Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][CH:3]=1.[ClH:16].[N:17](OCCC(C)C)=[O:18]>O1CCCC1>[ClH:16].[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[N:17]=[O:18]
Reactant: CC(C)CCON=O
Reactant: CC(C)c1ccc(-n2nccc2N)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)c1ccc(-n2ncc(N=O)c2N)cc1
Temperature: 2.5 °C

Procedure:
14.9 g (74 mmol) of 5-amino-1-(4-isopropylphenyl)pyrazole [sic] from Step 2.1 was dissolved in 130 mL of tetrahydrofuran. 42.2 g of 32% hydrochloric acid was added, and the reaction mixture was cooled to 0 to 5° C. Then, 9.5 g (81 mmol) of isopentyl nitrite was added dropwise with agitation so that the temperature did not exceed 5° C. Gradually, a yellowish precipitate formed which after an additional 1.5-hour agitation period in an ice bath was removed by suction filtration and washed with a small amount of tetrahydrofuran. Drying gave 12.3 g (46.1 mmol, 62% of the theoretical) of 5-amino-1-(4-isopropylphenyl)4-nitroso-1H-pyrazole hydrochloride.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:22]=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:24]=1[OH:25])[C:8]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1)=[O:9])([CH3:4])[CH3:3].CC(C1C=C(C=C(C(C)(C)C)C=1O)C(NCC1C=CC([N+]([O-])=O)=CC=1)=O)(C)C>>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:22]=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:24]=1[OH:25])[C:8]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)=[O:9])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(C(=O)NCCc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Agent: CC(C)(C)c1cc(C(=O)NCc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(C(=O)NCCc2ccc(N)cc2)cc(C(C)(C)C)c1O
Yield: 76 %

Procedure:
The experimental protocol used is the same as that described for intermediate 2.2, 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide replacing the 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide. A white powder is obtained with a yield of 76%. Melting point: 193-195° C.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].[Br:13][C:14]1[CH:18]=[C:17]([C:19]2[O:24][C:23](=[O:25])[C:22]3[CH:26]=[C:27]([Cl:31])[CH:28]=[C:29]([CH3:30])[C:21]=3[N:20]=2)[N:16]([C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][N:33]=2)[N:15]=1>O.O1CCCC1>[Br:13][C:14]1[CH:18]=[C:17]([C:19]([NH:20][C:21]2[C:29]([CH3:30])=[CH:28][C:27]([Cl:31])=[CH:26][C:22]=2[C:23]([N:4]([CH3:3])[NH:5][CH3:6])=[O:25])=[O:24])[N:16]([C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][N:33]=2)[N:15]=1
Reactant: CNNC
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CNN(C)C(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 134.3 %

Procedure:
To a mixture of 0.13 g of N,N′-dimethylhydrazine dihydrochloride, 1 ml of water, 0.14 g of potassium carbonate and 10 ml of tetrahydrofuran was added 0.23 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-one, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 30 ml of water, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with ethyl acetate to obtain 0.35 g of 3-bromo-N-[4-chloro-2-(N,N′-dimethylhydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:10][C:11]1[CH:12]=[C:13]([CH:47]=[CH:48][CH:49]=1)[C:14]([NH:16][C:17]1[S:18][C:19]2[CH2:46][CH2:45][CH2:44][CH2:43][C:20]=2[C:21]=1[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[CH:27][CH:26]=1)=[O:23])=[O:15])[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7].S(Cl)(Cl)=O.[NH:54]1[CH2:64][CH2:63][CH:57]([C:58]([O:60][CH2:61][CH3:62])=[O:59])[CH2:56][CH2:55]1>>[CH3:40][O:39][C:37]([C:36]1[CH:41]=[CH:42][C:33]([CH2:32][CH2:31][C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:22]([C:21]3[C:20]4[CH2:43][CH2:44][CH2:45][CH2:46][C:19]=4[S:18][C:17]=3[NH:16][C:14]([C:13]3[CH:12]=[C:11]([CH:49]=[CH:48][CH:47]=3)[CH2:10][N:4]([CH:5]([CH2:6][CH3:7])[CH2:8][CH3:9])[CH2:3][CH2:2][N:54]3[CH2:55][CH2:56][CH:57]([C:58]([O:60][CH2:61][CH3:62])=[O:59])[CH2:63][CH2:64]3)=[O:15])=[O:23])=[CH:30][CH:29]=2)=[CH:34][CH:35]=1)=[O:38]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCC(CC)N(CCO)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CCN(CCN(Cc2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(CCc5ccc(C(=O)OC)cc5)cc3)CCCC4)c2)C(CC)CC)CC1
Yield: 86.8 %

