Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([CH:14]([CH3:16])[CH3:15])=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[NH:23]1[C:31]2[C:26](=[CH:27][C:28](B(O)O)=[CH:29][CH:30]=2)[CH:25]=[CH:24]1>O1CCOCC1.O.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>[NH:23]1[C:31]2[C:26](=[CH:27][C:28]([C:2]3[CH:3]=[C:4]([C:9]4[O:10][C:11]([CH:14]([CH3:16])[CH3:15])=[N:12][N:13]=4)[C:5]([NH2:8])=[N:6][CH:7]=3)=[CH:29][CH:30]=2)[CH:25]=[CH:24]1
Reactant: CC(C)c1nnc(-c2cc(Br)cnc2N)o1
Reactant: OB(O)c1ccc2[nH]ccc2c1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nnc(-c2cc(-c3ccc4[nH]ccc4c3)cnc2N)o1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-3-(5-isopropyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-ylamine (250 mg, 0.883 mmol) in dioxane (15 mL) and water (7 mL) were added K2CO3 (365 mg, 2.649 mmol), indole-5-boronic acid (156 mg, 0.971 mmol) in a sealed tube. The reaction mixture was degassed by N2 for 20 min, then Pd(PPh3)4 (102 mg, 0.088 mmol) was added and stirred for 18 h at 100° C. Water (20 mL) was added and extracted with ethyl acetate (3×20 mL) and the organic layer was washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. Crude product was purified by column chromatography using 100-200 mesh silica gel compound eluted with 40% ethyl acetate in petroleum ether to afford the title compound as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C@H:6]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16])C.[OH-].[Na+]>CO.O>[C:21]([O:20][C:18]([NH:17][C@H:6]([CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16])[CH2:5][C:4]([OH:25])=[O:3])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Yield: 99.6 %

Procedure:
(R)-3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester 1e (10 g, 27.7 mmol) and sodium hydroxide (3.32 g, 83.1 mmol) were dissolved in the solvent mixture of 100 mL of methanol and 50 mL of water under stirring. The reaction mixture was reacted at 40-45° C. for 1-1.5 hours, then part of the solution was evaporated under reduced pressure. The residue was added with some water, then pH was adjusted to 2-3 with 1 N hydrochloric acid in an ice-water bath. The mixture was extracted with ethyl acetate (200 mL×3), and the combined organic phase was washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then recrystallized from ethyl acetate/n-hexane to obtain the title compound (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid 1f (9.2 g) as a white solid, which was directly used in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2F)=[N:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=NO)c2cc(C(F)(F)F)ccc2F)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2noc3ccc(C(F)(F)F)cc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.1 %

