, J=9 Hz), 2.22 (s, 3H), 1.62-1.90 (m, 2H), 1.01 (t, 3H, J=9 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[C:12]([C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20]([CH:24]=1)[C:21](Cl)=[O:22])([CH3:15])([CH3:14])[CH3:13].Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20]([CH:24]=1)[C:21]([NH:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:22])([CH3:15])([CH3:13])[CH3:14]
Reactant: COc1ccc(C(C)(C)C)cc1C(=O)Cl
Reactant: COc1ccc(CCN)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(CCNC(=O)c2cc(C(C)(C)C)ccc2OC)cc1

Procedure:
1.51 g (10.0 mmol) of 2-(4-methoxyphenyl)ethylamine were dissolved in 40 ml of pyridine and admixed with a spatula tip of 4-dimethylaminopyridine and then with a solution of 2.15 g (10.5 mmol) of 5-tert-butyl-2-methoxybenzoyl chloride. After the 2-(4-methoxyphenyl)ethylamine had been converted completely, the reaction mixture was poured into cold dilute hydrochloric acid, and the precipitated product was filtered off with suction and dried to give 5-tert-butyl-2-methoxy-N-[2-(4-methoxyphenyl)ethyl]benzamide as a colorless solid. The benzamide was introduced into cold chlorosulfonic acid. After the benzamide had been converted completely, the reaction mixture was poured onto ice and filtered off with suction, and the precipitate was dissolved in acetone. This solution was admixed with excess concentrated aqueous ammonia. After the exothermic reaction had subsided, the mixture was concentrated to a third of its original volume and the precipitate was filtered off with suction. The 5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methoxybenzenesulfonamide was obtained in the form of colorless crystals of melting point 165-168° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][CH:14]([CH2:19][CH2:20][CH3:21])[CH2:13][C:12]=3[NH:11][C:10]([CH3:22])=[C:9]2[C:23]#[N:24])[CH:5]=[C:4]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[C:3]=1[NH:32][C:33](=[O:43])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N+:40]([O-])=O)[CH:35]=1.C(O)(=O)C>C1COCC1.[Zn]>[NH2:40][C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=1)[C:33]([NH:32][C:3]1[C:4]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])=[CH:5][C:6]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][CH:14]([CH2:19][CH2:20][CH3:21])[CH2:13][C:12]=3[NH:11][C:10]([CH3:22])=[C:9]2[C:23]#[N:24])=[CH:7][C:2]=1[Br:1])=[O:43]
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(NC(=O)c2cccc([N+](=O)[O-])c2)c(NS(=O)(=O)CCC)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(NC(=O)c2cccc(N)c2)c(NS(=O)(=O)CCC)c1
Reaction time: 4 h

Procedure:
To a solution of N-[2-bromo-4-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinolin-4-yl)-6-(propane-1-sulfonylamino)-phenyl]-3-nitro-benzamide (412 mg) and acetic acid (520 μl) in THF (10 ml), cooled to 0° C., was added zinc dust (810 mg) under vigorous stirring. After stirring for 4 h, the mixture was filtered and concentrated in vacuo. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[N:24]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:15]3=[N:16][CH:17]=[C:18]4[CH:22]=[N:21][N:20]([CH3:23])[C:19]4=[C:14]3[CH:13]=2)=[CH:3]1.Cl[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:8][CH:9]=2)[C:4]([C:12]2[N:24]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:15]3=[N:16][CH:17]=[C:18]4[CH:22]=[N:21][N:20]([CH3:23])[C:19]4=[C:14]3[CH:13]=2)=[CH:3]1
Reactant: ClCCN1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(O)cc34)cc3c4c(cnc32)cnn4C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(OCCN5CCOCC5)cc34)cc3c4c(cnc32)cnn4C)cc1
Temperature: 50 °C
Yield: 21.6 %

Procedure:
A mixture of 1-methyl-3-(1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-indol-5-ol (0.21 g, 0.42 mmol), 4-(2-chloroethyl)morpholine (0.12 g, 0.78 mmol, Beta Pharm) and Cs2CO3 (0.42 g, 1.27 mmol) in DMF (4 mL) was heated at about 50° C. for about 20 h. After cooling to rt the mixture was filtered. The filtrate was purified by preparative reverse phase HPLC (Table 2, Method j) to give 4-(2-(1-methyl-3-(1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-indol-5-yloxy)ethyl)morpholine (0.053 g, 21%): LC/MS (Table 2, Method a) Rt=2.07 min; MS m/z 585 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[I-].[CH3:9][O:10][C:11]([CH2:13][CH2:14][C:15]1[N+:19]([CH3:20])=[CH:18][N:17](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:16]=1)=[O:12]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:20][N:19]1[C:15]([CH2:14][CH2:13][C:11]([O:10][CH3:9])=[O:12])=[CH:16][N:17]=[CH:18]1
Reactant: COC(=O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c[n+]1C
Agent: [I-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCc1cncn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
0.5 ml of trifluoroacetic acid is added to a solution of 200 mg (0.37 mmol) of 5-(2-methoxycarbonylethyl)-1-methyl-3-trityl-3H-imidazol-1-ium iodide in 2 ml of dichloromethane. The reaction medium is left to stir overnight at ambient temperature and the solvents are evaporated off. The residue is purified by silica chromatography (eluent 9/1 DCM/MeOH. 80 mg of methyl 3-(3-methyl-3H-imidazol-4-yl)propionate trifluoroacetate are obtained with a yield of 76%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12]>>[CH2:9]1[O:8][C:5]2[CH:6]=[CH:7][C:2]([CH:13]([C:11]#[N:12])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3][C:4]=2[O:10]1
Reactant: Clc1ccc2c(c1)OCO2
Reactant: CCOC(=O)CC#N
Product: CCOC(=O)C(C#N)c1ccc2c(c1)OCO2
Yield: 81.9 %