Procedure:
By a method similar to Preparation Example 37, 197 mg of methyl 4-(2-{4-[({2-[(3-{[(2-hydroxyethyl)(pentan-3-yl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate was reacted with 0.10 mL of thionyl chloride, and then the resultant was reacted with 325 mg of ethyl isonipecotate, thereby obtaining 206 mg of ethyl 1-(2-{[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)benzyl](pentan-3-yl)amino}ethyl)piperidine-4-carboxylate.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH:22][C:23](=[O:35])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:14]1([C:12]2[C:11]([C:18]([F:19])([F:21])[F:20])=[CH:10][C:9]3[NH:22][C:23](=[O:35])[CH2:24][C:25]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(C2=Nc3cc(N4CCC4)c(C(F)(F)F)cc3NC(=O)C2)ccn1

Procedure:
The title compound was prepared from {5-azetidin-1-yl-2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M52) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an orange solid (51 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([Br:1])=[C:3]([CH3:12])[CH:4]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C(=O)NN)ccc1Br
Product: CC(=O)NNC(=O)c1ccc(Br)c(C)c1
Temperature: 25 °C

Procedure:
4-Bromo-3-methylbenzoic hydrazide (D30, 7.5 g) was suspended in acetic anhydride (7 ml) giving rise to an exothermic reaction. The reaction mixture was cooled to room temperature and the product collected. The solid was washed with ethanol and diethyl ether to afford the title compound as a white powder (5.5 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[C:10]([OH:17])(CC=C)[CH2:11][CH:12]=[CH2:13].CC(C)([O-])C.[K+]>CN(C=O)C>[CH3:13]/[CH:12]=[CH:11]/[C:10]([C:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:17]
Reactant: C=CCC(O)(CC=C)C1=C(C)C=CCC1(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C=C/C(=O)C1=C(C)C=CCC1(C)C
Yield: 80 %

Procedure:
11.6 g (0.05M) of 2,6,6-trimethyl-1-[4-hydroxy-hepta-1,6-dien-4-yl]-cyclohexa-1,3-diene were treated as indicated in the preceding example with 8.6 g (0.075M) of potassium tert-butoxide in 50 ml of DMF. β-Damascenone was obtained in 80% yield (7.1 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]3)=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 7-(1-tert-butoxycarbonyl-4-ethoxycarbonylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (165 mg) in chloroform (1.5 ml) was added dropwise trifluoroacetic acid (0.5 ml), and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated and aqueous sodium hydrogencarbonate solution was added to the obtained residue. The mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dried under reduced pressure to give the title compound (135 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)[CH:12]=[CH:11][C:10]=1[C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:25][C:24]=2[CH:34]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:46][CH2:47][O:48][CH3:49])(=O)=O.CCOC(C)=O.O>CN(C=O)C>[F:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)[CH:12]=[CH:11][C:10]=1[C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH:28]3[CH2:29][CH2:30][N:31]([CH2:46][CH2:47][O:48][CH3:49])[CH2:32][CH2:33]3)=[N:25][C:24]=2[CH:34]=1
Reactant: Fc1cc(-n2cnnn2)ccc1-c1ccc2oc(C3CCNCC3)nc2c1
Reactant: COCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCCN1CCC(c2nc3cc(-c4ccc(-n5cnnn5)cc4F)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 355.1 %

Procedure:
5-[2-fluoro-4-(1H-tetrazol-1-yl)-phenyl]-2-(piperidin-4-yl)-benzo[d]oxazole 2,2,2-trifluoroacetate (30 mg, 0.06 mmol) was dissolved in DMF (2 ml) and added K2CO3 (40 mg, 0.29 mmol) and stirred the mixture at rt for 15 mins. To this mixture added 2-methoxyethyl methanesulfonate (45 mg, 0.29 mmol) and stirred at rt for 17 h. Work up (EtOAc/H2O) followed by purification by column chromatography on 60-120 mesh silicagel using a gradient mixture of DCM and MeOH (98:2) as eluent afforded the titled compound (90 mg) as a brown solid (15 mg). M.P.: 148-152° C. MS (m/z): 423.3 [M+H]+.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH2:12]([CH:14]1[NH:18][C:17](=[O:19])[C:16]([CH3:21])([CH3:20])[C:15]1=[O:22])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:12]([CH:14]1[N:18]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=2)[C:17](=[O:19])[C:16]([CH3:21])([CH3:20])[C:15]1=[O:22])[CH3:13]
Reactant: COc1cc(I)ccc1C#N
Reactant: CCC1NC(=O)C(C)(C)C1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(OC)c1