Procedure:
A solution of 4-[(2-Fluoro-5-trifluoromethyl-phenyl)-hydroxyimino-methyl]-piperidine-1-carboxylic acid tert-butyl ester (4.969 g, 0.013 M) in anhydrous THF (59 mL) was treated with Potassium tert-butoxide (13.4 mL of a 1M solution in THF, 0.0133 M-1.05 eq). The mixture was stirred at ambient temperature for 1 hour and then heated to 65° C. for 2 hours. The THF was removed under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with H2O (50 mL) and brine (50 mL) respectively. It was then dried over MgSO4, filtered and concentrated to give a solid (5 g) which was purified on silica ˜120 g, (eluting with ethylacetate/heptane (30:70) to give the product as a white solid (2.69 g, 57%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:23][N:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(O)CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)C.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:27]4[CH2:28][CH2:29][CH2:30][N:24]([CH3:23])[CH2:25][CH2:26]4)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: CN1CCCNCC1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)nn1)c1ccc(Cl)s1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: CN1CCCN(c2ccc(-n3cc(CNC(=O)c4ccc(Cl)s4)nn3)cc2)CC1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
The mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (4.1, 100 mg, 0.22 mmol), N-methylhomopiperazine (140 μL, 1.1 mmol), CuI (42 mg, 0.22 mmol), ethylene glycol (25 μL, 0.44 mmol), potassium phosphate (93 mg, 0.44 mmol) in 2 mL isopropanol in a sealed tube was stirred for 16 hrs at 120° C. The title compound was isolated directly from the reaction mixture using reverse phase prep HPLC. MS found for C20H23ClN6OS (M+H)+ 431.1, 433.1 (Cl pattern).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][C:4]=1[CH2:5][NH:6][CH:7]1[CH2:12][CH2:11][CH:10]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:8]1.[Cl:32][C:33]1[C:34]2[C:44]([F:45])=[CH:43][CH:42]=[C:41]([F:46])[C:35]=2[S:36][C:37]=1[C:38](Cl)=[O:39]>>[Cl:32][C:33]1[C:34]2[C:44]([F:45])=[CH:43][CH:42]=[C:41]([F:46])[C:35]=2[S:36][C:37]=1[C:38]([N:6]([CH2:5][C:4]1[CH:22]=[C:23]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:24]=[CH:25][C:3]=1[O:2][CH3:1])[CH:7]1[CH2:8][CH2:9][CH:10]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[CH2:11][CH2:12]1)=[O:39]
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(-c2cccnc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2cccnc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 173 (320 mg, 0.75 mmol) is treated with acid chloride 8 (221 mg, 0.83 mmol) using Method D to give the title compound.
Reaction SMILES: [N:1]1([C:11]2[C:12]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=4)[NH:17][C:13]=3[N:14]=[CH:15][N:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1>[Ni].C1(C)C=CC=CC=1.CC(C)=O>[N:1]1([C:11]2[C:12]3[CH:19]=[C:18]([C:20]4[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=4)[NH:17][C:13]=3[N:14]=[CH:15][N:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(-c2cc3c(N4CCCc5ccccc54)ncnc3[nH]2)cc1
Agent: [Ni]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: Nc1ccc(-c2cc3c(N4CCCc5ccccc54)ncnc3[nH]2)cc1

Procedure:
This product is obtained in a manner analogous to that described in Example 7 by hydrogenation of 4-(1,2,3,4-tetrahydroquinolin-1-yl)-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]-pyrimidine (Example 10) with Raney nickel. M.p. 243-245° C.; FAB-MS: (M+H)+ =342 (corresponds to C21H19N5); Rf value (toluene-acetone--4:6)=0.25.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O1CCCC1.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.7 g (10.2 mmol) of ethyl 4-hydroxybenzoate, 1.76 g (9.3 mmol) of 1-t-butoxycarbonyl-4-hydroxypiperidine, and 2.44 g (9.3 mmol) of triphenyl phosphine were dissolved in 40 ml of tetrahydrofuran, and 1.62 g (9.3 mmol) of diethyl azodicarboxylic acid was added thereto, and they were stirred at room temperature overnight. It was treated in an ordinary manner by treatment with ethyl acetate as the extractant to obtain the crude product. Then, it was purified by silica gel column chromatography to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[CH2:20]([CH:22]([CH2:28][CH3:29])[C:23](=O)[CH2:24][C:25]#[N:26])[CH3:21]>>[CH2:20]([CH:22]([C:23]1[C:24]([C:25]#[N:26])=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]2[C:2](=[CH:7][CH:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:4]=2)[N:1]=1)[CH2:28][CH3:29])[CH3:21]
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)c1ccccc1
Reactant: CCC(CC)C(=O)CC#N
Product: CCC(CC)c1nc2ccc(C(F)(F)F)cc2c(-c2ccccc2)c1C#N

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-trifluoromethyl-phenyl)-phenyl-methanone and 4-ethyl-3-oxo-hexanenitrile (prepared as described in example 101 step A). Off-white solid. MS (ESI): 369.4 (M+H)+.
Reaction SMILES: [Cl:1][CH:2]([Cl:35])[C:3]([N:5]([CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[CH:13]=2)[CH:7]=1)=[O:4].[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[NH2:27][CH2:26][CH2:25][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[CH:13]=2)[CH:7]=1)[C:3](=[O:4])[CH:2]([Cl:1])[Cl:35]
Reactant: CC(C)(C)OC(=O)NCCN(C(=O)C(Cl)Cl)c1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCN(C(=O)C(Cl)Cl)c1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1

