Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][S:10][C:4]=2[CH:3]1[NH:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1.[N+:24]([O-])([OH:26])=[O:25].[K+].[Br-]>C(O)(=O)C>[OH:1][CH:2]1[CH2:7][O:6][C:5]2[CH:8]=[C:9]([N+:24]([O-:26])=[O:25])[S:10][C:4]=2[CH:3]1[NH:11][C:12](=[O:23])[C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(NC1c2sccc2OCC1O)c1ccc(C(F)(F)F)cc1
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C(NC1c2sc([N+](=O)[O-])cc2OCC1O)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared as described in Example 9 starting with 5,6-dihydro-6-hydroxy-7-(4-trifluoromethylbenzamido)-7H-thieno[3,2-b]pyran (1.5 g, 4.04 mmol) and 90% nitric acid (2.5 mL) in acetic acid (20 mL) to give a yellow solid, 0.165 g (10%): mp 219°-220° C.; IR (KBr): 3310, 1661, 1538 and 1504 cm-1 ; MS: m/z 417 (MH+); 1H NMR (DMSO-d6): δ 1.26 (s, 3H), 1.45 (s, 3H), 3.92 (m, 1H, simplifies to d, J=8.9 Hz, with D2O), 4.98 (m, 1H, simplifies to d, J=8.9 Hz, with D2O), 5.99 (d, 1H, exchanges with D2O), 7.74 (s, 1H), 7.92 (d, J=8.5 Hz, 2H), 8.12 (d, J=8.5 Hz, 2H) and 9.30 (d, 1H, exchanges with D2O).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]2[CH:26]=[C:25](B(O)O)[S:24][C:23]=2[CH:30]=1>>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]2[CH:26]=[C:25]([C:2]3[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)=[CH:4][CH:3]=3)[S:24][C:23]=2[CH:30]=1
Reactant: O=C(CN1CCCC1)Nc1ccc(Br)cc1
Reactant: COc1ccc2cc(B(O)O)sc2c1
Product: COc1ccc2cc(-c3ccc(NC(=O)CN4CCCC4)cc3)sc2c1
Yield: 97 %

Procedure:
By essentially following the procedures described in Example 1, Part B, the title compound was prepared in 97% yield from N-(4-bromophenyl)-α-(1-pyrrolidinyl)acetamide (Part B) and 6-methoxybenzo[b]thiophene-2-boronic acid (Example 1, Part A).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:27]=[CH:26][C:18](/[CH:19]=[N:20]/[NH:21][C:22](SC)=[S:23])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH3:30][N:31]([CH3:39])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([NH2:38])[CH:33]=1>CN(C=O)C>[CH3:30][N:31]([CH3:39])[C:32]1[CH:33]=[C:34]([NH:38][C:22]([NH:21][N:20]=[CH:19][C:18]2[CH:17]=[CH:16][C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:28])([F:1])[F:29])=[CH:9][CH:8]=4)[N:11]=3)=[CH:27][CH:26]=2)=[S:23])[CH:35]=[CH:36][CH:37]=1
Reactant: CSC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CN(C)c1cccc(N)c1
Solvent: CN(C)C=O
Product: CN(C)c1cccc(NC(=S)NN=Cc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Temperature: 150 °C
Reaction time: 5 h
Yield: 78.3 %