Procedure:
Using 4-iodo-2-methoxybenzonitrile (459 mg), 5-ethyl-3,3-dimethylpyrrolidine-2,4-dione (250 mg), cesium carbonate (787 mg), tris(dibenzylideneacetone)dipalladium(0) (148 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (186 mg), and in the same manner as in Reference Example 3, the title compound was obtained as a colorless solid (yield: 300 mg, 65%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[O:12]=[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=2)[CH:16]=[CH:15][NH:14]1>>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][N:14]2[CH:15]=[CH:16][C:17]3[C:22](=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=3)[C:13]2=[O:12])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2cc[nH]c(=O)c2c1
Reactant: Clc1ccc(CCCBr)cc1
Product: COC(=O)c1ccc2ccn(CCCc3ccc(Cl)cc3)c(=O)c2c1

Procedure:
The title compound was prepared from 1-(3-bromopropyl)-4-chlorobenzene (0.35 g, 1.48 mmol) and methyl 1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.20 g, 0.98 mmol) following the procedure outlined in Example 3, step 1 (0.16 g, 44%). LC-MS: (FA) ES+ 356.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][C:4](=[O:11])/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8].C1(C)C=CC(S([CH2:22][N+:23]#[C-:24])(=O)=O)=CC=1.[H-].[Na+].[Cl-].[NH4+]>C(OCC)C.CS(C)=O>[CH3:1][CH:2]([CH3:12])[CH2:3][C:4]([C:5]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:22][NH:23][CH:24]=1)=[O:11]
Reactant: COC(=O)/C=C/C(=O)CC(C)C
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: COC(=O)c1c[nH]cc1C(=O)CC(C)C
Yield: 26.8 %

Procedure:
A solution of (E)-methyl 6-methyl-4-oxo-2-heptenoate (10 g) prepared as described in a) above and (para-toluenesulfonyl)methyl isocyanide (11.5 g) in a mixture of dry dimethyl sulfoxide (30 ml) and diethyl ether (30 ml) was added over one hour to sodium hydride (2.75 g of a 60% oil dispersion, 0.068 mol) stirred in dry diethyl ether (90 ml) under nitrogen. After a further hour saturated ammonium chloride solution was added and the mixture was extracted with ethyl acetate, which was washed well with water, dried, and evaporated to a gum. The gum was chromatographed with ethyl acetate-isohexane (2:3) to afford a solid (3.3 g) which was crystallised from ethyl acetate-cyclohexane to give the sub-title ester.
Reaction SMILES: CS(O[CH2:6][C:7]1([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25][CH2:24][C:9]2([O:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:10]2)[CH2:8]1)(=O)=O.[N-:36]=[N+:37]=[N-:38].[Na+].CCOCC>CS(C)=O.CCOC(C)=O>[N:36]([CH2:6][C:7]1([CH2:27][O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25][CH2:24][C:9]2([O:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:10]2)[CH2:8]1)=[N+:37]=[N-:38]
Reactant: COc1ccc(CN2CC3(CCCC(COCc4ccccc4)(COS(C)(=O)=O)C3)OC2=O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COc1ccc(CN2CC3(CCCC(CN=[N+]=[N-])(COCc4ccccc4)C3)OC2=O)cc1
Temperature: 120 °C
Yield: 93.9 %