Procedure:
tert-butyl 2-(2,2-dichloro-N-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenyl)acetamido)ethylcarbamate (100 mg, 0.18 mmol) was dissolved in anhydrous dichloromethane (3 mL) and cooled in an ice-bath under nitrogen. Then trifluoroacetic acid (3 mL) was added. After 3 h at 4° C. the mixture was concentrated under reduced pressure. The residue was dissolved and concentrated under reduced pressure again to give N-(2-aminoethyl)-2,2-dichloro-N-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenyl)acetamide trifluoroacetate salt as a white solid. 1H NMR (CDCl3): 8.04 (s, 1H), 7.65-7.62 (m, 2H), 7.43-7.30 (m, 4H), 6.73 (s, 1H), 5.95 (s, 1H), 4.21 (m, 2H), 3.35 ppm (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=[C:6]2[N:5]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]([CH3:35])[CH2:26][C:27]3[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=3)[N:19]=2)[CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+].[N+:41]([CH2:44][CH3:45])([O-:43])=[O:42]>>[CH3:35][CH:25]([NH:24][C:20]1[N:19]=[C:18]([N:5]2[CH2:4][CH2:3][C:2](=[O:1])[N:7]3[CH2:8][CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:11]=[C:6]23)[CH:23]=[CH:22][N:21]=1)[CH2:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[C:44]([N+:41]([O-:43])=[O:42])[CH3:45])=[CH:29][CH:28]=1
Reactant: CC(Cc1ccc(C=O)cc1)Nc1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(=Cc1ccc(CC(C)Nc2nccc(N3CCC(=O)N4CC=C(c5ccccc5)N=C43)n2)cc1)[N+](=O)[O-]

Procedure:
The mixture of 4-{2-[4-(4-oxo-8-phenyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl) -pyrimidin-2-ylamino]-propyl}-benzaldehyde (35 mg, 0.08 mmol), ammonium acetate (10 mg, 0.16 mmol) in nitroethane (5 mL) was heated to reflux for 4 h. The mixture was brought to room temperature and concentrated. The residue was dissolved in ethylacetate (20 mL), washed with water, saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated. M+1=524.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:20]([O:22][CH2:23][CH3:24])=[O:21])N=N[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:25](N1CCCC1)=[CH2:26]>C(Cl)(Cl)Cl>[C:1]1([C:7]2[N:8]=[C:9]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:26]=[CH:25][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1nnc(-c2ccc(C)cc2)c(-c2ccccc2)n1
Reactant: C=CN1CCCC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(-c2ccc(C)cc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure D, ethyl 5-phenyl-6-p-tolyl-1,2,4-triazine-3-carboxylate (Compound 12, 177 mg, 0.56 mmol) and crude 1-vinylpyrrolidine (Compound 38, 730 mg) in CHCl3 (10 ml) were reacted to produce the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][N:9]1[CH2:18][CH2:19][NH2:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)#[N:22].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:21]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:20][CH2:19][CH2:18][N:9]2[CH:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)=[CH:25][CH:24]=1)#[N:22]
Reactant: NCCN1Cc2ccccc2CC1Cc1ccccc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(CNCCN2Cc3ccccc3CC2Cc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 36.7 %

Procedure:
2-[3-benzyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine (27 mg, 0.1 mmol) obtained in Example 1-f), 4-cyanobenzylbromide (20 mg, 0.1 mmol), and potassium carbonate (17 mg, 0.12 mmol) were dissolved in 1 mL of acetonitrile, followed by stirring at 60° C. for 3 hours. After completion of the reaction, water was added to the reaction liquid, followed by extraction with ethyl acetate, and the organic layer was then washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified using silica gel chromatography (chloroform:methanol=10:1) to obtain 14 mg (yield 36.7%) of a title compound as a colorless oily substance.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH:4]([OH:9])[CH2:5][CH2:6][CH2:7][CH3:8].[C:10]1(=[O:20])[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.N1C=CC=CC=1>CCOCC>[C:10]([OH:15])(=[O:20])[C:11]1[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:13]([OH:9])=[O:14].[CH:1]#[C:2][CH2:3][CH:4]([OH:9])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C1OC(=O)c2ccccc21
Agent: C#CCC(O)CCCC
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(O)c1ccccc1C(=O)O

