Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[N:7][C:8](Cl)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][O:20][C:21]2[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=2)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>O.ClCCl>[CH2:1]([C:5]1[N:6]=[N:7][C:8]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=3)[CH2:16][CH2:17]2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(Cl)nn1
Reactant: CCOC(=O)c1ccc(OCCC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCc1ccc(N2CCC(CCOc3ccc(C(=O)OCC)cc3)CC2)nn1
Temperature: 140 °C
Reaction time: 4 h
Yield: 20.8 %

Procedure:
A mixture of 2.4 parts of 3-butyl-6-chloropyridazine, 4.2 parts of ethyl 4-[2-(4-piperidinyl)ethoxy]benzoate and 2.1 parts of sodium carbonate was stirred for 4 hours at 140° C. After cooling, the reaction mixture was taken up in water and dichloromethane. The separated organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off, washed with 2,2'-oxybispropane and dried at 50° C., yielding 1.2 parts (20.8%) of ethyl 4-[2-[1-(6-butyl-3-pyridazinyl)-4-piperidinyl]ethoxy]benzoate; mp. 91.4° C. (comp. 84).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][C:4]=1[C:18]1[N:23]=[N:22][C:21]([N:24]([CH3:35])[CH:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)=[CH:20][CH:19]=1.Br[C:37]1[N:38]=[CH:39][N:40]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:41]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CCO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:37]2[N:38]=[CH:39][N:40]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:41]=2)[CH:6]=[CH:5][C:4]=1[C:18]1[N:23]=[N:22][C:21]([N:24]([CH3:35])[CH:25]2[CH2:30][C:29]([CH3:31])([CH3:32])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)=[CH:20][CH:19]=1
Reactant: C[Si](C)(C)CCOCn1cnc(Br)c1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: COc1cc(-c2cn(COCC[Si](C)(C)C)cn2)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 150 °C
Yield: 90.8 %

Procedure:
To a microwave vial was added 6-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (Intermediate 9-3, 50 mg, 0.10 mmol), 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (57.7 mg, 0.21 mmol), Na2CO3 (22 mg, 0.21 mmol), and Pd(PPh3)2Cl2 (7.3 mg, 0.01 mmol), followed by DME (1 mL)/EtOH 0.25 mL)/(H2O (0.25 mL). The vial was purged with N2 for 10 minutes and the reaction mixture was heated at 150° C. in a microwave reactor for 20 minutes. The reaction mixture was filtered through celite and the filter cake was washed with EtOAc. The filtrate was concentrated in vacuo to give the crude product which was purified by silica gel chromotography (5%-15% MeOH/DCM) to afford 6-(2-methoxy-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (50 mg). MS: 551.6 [M+H+]).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[C:22]([C:27](O)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:59][N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1>CN(C=O)C.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([N:63]2[CH2:64][CH2:65][N:60]([CH3:59])[CH2:61][CH2:62]2)=[O:28])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[C:10]1=[O:20]
Reactant: O=C(O)c1ccccc1-c1ccc(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(C(=O)c2ccccc2-c2ccc(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.4 %

Procedure:
Charge a vial with 3′-chloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-2-carboxylic acid (example 6) (70 mg, 0.17 mmol), EDCl (65 mg, 0.34 mmol) and HOBt (23 mg, 0.17 mmol). Dissolve in DMF (0.1 M) and add triethylamine (95 μL, 0.68 mmol) and N-methyl piperazine (34 mg, 0.34 mmol). Stir at room temperature overnight. Pour into water and extract with ether. Dry over sodium sulfate, filter and concentrate. Purify over silica gel. Dissolve the residue in methylene chloride and acidify with 4N HCl in dioxane. Concentrate in vacuo which affords 57 mg (63%) of the title compound: Mass spectrum (apci) m/z=494.3 (M+H-HCl).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[C:10]([O-:13])([O-])=[O:11].[Na+].[Na+].C[N:17]([CH3:21])[C:18](=O)[CH3:19]>O.C(Cl)Cl.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>[CH3:21][N:17]1[C:18]2[CH:3]=[C:2]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][C:7]=3[CH:8]=[O:9])[CH:7]=[CH:6][C:19]=2[O:13][C:10]1=[O:11]
Reactant: CC(=O)N(C)C
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cn1c(=O)oc2ccc(-c3cnccc3C=O)cc21
Temperature: 100 °C