Procedure:
To a 50 mL round-bottomed flask containing (E)-methyl 2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbodithioate (250 mg, 0.571 mmol) in DMF (3 mL) was added N1,N1-dimethylbenzene-1,3-diamine (195 mg, 1.43 mmol). The contents were heated at 150° C. with stirring for 5 h before the solution was allowed to cool overnight. The mixture was filtered, and the filtrate was purified via RP-HPLC to afford the desired material (235 mg, 78%) as an off-white solid: mp 192-194° C.; 1H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 10.04 (s, 1H), 9.41 (s, 1H), 8.19 (s, 1H), 8.16-7.99 (m, 6H), 7.61 (d, J=8.3 Hz, 2H), 7.16 (t, J=7.2 Hz, 1H), 7.01 (m, 1H), 6.87 (m, 1H), 6.58 (m, 1H), 2.88 (s, 6H); ESIMS m/z 526 ([M+H]+).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=1[F:22])([CH3:14])[CH3:13])[CH2:2]2.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=[CH:17][C:16]=1[F:22])([CH3:14])[CH3:13])[CH2:2]2
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1cc(Br)ccc1F
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)(NC(=O)OC1CN2CCC1CC2)c1cc(-c2ccccc2)ccc1F
Yield: 39.3 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(5-bromo-2-fluorophenyl)propan-2-yl]carbamate (990 mg, 2.57 mmol), phenylboronic acid (209 mg, 1.71 mmol) and palladium (II) acetate gave the title compound as a white solid (257 mg, 26%). 1H NMR (400 MHz, CDCl3) δ 7.58-7.49 (m, 3H), 7.44-7.38 (m, 3H), 7.35-7.29 (m, 1H), 7.08 (dd, J=8.4, 12.1 Hz, 1H), 5.30 (s, 1H), 4.75-4.42 (m, 1H), 2.89 (d, J=10.2 Hz, 6H), 1.81-1.66 (m, 6H), 2.04-1.18 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3) δ 161.7, 159.3, 140.7, 137.3, 137.3, 131.7, 131.7, 131.0, 129.0, 127.5, 127.3, 126.7, 117.1, 116.9, 71.4, 55.8, 54.3, 47.6, 46.7, 28.6, 25.6, 24.8, 19.8 ppm. Purity: 92.0% UPLCMS (210 nm); retention time 0.95 min; (M+1) 382.9. Anal. Calcd. for C23H27FN2O2.0.4 (CHCl3): C, 65.39; H, 6.43; N, 6.52. Found: C, 65.39; H, 6.51; N, 6.42.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH2:22][CH2:23][CH:24]1[CH:29]([OH:30])[CH2:28][CH2:27][NH:26][CH2:25]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:27][CH2:28][CH:29]([OH:30])[CH:24]([CH2:23][NH2:22])[CH2:25]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: NCC1CNCCC1O
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Product: NCC1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCC1O
Yield: 52.8 %

Procedure:
The condensation of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with 3-aminomethyl-4-hydroxy-piperidine was carried out in a similar manner as described in example 1, gave the titled product. Yield 52.8%, m.p 202–04° C., C19H22F2N4O4, m/z 409 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[C:10]#[C:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:20])=[N:16][C:17]=1[CH2:18][CH3:19].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[C:28]([O:30][CH3:31])=[O:29].C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:31][O:30][C:28](=[O:29])[C:27]1[CH:26]=[CH:25][C:24]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[C:3]=2[C:10]#[C:11][C:12]2[C:17]([CH2:18][CH3:19])=[N:16][C:15]([NH2:20])=[CH:14][CH:13]=2)=[CH:23][C:22]=1[F:21]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: CCc1nc(N)ccc1C#Cc1c(Cl)ccnc1CC
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: COCCOC
Solvent: O
Product: CCc1nc(N)ccc1C#Cc1c(-c2ccc(C(=O)OC)c(F)c2)ccnc1CC
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
The title compound is synthesized according to general procedure GP3 starting from 1.29 g (4.5 mmol) 5-(4-Chloro-2-ethyl-pyridin-3-ylethynyl)-6-ethyl-pyridin-2-ylamine (A-30) using 1.34 mg (6.8 mmol) 3-Fluoro-4-methoxycarbonylphenyl boronic acid, 1.4 g (0.9 mmol) Pd(PPh3)4 and 1.19 g (8.6 mmol) K2CO3 in a mixture of 9 mL 1,2-dimethoxyethane and 2.25 mL water. The reaction mixture is stirred twice for 30 min at 130° C. under microwave irradiation. The product is precipitated by the addition of water, filtered off and purified by chromatography on silica gel using a cyclohexane/ethyl acetate gradient. Yield: 944 mg (52%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]([F:27])([F:26])[C:15]1[CH:25]=[CH:24][C:18]([O:19][CH:20]2[CH2:23][NH:22][CH2:21]2)=[CH:17][CH:16]=1>>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([N:22]2[CH2:23][CH:20]([O:19][C:18]3[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:27])[F:26])=[CH:25][CH:24]=3)[CH2:21]2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Product: COC(=O)c1cc(Cl)cnc1N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Yield: 66.7 %