Procedure:
Method B of the above general procedure was followed using 4-chloro-1,2-(methylenedioxy)benzene (157 mg, 1.00 mmol) and ethyl cyanoacetate (124 mg, 1.10 mmol). The reaction mixture was purified by column chromatography on silica gel (1:3 dichloromethane/hexanes) to give the desired product (191 mg, 82%) as a colorless oil: 1H NMR (CDCl3) δ 6.93-6.90 (m, 2H), 6.83-6.80 (m, 1H), 6.00 (s, 2H), 4.62 (s, 1H), 4.30-4.19 (m, 2H), 1.29 (t, 7.2 Hz, 3H). 13C{1H} NMR (CDCl3) δ 165.07, 148.46, 148.44, 123.33, 121.76, 115.75, 108.79, 108.25, 101.68, 63.34, 43.31, 13.92. Anal. Calcd. for C12H11NO4: C, 61.80; H, 4.75; N, 6.01. Found: C, 62.08: H, 4.62: N, 6.13.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7](C(=O)C(F)(F)F)[CH2:6][CH2:5]2.O.O.[NH4+].[CH3:21][N:22]1C(=O)CCC1>>[CH2:8]1[C:9]2[C:4](=[CH:3][C:2]([C:21]#[N:22])=[CH:11][CH:10]=2)[CH2:5][CH2:6][NH:7]1
Reactant: O=C(N1CCc2cc(Br)ccc2C1)C(F)(F)F
Reactant: CN1CCCC1=O
Agent: [NH4+]
Solvent: O
Product: N#Cc1ccc2c(c1)CCNC2

Procedure:
The compound (2.23 g) obtained in Example 17-2 was dissolved in NMP (27 ml) and added with cuprous cyanide (1.56 g) and the whole was refluxed under heating for 4 hours. After completion of the reaction, the whole was cooled with ice and added with water and ammonium water. The resultant was subjected to extraction with chloroform and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The resultant was dissolved in diethyl ether and added with a 4 mol/l hydrogen chloride/dioxane solution. The precipitate was filtrated and washed with diethylether. The resultant was dried under heating, thereby obtaining a hydrochloride (1.95 g) of the subject compound as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH2:14])[CH:7]=1.[CH:16](OC)(OC)OC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:16])[CH:7]=1
Reactant: COC(OC)OC
Reactant: Cc1ccc(Cl)cc1-c1ccncc1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Product: CNc1cnccc1-c1cc(Cl)ccc1C

Procedure:
To a solution of 4-(5-chloro-2-methyl-phenyl)-pyridin-3-ylamine (500 mg, 2.29 mmol) in trimethyl orthoformate (1.94 g, 2.00 mL, 18.3 mmol, CAS RN 149-73-5) was added 2-3 drops of TFA. The reaction mixture was stirred at reflux for 2 hours and then concentrated under vacuum. The residue was dissolved in 5 ml toluene and evaporated (repeated 3 times). The residue was dissolved in THF (10 mL) and LiAlH4 (260 mg, 6.86 mmol) was added in portions at 0° C. The cooling bath was removed, the reaction mixture stirred at room temperature for 1 hour and then poured on 30 mL 10% aqueous NH4Cl solution and 30 mL EtOAc. The layers were separated and the aqueous layer extracted a second time with 30 mL EtOAc. The combined organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow solid (331 mg, 62%). MS (ESI): m/z=233.084 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N+:16]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCCCCC.N#N>CCO.[Pd]>[NH2:16][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=1
Reactant: CC(C)(C)c1cc([N+](=O)[O-])cc2c1OCC2(C)C
Agent: [Pd]
Agent: N#N
Solvent: CCCCCC
Solvent: CCO
Product: CC(C)(C)c1cc(N)cc2c1OCC2(C)C
Reaction time: 3 h