Procedure:
A mixture consisting of 6.3 parts of 1-octyn-4(RS)-ol, 7.4 parts of phthalic anhydride and 10 parts by volume of pyridine is heated at the reflux temperature for about 3 hours, then allowed to cool for about 16 hours. At the end of that time the mixture is diluted with ether, then is washed with dilute hydrochloric acid. Extraction with dilute sodium hydroxide, followed by acidification of the alkaline extract affords an aqueous solution which is then extracted with ether. The ether extract is dried over anhydrous sodium sulfate, decolorized with activated carbon and stripped of solvent to afford 1-octyn-4(RS)-ol phthalate.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[C:11]=3[CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[CH3:19]O>S(=O)(=O)(O)O>[CH3:19][O:15][C:14]([C:12]1[C:11]2[CH:17]=[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]=2[CH:13]=1)=[O:16]
Reactant: CO
Reactant: O=C(O)C1=Cc2ccc(C3CCCCC3)cc21
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)C1=Cc2ccc(C3CCCCC3)cc21

Procedure:
A solution of 15 g of 5-cyclohexyl-1-benzocyclobutenecarboxylic acid in 150 ml of absolute methanol and 1.5 ml of concentrated sulphuric acid is boiled for 14 hours under reflux whilst excluding water. The reaction mixture is evaporated in vacuo at 30° C to a volume of approx. 30 ml and the evaporation residue is partitioned between three times 200 ml of ether and twice 200 ml of ice water. The combined organic phases are successively washed with saturated sodium bicarbonate solution and water, dried over sodium sulphate and evaporated in vacuo. Distillation of the evaporation residue in a high vacuum yields 5-cyclohexyl-1-benzocyclobutenecarboxylic acid methyl ester in the fraction boiling at approx. 150° C/0.07 mm Hg.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=[C:6]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[CH2:5][C@@H:4]1[CH3:26]>CCO.[Pd]>[NH2:23][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:17]=1[C@@H:6]1[CH2:7][C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[C@@H:3]([O:2][CH3:1])[C@H:4]([CH3:26])[CH2:5]1.[NH2:23][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:17]=1[C@H:6]1[CH2:7][C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[C@H:3]([O:2][CH3:1])[C@@H:4]([CH3:26])[CH2:5]1
Reactant: CO[C@@H]1[C@@H](C)CC(c2ccncc2[N+](=O)[O-])=C[C@H]1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CO[C@@H]1[C@@H](C)C[C@@H](c2ccncc2N)C[C@H]1NC(=O)OC(C)(C)C
Product: CO[C@H]1[C@H](C)C[C@H](c2ccncc2N)C[C@@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 12 %
Yield: 15 %

Procedure:
To a solution of (+/−)-tert-butyl ((1R,5S,6R)-6-methoxy-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-en-1-yl)carbamate (1.0 equiv.) in degassed EtOH (0.10 M) was added Pd/C (0.1 equiv.). The mixture was purged with H2, and allowed to to stir under an atm of H2 overnight at RT. The reaction was filtered through a pad of celite and the cake was washed with MeOH. The organics were concentrated and purified by ISCO SiO2 chromatography. Purification was completed via SFC (30% MeOH, 100 mL/min, AD column) to yield tert-butyl ((1S,2S,3R,5S)-5-(3-aminopyridin-4-yl)-2-methoxy-3-methylcyclohexyl)carbamate (15% yield, 99% ee) and tert-butyl ((1R,2R,3S,5R)-5-(3-aminopyridin-4-yl)-2-methoxy-3-methylcyclohexyl)carbamate (12% yield, 99% ee). LC/MS (m/z)=336.3 (MH+), Rt=0.58 min.
Reaction SMILES: [C:1]([NH2:10])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CCN(CC)CC.[C:18](=S)=[S:19].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1>[N:10]([C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2])=[C:18]=[S:19]
Reactant: CC(C)(N)c1ccccc1
Reactant: S=C=S
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(N=C=S)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Cumylamine (5.32 mL, 37.0 mmol) (TCI America) and Et3N (16.97 mL, 122 mmol) (Aldrich) were mixed in THF (40 mL) at 0° C. under a nitrogen atmosphere. Carbon disulfide (2.224 mL, 37.0 mmol) (J.T.Baker) was added dropwise via syringe over the course of 10 min. The reaction was stirred at 0° C. for 1 h before being warmed to RT and stirred for 1 h. p-Toluenesulfonyl chloride (7.76 g, 40.7 mmol) (Fluka) was added, and the reaction was stirred at RT for 1 h. The mixture was quenched with 1 M HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated to give (2-isothiocyanatopropan-2-yl)benzene.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.CO.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:22]1([C:2]2[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(C(=O)OC)c(I)c1
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: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(C(=O)OC)c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.3 %