Procedure:
A mixture of 3-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-0)-3H-benzooxazol-2-one (330 mg, 1.2 mmol), 3-Bromo-pyridine-4-carbaldehyde (186 mg, 1 mmol), polymer bound Pd(PPh3)4 (642 mg, 0.07 mmol), Na2CO3 (2 M in water, 1 mL, 2 mmol) in N,N-Dimethylacetamide (9 mL) and water (1 mL) was heated to 100° C. by microwave for 1 h. The reaction mixture was cooled to room temperature. The suspension was diluted with CH2Cl2 (15 mL) and filtered through a pad of celite. The filtrate was concentrated in vacuo to reddish brown solid. This crude material was purified by flash column (0-10% CH3OH in CH2Cl2, v/v) and afforded 152 mg of the desired product. ESI-MS m/z: 255.0 [M+1]+, Retention time 1.03 min; 1HNMR (DMSO, 400.342 MHz): δ 3.39 (s, 3H), 7.27 (dd, J=8.2, 1.8 Hz, 1H), 7.50 (d, J=8.2 Hz, 1H), 7.57 (d, J=1.8 Hz, 1H), 8.85 (m, 2H), 10.0 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH2:14][OH:15])=[CH:11][S:12][CH:13]=2)=[CH:5][CH:4]=1)[CH3:2].C(C1C=CC(C2C=C(C(F)(F)F)SC=2CO[C:35]2[C:40]([F:41])=[CH:39][C:38]([CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])=[CH:37][C:36]=2[F:49])=CC=1)C>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]([CH2:14][O:15][C:35]3[C:36]([F:49])=[CH:37][C:38]([CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[CH:39][C:40]=3[F:41])=[CH:11][S:12][CH:13]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cc(F)c(OCc2sc(C(F)(F)F)cc2-c2ccc(CC)cc2)c(F)c1
Reactant: CCc1ccc(-c2cscc2CO)cc1
Product: CCc1ccc(-c2cscc2COc2c(F)cc(CCC(=O)O)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 217 by coupling of (4-(4-ethylphenyl)thiophen-3-yl)methanol and ethyl 3-(4-hydroxy-3,5-difluoro phenyl) propanoate followed by hydrolysis of ethyl 3-(4-((3-(4-ethylphenyl)-5-(trifluoromethyl)thiophen-2-yl)methoxy)-3,5-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.48 (m, 3H), 7.25 (d, J=7.0 Hz, 2H), 6.72 (d, J=6.5 Hz, 2H), 5.08 (s, 2H), 2.88 (t, J=5.5 Hz, 2H), 2.70 (m, 4H), 1.30 (t, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[C:15](OC)=[O:16])[C:11]([CH:19]([CH3:21])[CH3:20])=[N:10][C:9]=2[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[CH2:15][OH:16])[C:11]([CH:19]([CH3:21])[CH3:20])=[N:10][C:9]=2[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)/C=C/n1c(C(C)C)nc(-c2ccncc2)c1-c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)c1nc(-c2ccncc2)c(-c2ccc(F)cc2)n1/C=C/CO
Reaction time: 1 h

Procedure:
A stirred suspension in toluene of methyl (E)-3-[5-(4-fluorophenyl)-2-(1-methylethyl)-4-(4-pyridinyl)-1H-imidazol-1-yl]-2-propenoate, 1'-oxide, (0.22 g), at -78° under nitrogen was treated with diisobutylaluminium hydride (1.5M in toluene; 0.8 ml). The mixture was stirred at -40° for 1 h and then allowed to warm to 0° before addition of water (1 ml) and ethyl acetate (20 ml). After stirring for 0.5 h the organic layer was separated, washed with brine, dried and evaporated to dryness. The residue was purified by CC eluting with a mixture of ethyl acetate, petroleum ether (bp. 40°-60°) and methanol (5:5:2) to give the title compound (0.05 g), δ(CDCl3) 8.39(m,2H,C-2 and C-6 protons of pyridine), 6.60(d,1H,J15 Hz,NCH=CH), 5.58(dd,1H,J15 and 6 Hz,NCH=CH), 4.18(m,2H,CH2OH), 3.17(septet,1H,J7 Hz,CH(CH3)2), 1.42(d,6H,J7 Hz,CH(CH3)2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:6]([NH2:8])[CH:7]=1.C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.C1OCCOCCOCCOCCOCCOC1.C(O[N:49]=O)(C)(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:9]([S:10]([CH3:13])(=[O:12])=[O:11])=[N:49][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)ON=O
Reactant: CS(=O)(=O)Cc1ccc(Br)cc1N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1n[nH]c2cc(Br)ccc12