Procedure:
A mixture of 7-tert-butyl-3,3-dimethyl-5-nitro-2,3-dihydrobenzo[b]furan (2.2 g, 8.8 mmol) and 10% Pd on charcoal (220 mg) in EtOH (60 mL) is hydrogenated at 24° C. and 40 psi of H2 for 3 h. The reaction is monitored by TLC (EtOAC:hexane, 1:19). The reaction mixture is vented to N2, filtered through Celite, and evaporated to yield 5-amino-7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan as a purple solid.
Reaction SMILES: [NH2:1][CH:2]([C:6]#[N:7])[C:3]([NH2:5])=[O:4].Cl.[C:9]1([CH2:15][C:16](=[NH:20])OCC)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:21](N)[CH2:22][CH3:23]>C(#N)C>[NH2:7][C:6]1[N:20]([CH2:21][CH2:22][CH3:23])[C:16]([CH2:15][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:1][C:2]=1[C:3]([NH2:5])=[O:4]
Reactant: CCOC(=N)Cc1ccccc1
Reactant: CCCN
Reactant: N#CC(N)C(N)=O
Agent: Cl
Solvent: CC#N
Product: CCCn1c(Cc2ccccc2)nc(C(N)=O)c1N
Temperature: 25 °C
Yield: 21.1 %

Procedure:
A solution of 2-amino-2-cyanoacetamide (prepared as described in WO 94/00453; 250 mg, 2.5 mmol) in acetonitrile (6 mL) was added to ethyl 2-phenylethanimidoate hydrochloride (prepared as described in J. Med. Chem. 38 (18), 3676 (1995); 500 mg, 2.5 mmol), and the suspension stirred at room temperature for an hour, then cooled in an ice-bath. The resulting precipitate was filtered off, n-propylamine (160 μL, 2.5 mmol) added to the filtrate and the solution stirred at room temperature for 72 hours. The reaction mixture was concentrated under reduced pressure, and the residue purified by column chromatography on silica gel using dichloromethane: methanol (95:5) as eluant to afford the title compound as a tan coloured solid (136 mg, 21%).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=2[CH:6]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[Cl:12])=[CH:6][C:5]=2[CH:7]=1
Reactant: Clc1ccc2sc(Br)cc2c1
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Clc1ccc2sc(-c3ccccc3Cl)cc2c1
Temperature: 100 °C
Yield: 94.7 %

Procedure:
To a solution of 1.03 g (4.16 mmol) 2-bromo-5-chlorobenzothiophene in 12 ml DME under argon were added 1.0 g (6.4 mmol) 2-chlorobenzeneboronic acid, 88 mg Pd(PPh3)4, and 6.4 ml 1M aqueous sodium carbonate solution, and the mixture was heated overnight at 100° C. in a sealed tube. After cooling 20 ml water and 20 ml ethyl acetate were added followed by vigorous stirring. The organic layer was dried over sodium sulfate and concentrated in vacuo, and the title compound was purified by chromatography on silica gel with hexane/ethyl acetate 97:3 to give 1.1 g (95%) of a colorless oil, which slowly solidified; MS 278 (M+).
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[C:4]([N:6]1[C@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][O:8][C:7]1=[O:18])=[O:5].[CH2:19]([N:26]([CH2:30][Si](C)(C)C)[CH2:27]OC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:26]1[CH2:27][C@@H:2]([CH3:1])[C@H:3]([C:4]([N:6]2[C@H:10]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:9][O:8][C:7]2=[O:18])=[O:5])[CH2:30]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C/C=C/C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Product: C[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 44.9 %

Procedure:
The compound from step 5a (245 mg, 1.00 mmol) was reacted with N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine (254 mg, 1.2 mmol) according to the procedure of Example 1d, to afford the title compound (170 mg). MS m/z 379 (M+H)+. NMR (CDCl3) d 7.15-7.40 (10H, m), 4.69 (1H, m), 4.20 (1H, dd, J=16.5, 9.0 Hz), 4.18 (1H, dd, J=9.0, 6.0 Hz), 3.71 (1H, d, J=13.5 Hz), 3.65 (1H, m), 3.56 (1H, d, J+13.5 Hz), 3.24 (1H, dd, J=13.5, 3.3 Hz), 2.70-3.10 (4H, m), 2.17 (1H, dd, 8.4, 7.5 Hz), 1.08 (3H, d, J=6.9 Hz).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][C:4]([OH:6])=[O:5].[C:11]([Cl:14])(=O)C>CO>[Cl-:14].[CH3:11][O:5][C:4](=[O:6])[CH2:3][C@@H:2]([NH3+:1])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[C@H](N)CC(=O)O
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)C[C@@H]([NH3+])C(C)(C)C
Product: [Cl-]
Temperature: 65 °C
Reaction time: 3 h

Procedure:
(R)-3-amino-4,4-dimethylpentanoic acid, 2a, was dissolved in methanol (1.4 L). The solution was cooled in an ice bath and acetyl chloride (67.0 mL, 947.0 mmol) was added dropwise (maintaining the temperature below 10° C.). The reaction mixture was heated to 65° C. and stirred at that temperature for 3 h. The reaction mixture was cooled to room temperature and then flushed with toluene to remove volatiles. The crude material was used without further purification: 1H NMR (400 MHz, MeOH-d4) δ 3.75 (s, 3H), 3.41 (t, 1H), 2.88 (dd, 1H), 2.64-2.46 (m, 1H), 1.04 (s, 9H).