Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:8]2[CH2:9][CH:10]([OH:12])[CH2:11][CH:5]1[CH2:6][CH2:7]2.Cl[C:14]1[N:18]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]3([CH3:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21][CH2:20]2)[C:17]2[CH:34]=[CH:35][CH:36]=[CH:37][C:16]=2[N:15]=1>CN(C=O)C>[CH3:3][N:4]1[CH:8]2[CH2:7][CH2:6][CH:5]1[CH2:11][CH:10]([O:12][C:14]1[N:18]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]4([CH3:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:21][CH2:20]3)[C:17]3[CH:34]=[CH:35][CH:36]=[CH:37][C:16]=3[N:15]=1)[CH2:9]2
Reactant: CC1(N2CCC(n3c(Cl)nc4ccccc43)CC2)CCCCCCC1
Reactant: CN1C2CCC1CC(O)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C2CCC1CC(Oc1nc3ccccc3n1C1CCN(C3(C)CCCCCCC3)CC1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
To a stirred suspension of NaH (60% oil suspension, 102.8 mg, 2.57 mmol was used after washing with n-hexane) in DMF (1.5 ml) was added a solution of tropine (190.6 mg, 1.35 mmol) in DMF (1.5 ml) dropwise at 0° C. After 0.5 hour stirring, a solution of 2-chloro-1-[1-(1-methylcyclooctyl)-4-piperidinyl]-1H-benzimidazole (162 mg, 0.45 mmol) in DMF (3 ml) was added to the reaction mixture at 0° C. The resulting mixture was stirred at room temperature for 23 hours and then at 120° C. for 19 hours. After cooling down to 0° C., the reaction mixture was quenched with water and extracted with CH2Cl2. The extracts combined were washed with brine, dried (Na2SO4), filtered, and concentrated to give 391.1 mg of crude oil, which was purified by preparative TLC (1 mm thick plate×3, CH2Cl2/MeOH:10/1) to afford 42.3 mg (20%) of title compound as a brown oil.
Reaction SMILES: [ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:29][C:30]1[O:34][C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:32][C:31]=1[CH2:41][CH2:42]OS(C)(=O)=O>>[ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:42][CH2:41][C:31]4[N:32]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[O:34][C:30]=4[CH3:29])[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Agent: Cl
Product: Cc1oc(-c2ccccc2)nc1CCN1CN(c2ccccc2)C2(CCN(C3CCCCCCCCC3)CC2)C1=O

Procedure:
The title compound, white solid, m. p. 140° C. and MS: m/e=555.3 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and methanesulfonic acid 2-(5-methyl-2-phenyloxazol-4-yl)-ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([OH:22])=O)=[CH:12][N:11]=1.[CH:23]1([CH2:26][NH2:27])[CH2:25][CH2:24]1>>[CH:23]1([CH2:26][NH:27][C:20]([C:13]2[C:14]([C:16]([F:19])([F:18])[F:17])=[N:15][C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[N:11][CH:12]=2)=[O:22])[CH2:25][CH2:24]1
Reactant: O=C(O)c1cnc(Nc2ccc(Cl)cc2Cl)nc1C(F)(F)F
Reactant: NCC1CC1
Product: O=C(NCC1CC1)c1cnc(Nc2ccc(Cl)cc2Cl)nc1C(F)(F)F
Yield: 63 %

Procedure:
In a manner similar to Reference Example 1 (c) 2-(2,4-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (80 mg) and cyclopropylmethylamine (19 mg, ex Lancaster) afforded the title compound (58 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:37]1[N:38]=[N:39][CH:40]=[CH:41][CH:42]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:37]4[N:38]=[N:39][CH:40]=[CH:41][CH:42]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: Clc1cccnn1
Product: C[C@@H](c1ccc(-c2cccnn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 3-chloropyridazine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.067, m/z=436.1; 1H NMR (CDCl3) 0.82 (m, 3H), 1.52 (d, 3H), 1.65 (m, 1H), 1.80-1.98 (m, 2H), 2.11-2.28 (m, 3H), 2.91 (m, 1H), 3.51 (t, 3H), 5.68 (m, 1H), 6.94-7.04 (m, 4H), 7.18 (m, 2H), 7.47 (m, 1H), 7.71 (d, 1H), 7.78 (d, 2H), 9.08 (d, 1H).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C:9]([C:24]([OH:26])=[O:25])=[CH:10][S:11][C:12]=1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1.[CH:27]1([CH2:30][C:31](N(OC)C)=[O:32])[CH2:29][CH2:28]1.O>O1CCCC1>[CH:27]1([CH2:30][C:31]([C:10]2[S:11][C:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=3)=[C:8]([O:7][CH3:6])[C:9]=2[C:24]([OH:26])=[O:25])=[O:32])[CH2:29][CH2:28]1
Reactant: COc1c(C(=O)O)csc1Cc1cccc(C(F)(F)F)c1
Reactant: CON(C)C(=O)CC1CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1c(Cc2cccc(C(F)(F)F)c2)sc(C(=O)CC2CC2)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28.1 %