Procedure:
To a suspension of {5-bromo-2-[(methylsulfonyl)methyl]phenyl}amine (Intermediate 74) (0.26 g) in chloroform (8 ml) was added potassium acetate (0.11 g) and acetic anhydride (0.195 ml). The mixture was heated under nitrogen at reflux for 18 h. 18-Crown-6 (0.26 g) and tert-butylnitrite (0.35 ml) were added and the mixture was stirred at reflux for a further 88 h. The mixture was concentrated under vacuum and the residue was purified by column chromatography on silica eluting with cyclohexane:ethylacetate (4:1 to 1:1) to give the title compound (0.14 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[N:10][C:11]([OH:14])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19].N12CCN(CC1)CC2.CCCCCCC>ClCCl>[CH3:1][C:2]1([CH3:15])[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][C:18](=[O:19])[N:17]([CH3:16])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CC1(C)CCN(c2ccc(O)nc2)CC1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: CCCCCCC
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(N2CCC(C)(C)CC2)cn1)c1ccccc1
Yield: 41 %

Procedure:
A solution of 4,4-dimethyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ol (0.86 g, 4.17 mmol), N-methyl-N-phenylcarbamoyl chloride (0.71 g, 4.17 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.47 g, 4.17 mmol) in dichloromethane (10 mL) was stirred at room temperature for 2 hours. Extra dichloromethane was added and the solution was washed with water, dried over sodium sulphate, filtered and evaporated in vacuo. Crystallisation from ethyl acetate:heptane yielded the title compound (0.58 g, 41% yield)
Reaction SMILES: [NH2:1][C:2]1[C:12]([NH2:13])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:14][CH2:15][CH:16]([F:18])[F:17])[CH:3]=1.[Cl:19][C:20]1[CH:36]=[CH:35][C:23]([CH2:24][NH:25][C:26]([C:28]2([C:31]([F:34])([F:33])[F:32])[CH2:30][CH2:29]2)=[O:27])=[CH:22][C:21]=1[N:37]=[C:38]=S.CC(C)N=C=NC(C)C>C1COCC1>[Cl:19][C:20]1[CH:36]=[CH:35][C:23]([CH2:24][NH:25][C:26]([C:28]2([C:31]([F:34])([F:33])[F:32])[CH2:29][CH2:30]2)=[O:27])=[CH:22][C:21]=1[NH:37][C:38]1[NH:1][C:2]2[CH:3]=[C:4]([O:14][CH2:15][CH:16]([F:17])[F:18])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][C:12]=2[N:13]=1
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Reactant: CCOC(=O)c1cc(N)c(N)cc1OCC(F)F
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2nc(Nc3cc(CNC(=O)C4(C(F)(F)F)CC4)ccc3Cl)[nH]c2cc1OCC(F)F

Procedure:
The sub-title compound was prepared in accordance with Example 59 (h) using ethyl 4,5-diamino-2-(2,2-difluoroethoxy)benzoate (0.466 g; 1.79 mmol; crude material from step (c)), N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (0.600 g; 1.79 mmol), DIC (0.226 g; 1.79 mmol) and THF (40 mL). Yield: 0.620 g (62%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([NH:15][N:16]=[C:17]([C:19]2[C:23]([OH:24])=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)[S:21][CH:20]=2)[CH3:18])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.Cl>CN1CCCC1=O>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([C:22]2[S:21][CH:20]=[C:19]([C:17](=[N:16][NH:15][C:13](=[O:14])[C:11]3[CH:10]=[CH:9][C:5]([C:6]([N:54]4[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]4)=[O:7])=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=3)[CH3:18])[C:23]=2[OH:24])=[CH:30][CH:29]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CN1CCNCC1
Reactant: CC(=NNC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(=NNC(=O)c1ccc(C(=O)N2CCN(C)CC2)c([N+](=O)[O-])c1)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Reaction time: 2 h
Yield: 10 %