Procedure:
The title compound (D78) (200 mg) was prepared according to the experimental procedure described in Description 62 starting from Methyl 2,5-dichloronicotinate (160 mg, 0.775 mmol) and 3-(4-(trifluoromethyl)phenoxy)azetidine (D52) (202.13 mg, 0.903 mmol).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH:11]=[CH:12][CH:13]=1.[CH3:26][O:27][C:28](=[O:31])[CH2:29]Br>CC(C)=O>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[CH:15]=[CH:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[O:7][CH2:29][C:28]([O:27][CH3:26])=[O:31]
Reactant: Oc1cccc(C=Cc2ccc3ccccc3n2)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1cccc(C=Cc2ccc3ccccc3n2)c1

Procedure:
A suspension of milled potassium carbonate (0.5 g), quinoline from Step 2 (1.1 g), and methylbromoacetate (4.0 ml) in acetone (25 ml) were refluxed overnight. The reaction mixture is poured onto water, extracted with ethyl acetate dried and evaporated. Chromatography of the residue on SiO2 using 30 to 40% ether/hexane afforded the title compound: m.p. 110-112°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:21]=1[S:28](Cl)(=[O:30])=[O:29].N12CCN(CC1)CC2>C(#N)C>[CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1)[S:28]([C:21]1[C:22]([F:27])=[CH:23][C:24]([F:26])=[CH:25][C:20]=1[F:19])(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)c1c(F)cc(F)cc1F
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2c(F)cc(F)cc2F)c(OC)c1
Yield: 17.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (600 mg, 2.44 mmol) prepared in Example 14a, 2,4,6-trifluorobenzenesulfonyl chloride (1.50 g, 6.51 mmol), 1,4-diazabicyclo[2.2.2]octane (549 mg, 4.89 mmol) and acetonitrile (12 mL), to yield the title compound (192 mg, 18%) as a colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16]([Cl:22])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH3:15])[CH:11]=1.[N-:23]=[N+:24]=[N-:25].[Na+].[Cl-].[NH4+]>CN(C)C=O>[Cl:22][C:16]1[CH:17]=[C:18]([C:20]2[NH:25][N:24]=[N:23][N:21]=2)[CH:19]=[C:2]([Cl:1])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH3:15])[CH:11]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(CCCCCOc2c(Cl)cc(C#N)cc2Cl)on1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(CCCCCOc2c(Cl)cc(-c3nnn[nH]3)cc2Cl)on1
Temperature: 100 °C
Yield: 62.2 %

Procedure:
A mixture of 14.7 g 5-[5-(2,6-dichloro-4-cyanophenoxy)pentyl]-3-methylisoxazole (Example 32a), 2.96 g sodium azide and 0.32 g ammonium chloride in 150 ml dimethylformamide was stirred and heated at 100° C. for 24 hrs. The reaction mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate and washed with 2N hydrochloric acid. The organic layer was dried over magnesium sulfate and concentrated in vacuo to a solid residue. The latter was recrystallized from ethyl acetate to give 10.3 g (62%) 5-{5-[2,6-dichloro-4-(1H-tetrazol-5yl)phenoxy]pentyl}-3-methylisoxazole, m.p. 122-123° C.
Reaction SMILES: I[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][C:55]3[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=3)=[CH:49][CH:48]=2)=[C:25]([CH2:27][CH2:28][NH:29][CH:30]2[CH2:39][CH2:38][CH2:37][C:36]3[N:35]=[C:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:33]=[CH:32][C:31]2=3)[CH:26]=1>C(#N)C>[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][C:55]3[CH:56]=[CH:57][C:58]([F:61])=[CH:59][CH:60]=3)=[CH:49][CH:48]=2)=[C:25]([CH2:27][CH2:28][N:29]([CH2:2][CH2:3][C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[CH:30]2[CH2:39][CH2:38][CH2:37][C:36]3[N:35]=[C:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:33]=[CH:32][C:31]2=3)[CH:26]=1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1cc(F)ccc1OCc1ccc(CCc2ccc(F)cc2)cc1
Reactant: COC(=O)c1ccc(CCI)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccc(C(=O)OC)cc1)CCc1cc(F)ccc1OCc1ccc(CCc2ccc(F)cc2)cc1
Temperature: 140 °C
Reaction time: 4 h