Procedure:
To a light orange solution of (7-((benzyloxy)methyl)-3-(4-methoxybenzyl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl methanesulfonate (5.71 g, 11.3 mmol) in DMSO (45.4 mL) was added sodium azide (2.21 g, 34.0 mmol). The reaction was heated at 120° C. behind a blast shield. After 4 days the reaction was cooled to RT and diluted with 1:1 EtOAc:Et2O (150 mL). This mixture was washed with water (3×100 mL), and the resulting organic layer was dried over magnesium sulphate, filtered, and concentrated to provide 7-(azidomethyl)-3-{[4-(methyloxy)phenyl]methyl}-7-{[(phenylmethyl)oxy]methyl}-1-oxa-3-azaspiro[4.5]decan-2-one (4.78 g, 89% crude yield) which was used without further purification. MS (m/z) 451.0 (M+H+).
Reaction SMILES: C(C1C=CC(C(Cl)=O)=CC=1)CCC.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([F:36])[CH:30]=1.[CH2:37]([C:41]1[CH:46]=[CH:45][C:44]([C:47]([N:49]=[C:50]=[S:51])=[O:48])=[CH:43][CH:42]=1)[CH2:38][CH2:39][CH3:40]>C1(C)C=CC=CC=1.C(O)C>[CH2:37]([C:41]1[CH:46]=[CH:45][C:44]([C:47]([N:49]=[C:50]=[S:51])=[O:48])=[CH:43][CH:42]=1)[CH2:38][CH2:39][CH3:40].[CH2:37]([C:41]1[CH:46]=[CH:45][C:44]([C:47]([NH:49][C:50]([NH:33][C:32]2[CH:34]=[CH:35][C:29]([O:28][C:19]3[C:18]4[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=4)[N:22]=[CH:21][CH:20]=3)=[CH:30][C:31]=2[F:36])=[S:51])=[O:48])=[CH:43][CH:42]=1)[CH2:38][CH2:39][CH3:40]
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: CCCCc1ccc(C(=O)Cl)cc1
Agent: CCCCc1ccc(C(=O)N=C=S)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
4-Butyl-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-butyl-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-butyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (68 mg, yield 80%).
Reaction SMILES: [Na].[CH:2]1([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15]([F:17])[CH:16]=[C:11]3[C:10]([C:18]#[N:19])=[N:9]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:20]([OH:23])(=[O:22])[CH3:21].[Cl-].[NH4+:25]>CO>[C:20]([OH:23])(=[O:22])[CH3:21].[CH:2]1([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15]([F:17])[CH:16]=[C:11]3[C:10]([C:18](=[NH:25])[NH2:19])=[N:9]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [NH4+]
Reactant: N#Cc1nn(CC2CCCC2)c2ncc(F)cc12
Agent: [Cl-]
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: N=C(N)c1nn(CC2CCCC2)c2ncc(F)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon, 296 mg (12.861 mmol) of sodium were, a little at a time, stirred into methanol. After the sodium had been consumed, 3.670 g (purity 86%, about 12.861 mmol) of 1-(cyclopentylmethyl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile were added a little at a time, and the mixture was stirred at RT for 2 h. 3.004 g (50.021 mmol) of acetic acid and 825 mg (15.433 mmol) of ammonium chloride were then added, and the mixture was boiled under reflux overnight. The reaction mixture was concentrated, the residue was triturated with 1N sodium hydroxide solution and the precipitate was filtered off with suction and dried under high vacuum. This gave 2.840 g (purity 98%, 83% of theory) of the target compound.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:19]3[C@:18]4([CH3:23])[C:20]([CH3:22])([CH3:21])[C@@H:15]([CH2:16][CH2:17]4)[C:14]=3[C:13](=[O:24])[N:12]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[CH:6][CH:5]=1.[BH4-].[Na+].[Cl-].[NH4+].O.[Cl-].[Na+].O>O1CCCC1.ClCCl.CO>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[N:12]1[C:13](=[O:24])[C:14]2[C@H:15]3[C:20]([CH3:22])([CH3:21])[C@:18]([CH3:23])([CH2:17][CH2:16]3)[C:19]=2[N:11]1[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(Cn2c3c(c(=O)n2-c2ccc(F)cc2F)[C@@H]2CC[C@@]3(C)C2(C)C)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1ccc(CO)cc1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 42.6 %