Procedure:
To a N-methyl-2-pyrrolidinone (1.0 mL) solution of 2-nitro-4-[(2-{1-[5-(4-t-butylphenyl)-4-hydroxy-3-thienyl]-ethylidene}hydrazino)carbonyl]benzoic acid (50 mg, 0.10 mmol, see the synthetic example 47) and triethylamine (16 μL, 0.11 mmol) was added isobutyl chloroformate (26 μL, 0.20 mmol) at 0° C. The reaction mixture was stirred for 2 hours at this temperature, and then N-methyl piperazine (45 μL, 0.40 mmol) was added. After stirring for 1 hour is at room temperature, the reaction mixture was acidified with 1M aqueous HCl solution (1.0 mL) and concentrated under the reduced pressure. To the residue was added water, then the precipitate was collected by filtration, washed with water, isopropanol and methanol, then dried by means of a vacuum pump to give the desired product as a pale yellow solid (yield 10%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([BH3-])#N.[Na+].O.[OH-].[Na+]>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a solution of methyl 1H-indole-5-carboxylate 19a (2 g, 11.4 mmol) in glacial acetic acid (15 mL) at 0° C. was slowly added sodium cyanoborohydride (1.08 g, 17.2 mmol). The mixture was allowed to warm up and stirred at room temperature for 2 h. Water was added to the resulting mixture at 0° C., and the solution was adjusted to pH˜12 with 1N aqueous NaOH. The mixture was extracted with CH2Cl2 and the organic layer was washed with brine and dried over Na2SO4. The solution was concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/heptane) to give compound 24a (1.79 g). MS m/z (M+H+) 178.1.
Reaction SMILES: CC1C=CC(S([O-])(=O)=O)=CC=1.[NH2:12][C:13]([C:15]1[C:23]2[C:19](=[CH:20][N:21]([C:24]3[CH:29]=[CH:28][C:27]([C@@H:30]4[CH2:35][CH2:34][CH2:33][NH2+:32][CH2:31]4)=[CH:26][CH:25]=3)[N:22]=2)[CH:18]=[CH:17][CH:16]=1)=[O:14].[S:36](=[O:40])(=[O:39])([OH:38])[OH:37].O>CO>[S:36]([O-:40])([O-:39])(=[O:38])=[O:37].[NH2:12][C:13]([C:15]1[C:23]2[C:19](=[CH:20][N:21]([C:24]3[CH:29]=[CH:28][C:27]([C@@H:30]4[CH2:35][CH2:34][CH2:33][NH2+:32][CH2:31]4)=[CH:26][CH:25]=3)[N:22]=2)[CH:18]=[CH:17][CH:16]=1)=[O:14].[NH2:12][C:13]([C:15]1[C:23]2[C:19](=[CH:20][N:21]([C:24]3[CH:29]=[CH:28][C:27]([C@@H:30]4[CH2:35][CH2:34][CH2:33][NH2+:32][CH2:31]4)=[CH:26][CH:25]=3)[N:22]=2)[CH:18]=[CH:17][CH:16]=1)=[O:14]
Reactant: O=S(=O)(O)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: NC(=O)c1cccc2cn(-c3ccc([C@@H]4CCC[NH2+]C4)cc3)nc12
Solvent: O
Solvent: CO
Product: O=S(=O)([O-])[O-]
Temperature: 40 °C
Reaction time: 24 h

Procedure:
50 mg of tert-butyl(3S)-3-{4-[7-(aminocarbonyl)-2H-indazol-2-yl]phenyl}piperidine-1-carboxylate (Example 1, D3) as a compound stock solution was reacted with 1 mole equivalent of sulfuric acid, added as a 1 Molar solution in 1:1 (v/v) methanol:water solution. Excess solvent was removed under centrifugal evaporation and 1 mL of the methanol:water solution added at ambient room temperature (˜25° C.). The resultant solution stirred at 40° C. for 24 hours. The experiment was left to gently evaporate under atmospheric conditions where a colorless solid was observed.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23](=[O:24])[C:22]3[C@@H:21]4[C:25]([CH3:27])([CH3:26])[C@@:18]([CH3:28])([CH2:19][CH2:20]4)[C:17]=3[NH:16]2)=[CH:11][CH:10]=1>[OH-].[Na+]>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23](=[O:24])[C:22]3[C@@H:21]4[C:25]([CH3:27])([CH3:26])[C@@:18]([CH3:28])([CH2:19][CH2:20]4)[C:17]=3[N:16]2[CH3:5])=[CH:11][CH:10]=1
Reactant: COS(=O)(=O)OC
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3)c(=O)c12
Agent: [Na+]
Agent: [OH-]
Product: Cn1c2c(c(=O)n1-c1ccc(F)cc1)[C@H]1CC[C@]2(C)C1(C)C
Yield: 13.7 %

Procedure:
A mixture of dimethyl sulfate (1.1 mL, 11.6 mmol) and (4S,7R)-2-(4-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 13; 1.65 g, 5.8 mmol) in 1 M NaOH (25 mL) was heated at 50 degrees overnight, and then allowed to stand at room temperature over the weekend. The precipitate was filtered off, washed with water, and recrystallized from ethyl acetate to give (4S,7R)-2-(4-fluoro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (239 mg, 14%) as a white solid. ES(+)-MS (M+H) 301.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[H-].[Na+].CI.[C:16](OCC)(=O)C>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][O:11][CH3:16])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCOC(C)=O
Reactant: COc1ccc(CO)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: COCc1ccc(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88 %