Procedure:
305 mg (1.05 mmol) of methyl 4-(2-iodoethyl)benzoate and 56 mg (0.53 mmol) of anhydrous sodium carbonate were added to a solution of 200 mg (0.35 mmol) of ethyl 5-({2-[5-fluoro-2-({4-[2-(4-fluorophenyl)ethyl]benzyl}oxy)phenyl]ethyl}amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 143A) in 3 ml of dry acetonitrile, and the mixture was stirred in a microwave apparatus (Biotage Initiator) at 140° C. for 4 hours. The reaction solution was then cooled and purified directly by preparative HPLC (mobile phase: acetonitrile/water 9:1). This gave 75 mg (0.10 mmol, 29% of theory) of the title compound.
Reaction SMILES: [C:1](=[O:20])([O:8][C:9]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=1[F:19])[O:2][CH2:3][CH2:4][CH2:5][CH2:6]Cl.[Na+].[I-:22]>CC#N>[C:1](=[O:20])([O:8][C:9]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=1[F:19])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][I:22]
Reactant: [I-]
Reactant: O=C(OCCCCCl)Oc1c(F)c(F)c(F)c(F)c1F
Agent: [Na+]
Solvent: CC#N
Product: O=C(OCCCCI)Oc1c(F)c(F)c(F)c(F)c1F
Yield: 89.7 %

Procedure:
A mixture of 4-chlorobutyl pentafluorophenyl carbonate (1.69 g, 5.3 mmol) and NaI (7.99 g, 53.3 mmol) in CH3CN (20 ml) was refluxed under nitrogen for 960 minutes. Then the solvent was evaporated and the residue taken up with CH2Cl2 and washed with water (2×50 ml). The organic phase was then dried and evaporated yielding 4-iodobutyl pentafluorophenyl carbonate (1.95 g, 90%) as a yellow oil that was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][N:15]=1)[CH2:6][C:7](=O)[CH2:8][C:9](=O)C)#[N:2].Cl.[CH3:17][C:18]1[CH:19]=[C:20]([NH:24][NH2:25])[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[N:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([CH3:17])[CH:19]=3)[N:25]=[C:8]([CH3:9])[CH:7]=2)[CH:13]=[CH:14][N:15]=1)#[N:2]
Reactant: Cc1cccc(NN)c1
Reactant: CC(=O)CC(=O)Cc1ccnc(C#N)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cccc(-n2nc(C)cc2-c2ccnc(C#N)c2)c1
Yield: 81.7 %