Procedure:
A mixture of 4-[(4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-3-oxo-2,3,4,5,6,7-hexahydro-4,7-methano-indazol-1-ylmethyl]-benzoic acid methyl ester (Example 104; 189 mg, 0.42 mmol) and pulverized sodium borohydride (102 mg, 2.7 mmol) in tetrahydrofuran (2 mL) was heated at 65° C. for 15 min. Methanol (2 mL) was added dropwise over a period of 2 min and gas evolution was noted. The mixture was heated at 65° C. for 1 h, and then an additional portion of methanol (1 mL) was added. The mixture was heated at 65° C. for 1 h, and then an additional portion of sodium borohydride (ca. 50 mg) was added. The mixture was heated at 65° C. for 1 h, and then an additional portion of sodium borohydride (ca. 50 mg) was added. The mixture was heated at 65° C. for 1 h, and then it was cooled to room temperature. Saturated aqueous ammonium chloride (6 mL) and dichloromethane (30 mL) were added. The mixture was stirred at room temperature for 10 min. 1:1 Water/brine (20 mL) was added and the mixture was extracted with dichloromethane (3×30 mL). The combined organic extracts were dried (magnesium sulfate), filtered, and evaporated. The residue was purified using an ISCO 12 g column, eluting with 75-100% ethyl acetate/hexanes. Fractions containing the product were concentrated, co-evaporated with ether and petroleum ether, and then dried under high vacuum at 50° C. overnight give (4R,7S)-2-(2,4-difluoro-phenyl)-1-(4-hydroxymethyl-benzyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (76 mg, 43%) as a white solid. ES(+)-MS (M+H) 425.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][C@@H:28]([CH3:41])[CH2:29][N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]1=[O:40])(C(C)(C)C)(C)C>C1COCC1>[OH:26][CH2:27][C@@H:28]([CH3:41])[CH2:29][N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]1=[O:40]
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)Cn1c(=O)ccc2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](CO)Cn1c(=O)ccc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
TBAF (1.2 g, 4.6 mmol) and (s)-1-[3-(tert-butyldimethylsilanyloxy)-2-methylpropyl]-1H-quinolin-2-one (0.31 g, 0.93 mmol) were dissolved in THF (5 mL) and stirred under an Argon atmosphere at rt overnight. The mixture was concentrated under reduced pressure and dissolved in EtOAc (30 mL). The solution was washed with water (15 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue thereof was filtered through silica to give the crude title compound (0.19 g), which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[C:23](=[O:25])=[O:24]>O1CCCC1>[CH:9]1([O:8][C:5]2[CH:6]=[CH:7][C:2]([C:23]([OH:25])=[O:24])=[CH:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: O=C=O
Reactant: Brc1ccc(OC2CC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1ccc(OC2CC2)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 46.7 %

Procedure:
To a −78° C. solution of 1-bromo-4-(cyclopropoxy)benzene (33 g, 154.9 mmol) in tetrahydrofuran (500 mL) add 1.6 M butyl lithium in hexane (96.8 mL, 154.9 mmol) while maintaining a temperature below −70° C. Stir the mixture at −78° C. for 20 minutes after the addition. Add dry ice (464.6 mmol) in 3 portions 5 minutes apart. Stir the mixture at −78° C. for 30 minutes. Remove the cooling bath and quench the mixture with 10% sodium hydrogen sulfate (NaHSO4) (200 mL). Warm the mixture to ambient temperature and extract 3× with EtOAc (300 mL). Combine the organics and wash once with brine, dry over sodium sulfate, filter, and concentrate under reduced pressure. Suspend the residue in diethyl ether and filter. Dry the solid in a vacuum oven to give the title compound (12.9 g, 47%): MS (m/z): 179 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[CH2:5][N:6]([CH3:8])[CH3:7])[CH3:2].Br[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1>>[CH3:7][N:6]([CH2:5][CH:4]1[CH2:14][CH:15]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:16]2[C:1](=[CH:2][CH:13]=[CH:12][CH:11]=2)[O:3]1)[CH3:8]
Reactant: Cc1ccc(Br)cc1
Reactant: CCOC(=O)CN(C)C
Product: Cc1ccc(C2CC(CN(C)C)Oc3ccccc32)cc1

Procedure:
The process of example 4 was repeated using N,N-dimethylglycine ethyl ester in place of the N,N-dimethylalanine ethyl ester in part (a), and using 4-bromotoluene in place of the 4-bromochlorobenzene in part (c) to yield the title compound, m.p. 114°-116° C.
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:11]=[C:10](F)[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].Cl>C1COCC1>[F:2][C:3]1[CH:11]=[C:10]([NH2:1])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: N
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1F
Agent: Cl
Solvent: C1CCOC1
Product: Nc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Aq ammonia (6.0 mL, 32% in water) is added to a mixture of 2,4-difluoro-5-nitro-benzoic acid (6.0 g, 30 mmol) in THF (80 mL) and it is stirred over the weekend at rt. The mixture is acidified with 6N aq HCl-solution and the precipitate is filtered, washed with water and dried at 55° C. and directly used in the next step.