Procedure:
To a solution of (3-bromo-4-methoxy-phenyl)-methanol (500 mg, 2.304 mmol, example 28) in tetrahydrofuran (5 mL) cooled to 0° C. was added sodium hydride (70 mg, 2.765 mmol). After 5 min, methyl iodide (287 μL, 4.608 mmol) was added. The reaction was then stirred at room temperature for 30 min. Thin layer chromatography (KP-Sil™ 32-63 μm, 60 Å silica gel, 40% ethyl acetate in hexanes) showed a mixture of starting material and product (higher Rf spot). Additional sodium hydride (58 mg) and methyl iodide (0.287 μL) were added and the reaction mixture was stirred at room temperature for 12 h. Water (5 mL) was added to quench the excess sodium hydride and the product was extracted with diethyl ether (2×50 mL). The organic layers were washed with brine (1×5 mL) and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 20% ethyl acetate in hexanes yielded 2-bromo-1-methoxy-4-methoxymethyl-benzene (467 mg, 88%).
Reaction SMILES: [C:1]([C@H:3]1[O:8][CH2:7][C@@H:6]([CH2:9][OH:10])[N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4]1)#[CH:2].[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19].[F:30][C:31]([F:35])([F:34])[CH2:32][NH2:33]>N1C=CC=CC=1>[C:1]([C@H:3]1[O:8][CH2:7][C@H:6]([CH2:9][O:10][C:18]([NH:33][CH2:32][C:31]([F:35])([F:34])[F:30])=[O:19])[N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4]1)#[CH:2]
Reactant: C#C[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)CO1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCC(F)(F)F
Solvent: c1ccncc1
Product: C#C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](COC(=O)NCC(F)(F)F)CO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-Butyl (2R,5R)-2-ethynyl-5-(hydroxymethyl)morpholine-4-carboxylate (0.51 g, 2.1 mmol) in 6 mL of pyridine was added carbonyldiimidazole (0.45 g, 2.8 mmol). The mixture was stirred at ambient temperature for 3 h. Trifluoroethylamine (4.1 mL, 53 mmol) was added, the vessel was sealed and heated to 50° C. for 24 h. The pyridine was removed in vacuo and the residue was dissolved in EtOAc and washed with water and brine. The EtOAc solution was dried (MgSO4), filtered, and the solvent was removed in vacuo. The residue was chromatographed on a 40 g SiO2 column using a gradient elution of 0-50% EtOAc in hexanes. Fractions containing product were combined and removal of solvents in vacuo gave a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)[C@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:57]([C:59]1[CH:64]=[C:63]([I:65])[CH:62]=[CH:61][N:60]=1)[NH2:58]>CN(C=O)C.O>[CH3:1][C:2]1([CH3:23])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:58][NH:57][C:59]3[CH:64]=[C:63]([I:65])[CH:62]=[CH:61][N:60]=3)=[O:13])=[CH:15][CH:16]=2)[C@H:3]1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC1(C)OC(=O)N(c2ccc(C(=O)O)cc2)[C@H]1c1ccccc1
Reactant: NNc1cc(I)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC1(C)OC(=O)N(c2ccc(C(=O)NNc3cc(I)ccn3)cc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
(S)-4-(5,5-Dimethyl-2-oxo-4-phenyloxazolidin-3-yl)benzoic acid (1500 mg, 4.82 mmol) was dissolved in DMF (9.636 mL) at room temperature. To the reaction mixture were added N-ethyl-N-isopropylpropan-2-amine (2.514 mL, 14.45 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1.832 g, 4.82 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) and 2-hydrazinyl-4-iodopyridine (1.132 g, 4.82 mmol). The vial was sealed and immersed in a 55° C. oil bath. After stirring overnight, LC-MS indicated complete conversion. After cooling to room temperature, the reaction mixture was transferred to water in a flask in an ice/water bath. The solution was washed with DCM (3×50 mL). The combined organic layers were then washed with water (2×50 mL) and brine (50 mL). The organic extract was dried over Na2SO4. The residual material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 10% MeOH in DCM, to provide (S)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)-N′-(4-iodopyridin-2-yl)benzohydrazide (1.53 g, 2.90 mmol, 60.1% yield) as an off-white solid. m/z (ESI) 529.0 (M+H)+.