Procedure:
To a mixture of 1-(2-cyanoisonicotinyl)-1,3-butanedione (1.10 g, 0.0058 mol) and 3-methylphenylhydrazine hydrochloride (0.97 g, 0.0061 mol) in 20 mL of ethanol was added triethylamine (0.85 mL, 0.0061 mol) dropwise. The reaction mixture was heated at reflux overnight (about eighteen hours). The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was purified by chromatography on silica gel (ethyl acetate/hexane, 2:8) to give 1.30 g (87% yield) of product as a yellow solid: mp: 128-130° C.; Anal. Calc'd. for C17H14N4: C, 74.43; H, 5.14; N, 20.42. Found: C, 74.53; H, 5.22; N, 20.29.
Reaction SMILES: [Mg].[C:2]1([CH3:18])[CH:7]=[C:6](C)[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10](OCC=C(C)C)=O>C(OCC)C>[CH3:7][C:2]([CH3:18])=[CH:3][CH2:4][CH2:5][C:4]1([CH3:9])[C:3]2([CH3:10])[CH:2]3[CH2:18][CH:5]1[CH2:6][CH:7]23
Reactant: CC(C)=CCOC(=O)c1c(C)cc(C)cc1C
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)=CCCC1(C)C2CC3C(C2)C31C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
10 grams (0.046 moles) of π-bromotricyclene having the structure: ##STR61## prepared according to the process of Corey et al., J. Am. Chem. Soc. 79, 5773 (1957) in 500 ml of absolute diethyl ether is added to 70 g (2.9 moles) of magnesium in 100 ml of ether during 7 hours. The mixture is heated at reflux for an additional 1.5 hours. The Grignard reagent is filtered through a glass-wood plug into γ,γ -dimethylallyl mesitoate (12.8 g., 0.055 mole, b.p. 95°-100° (0.1 mm.)) in 50 ml of ether. The time required for the addition was 2 hours. The excess magnesium is rinsed with 100 ml of ether and the washing is also added to the ester. The mixture is allowed to stand at room temperature for 96 hours. At the end of this time, a fine white percipitate appears in considerable quantity. To the ether solution is added with stirring a saturated ammonium chloride solution, and stirring is continued until both aqueous and ether layers are clear. The ether solution is washed with 10% sodium hydroxide, water and dried over sodium sulfate. The crude oil (12 g) after evaporation of ether is dissolved in pentane and chromatographed on alumina. The product is eluted with pentane and distilled to give two fractions: no. 1, 1.29 g., b.p. 56°-130° (15-20 mm.), N25D 1.4496; no. 2 2.81 g, b.p. 130°-140° (15-20 mm), n25D 1.4820. The residue from the distillation which solidified is largely bi-π-tricyclyl. Fraction 2 is redistilled, dissolved in pentane and chromatographed on alumina. The eluate is distilled and yields 1.7 g of oil, b.p. 116°-120° (8 ± 2 mm.), n25D 1.4822; infrared absorption at 1670, 858 and 840 cm,- 1 ; alpha26D + 18.4° , +17.2° (pure liquid).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[N:20]=[N:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][C:26]1([NH2:30])[CH2:29][O:28][CH2:27]1>>[CH3:25][C:26]1([NH:30][C:21]([C:18]2[N:19]=[N:20][C:15]([O:14][CH2:13][C:12]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[N:10][C:11]=3[CH3:24])=[CH:16][CH:17]=2)=[O:23])[CH2:29][O:28][CH2:27]1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)nn1
Reactant: CC1(N)COC1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC2(C)COC2)nn1
Yield: 94 %

Procedure:
As described for example 75b, 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (85 mg, 0.26 mmol), was converted, using 3-methyl-3-oxetanamine instead of isopropylamine, to the title compound (96 mg, 94%) which was obtained as a light yellow solid. MS: m/e=399.2 [M+H]+.
Reaction SMILES: O.[CH2:2](I)I.[CH3:5][C:6]1[CH2:11][CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[C:7]=1[CH2:14][OH:15]>CC(O)=O.[Zn]>[CH3:13][C:8]1([CH3:12])[CH2:9][CH2:10][CH2:11][C:6]2([CH3:2])[C:7]1([CH2:14][OH:15])[CH2:5]2
Reactant: ICI
Reactant: CC1=C(CO)C(C)(C)CCC1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)CCCC2(C)CC12CO
Temperature: -5 °C
Reaction time: 0.05 h