Procedure:
A mixture of dimethyl 2-iodoterephthalate (22.8 g, 71.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (4.14 g, 3.38 mmol) in toluene (120 mL) was stirred for 10 minutes. Aqueous sodium carbonate (2 M, 160 mL) and a solution in methanol (40 mL) of phenylboronic acid (10.4 g, 85.3 mmol) were then added and the reaction mixture was stirred at reflux for 15 hours. The reaction mixture was cooled to ambient temperature and extracted with ether. The organic phase was washed with water (2×) and brine, dried, and concentrated in vacuo to give dimethyl 2-phenylterephthalate as a dark brown oil (18.4 g) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([C:12]2[C:13]([CH2:26][CH2:27][CH3:28])=[N:14][CH:15]=[CH:16][C:17]=2OC2C=CC(Cl)=CC=2)=O)=[C:4](F)[CH:3]=1.[CH3:30][NH:31][NH2:32].C([O:36][CH2:37][CH3:38])(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:10]([C:12]3[C:13]([CH2:26][CH2:27][CH3:28])=[N:14][C:15]([O:36][C:37]4[CH:38]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[CH:16][CH:17]=3)=[N:32][N:31]2[CH3:30])=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCCc1nccc(Oc2ccc(Cl)cc2)c1C(=O)c1cc(OC)c(Cl)cc1F
Reactant: CCOC(C)=O
Reactant: CNN
Solvent: CS(C)=O
Product: CCCc1nc(Oc2ccc(Cl)cc2)ccc1-c1nn(C)c2cc(Cl)c(OC)cc12

Procedure:
A solution of the ketone from Step 7 of Example 12 (0.86 g, 2.0 mmol) and methylhydrazine (0.18 g, 4.0 mmol) in DMSO (10 mL) was heated at 80° C. for 1 h. The mixture was diluted with ethyl acetate, washed with water and dried over magnesium sulfate. After removal of the solvent, the residue was purified by chromatography on silica gel to give the title product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]2[C:10]([C:11](=[O:15])[C:12]([OH:14])=O)=[CH:9][NH:8][C:7]=12.[C:18]1([N:24]2[C:28]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][N:26]=[N:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]2[C:10]([C:11](=[O:15])[C:12]([N:32]3[CH2:33][CH2:34][N:29]([C:28]4[N:24]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[N:25]=[N:26][N:27]=4)[CH2:30][CH2:31]3)=[O:14])=[CH:9][NH:8][C:7]=12
Reactant: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: c1ccc(-n2nnnc2N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To a solution of 2-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (5.3 g, 20.8 mmol) (prepared as described on US20050090522A1) in DMF (100 mL) was added 1-(1-phenyl-1H-tetrazol-5-yl)piperazine (4.8 g, 20.8 mmol), TBTU (7.4 g, 23.0 mmol), and N,N-diisopropylethylamine (12.0 mL, 68.9 mmol). The mixture was stirred at rt for 16 hr. The solvent was removed under reduced pressure, and the remaining residue was dissolved in hot MeOH. Upon cooling, precipitate formed. The precipitate was collected by filtration, and was washed with H2O (3×75 mL). The mother liquor was concentrated under reduced pressure, then subjected to a second crystallization using the same method. The combined precipitates gave 1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione as a light brown solid (7.3 g, 15.6 mmol). 1H NMR (500 MHz, CDCl3) δ 9.64 (s, 1H), 8.11 (s, 1H), 7.76 (s, 1H), 7.62-7.50 (m, 5H), 4.00 (s, 3H), 3.83-3.81 (m, 2H), 3.57-3.56 (m, 2H), 3.43-3.41 (m, 2H), 3.33-3.32 (m, 2H). LCMS: m/e 467.3 (M+H)+, ret time 1.99 min (method 2).