Procedure:
A solution of 0.4 g of Cu(OAc2).H2O in 20 mL of hot HOAc was treated with 8.8 g (0.13 g-atom) of Zn dust with shaking for 3 min, and the acid was decanted. The Zn-Cu couple was washed by decantation with 30 mL of 1:1 HOAc/Et2O, followed by Et2O (6×30 mL). Next, 20 mL of Et2O was added together with a crystal of I2. A mixture of 18.8 g (70 mmol) of CH2I2 and 3.08 g (20 mmol) of β-cyclogeraniol (l) was added dropwise over a 20-min period, with warming to maintain a gentle reflux. Heating at reflux was continued for an additional 2 h. The cooled solution was decanted, the residue was washed with Et2O, and the total Et2O volume was brought to 200 mL. The solution was cooled in ice/H2O, and pyridine (8 to 9 mL) was added dropwise until no further ZnI2 -pyridine complex separated. The reaction was cooled to -5° C. overnight, filtered twice, and evaporated. Further complex separated on evaporation. TLC (9:1 hexane/EtOAc) demonstrated a single product. The crude oil was eluted through a 3×25 cm silica gel column by 9:1 hexane/Et2O, followed by 1:1 hexane/Et2O. The spectrally pure, colorless oil weighed 3.4 g (quant): IR (film) 3400 (OH), 1460, 1385, 1365, 1155, 1035, 1010, 705 cm-1 ; 1H NMR (CDCl3) δ0.22 (d, J=4.5 Hz, 1, cyclopropyl H), 0.49 (d, J=4.5 Hz, 1, cyclopropyl H), 0.99 (s, 3, CH3), 1.21 (s, 3, CH3), 1.26 (s, 3, CH3), 1.0-1.8 [m, 7, (CH2)3, OH], 3.51 and 3.92 (d, J=12 Hz, 1, and dd, J=12 and 3.5 Hz, 1, CH2O); 13C NMR (CDCl3), 65.8, 38.0, 35.5, 31.9, 31.3, 29.2, 27.4, 23.9, 22.5, 21.7, 18.0 ppm; MS calcd for C11H20O 168.1514, found 168.1521.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[H-].[Na+].[CH:14](OCC)=[O:15]>C(O)C.O1CCCC1>[OH:15][CH:14]=[C:8]1[C:7](=[O:10])[CH2:6][CH2:5][C:4]2([O:3][CH2:2][CH2:1][O:11]2)[CH2:9]1
Reactant: CCOC=O
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C1CCC2(CC1=CO)OCCO2

Procedure:
1,4-Cyclohexanedione monoethylene ketal (5.00 g) was added to a mixture of sodium hydride (1.40 g of a 60% suspension in mineral oil), 10 ml of ethyl formate, 1 drop of ethanol and 200 ml of tetrahydrofuran. The reaction mixture was heated at reflux for 2.5 hours, cooled and partitioned between water and ethyl ether. The ethereal layer was extracted several times with 0.5N sodium hydroxide and the combined aqueous portions were washed once with ether. The aqueous solution was acidified slowly to a pH of 4 with 5N hydrochloric acid and the slurry was exhaustively extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and concentrated in vacuo to provide a dark oil. The oil was distilled bulb-to-bulb (120° C./lmm) to afford 7-(hydroxymethylene)-1,4-dioxaspiro-[4.5]decan-8-one as a colorless oil.
Reaction SMILES: [C:1]12([N:6]3[CH:29]=[C:28]4[C:8]([C:9](=[O:30])[CH2:10][C:11]5([CH2:27]4)[CH2:16][CH2:15][N:14](C(OCC4C=CC=CC=4)=O)[CH2:13][CH2:12]5)=[N:7]3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.CC1CC=CCC=1>C(OCC)(=O)C.[Pd]>[C:1]12([N:6]3[CH:29]=[C:28]4[C:8]([C:9](=[O:30])[CH2:10][C:11]5([CH2:27]4)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]5)=[N:7]3)[CH2:2][CH:3]([CH2:5]1)[CH2:4]2
Reactant: O=C1CC2(CCN(C(=O)OCc3ccccc3)CC2)Cc2cn(C34CC(C3)C4)nc21
Agent: [Pd]
Agent: CC1=CCC=CC1
Solvent: CCOC(C)=O
Product: O=C1CC2(CCNCC2)Cc2cn(C34CC(C3)C4)nc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of benzyl 2-(bicyclo[1.1.1]pentan-1-yl)-7-oxo-2,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carboxylate (150 mg, 0.37 mmol) in ethyl acetate (10 mL) was added 10% palladium on carbon (1 mg) and 1-methylcyclohexane-1,4-diene (0.1 mL, 0.9 mmol). The reaction was heated to 80° C. and stirred for 2 hours. The reaction was cooled to room temperature and filtered through Celite. The filtrate was concentrated to give the title compound (100 mg, 100%) as an oil. +ESI (M+H) 272.4; 1H NMR (400 MHz, CDCl3, δ): 7.26 (s, 1 H), 2.82 (dd, J=6.63, 4.49 Hz, 4 H), 2.69 (s, 2 H), 2.60 (s, 1 H), 2.56 (s, 2 H), 2.30 (s, 6 H), 1.47-1.55 (m, 4 H).