Procedure:
2M butyl lithium in hexanes (1.75 ml) was added slowly to a solution of 4-methoxy-5-[(3-trifluoromethylphenyl)methyl]thiophene-3-carboxylic acid (500 mg) in tetrahydrofuran (30 ml) at −78° C. The resultant red solution was stirred for 20 minutes and then 2-cyclopropyl-N-methoxy-N-methylacetamide (229 mg) in tetrahydrofuran (3 ml) was added. The mixture was stirred for 20 minutes at −78° C. and was then allowed to warm to room temperature. After 5 hours water was added and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated. Purification of the residue by chromatography, eluting with 10:10:1 isohexane:ether:acetic acid, gave the sub-title compound (177 mg).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[CH:2]1[O:4][CH2:3]1.[CH2:17]([SiH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19][CH3:20]>>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][Si:21]([CH2:17][CH2:18][CH2:19][CH3:20])([CH3:23])[CH3:22])[CH:2]1[O:4][CH2:3]1
Reactant: C=CCCCCCCCCCOCC1CO1
Reactant: CCCC[SiH](C)C
Product: CCCC[Si](C)(C)CCCCCCCCCCCOCC1CO1
Temperature: 60 °C
Reaction time: 24 h
Yield: 82.6 %

Procedure:
A 100-ml flask equipped with a stirrer was charged with 13.6 g (60 mmol) of 10-undecenyl glycidyl ether, 5.8 g (50 mmol) of butyldimethylsilane and 4 mg (0.01 mmol) of H2PtCl6. The contents were stirred at 60° C. for 24 hours. The resultant reaction mixture was distilled under reduced pressure (145°-154° C./6×10-3 Torr), thereby obtaining 14.15 g (yield: 82.6%) of 11-(butyldimethylsilyl)undecyl glycidyl ether.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].[C:13]1(=[O:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[N:15][NH:14]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:23]=[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]1[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9]
Reactant: O=Cc1cccc(OCCBr)c1
Reactant: O=c1[nH]ncc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCCn2ncc3ccccc3c2=O)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
A mixture of 3-(2-bromoethoxy)benzaldehyde (6.00 g), 1(2H)-phthalazinone (4.21 g), potassium carbonate (7.24 g) and N,N-dimethylformamide (40 ml) was stirred at 80° C. for 5 hours. After cooling, the reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated to obtain 3-[2-[1-oxo-2(1H)-phthalazinyl]ethoxy]benzaldehyde (6.94 g, yield 90%) as colorless crystals. This was recrystallized from acetone-hexane. Melting point: 110–111° C.
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:55])[C:31]=1[NH:32][C:33]1[C:42]2[C:37](=[C:38]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51](O)=[O:52])[C:39]([O:43][CH3:44])=[CH:40][CH:41]=2)[O:36][C:35](=[O:54])[CH:34]=1.[NH4+].[OH-]>CS(C)=O>[Cl:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:55])[C:31]=1[NH:32][C:33]1[C:42]2[C:37](=[C:38]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([NH2:2])=[O:52])[C:39]([O:43][CH3:44])=[CH:40][CH:41]=2)[O:36][C:35](=[O:54])[CH:34]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCC(N)=O
Reaction time: 1 h

Procedure:
HATU (100 mg, 0.26 mmol) was added to a solution of 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)hexanoic acid (100 mg, 0.21 mmol, Example 44) and DMSO (2 mL). After 1 h, 28% NH4OH solution (0.4 mL, 2.9 mmol) was added. After an additional hour, the reaction was concentrated and purified by reverse-phase HPLC (1:4→7:3; acetonitrile:water) to give 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)hexanamide: 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.21 (br, 1H), 7.20 (d, 1H), 6.67 (br, 1H), 4.63 (s, 1H), 3.97 (t, 2H), 3.92 (s, 3H), 2.05 (t, 2H), 1.67 (m, 2H), 1.52 (m, 2H), 1.44 (m, 2H); MS (ESI): 465.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(OCC(F)(F)F)c(Cl)c1
Product: CC(N[S@](=O)C(C)(C)C)c1cnc(OCC(F)(F)F)c(Cl)c1
Yield: 57 %

Procedure:
The title compound is prepared in 57% yield (0.65 g, white solid) from 1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.8 g, 3.15 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:21]O>>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH3:21])=[O:6]
Reactant: CO
Reactant: COc1ccc(C(=O)O)c(OC)c1OC
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC)c(OC)c1OC
Temperature: 80 °C
Reaction time: 3 h

Procedure:
2,3,4-trimethoxybenzoic acid (7.3 g) was dissolved in methanol (73 ml), mixed with sulfuric acid (15 ml), and stirred for 3 hours while heating at 80° C. The resultant was allowed to stand for cooling, evaporated under reduced pressure for removing the solvent, and the residue was added to cold water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate water and then with a saturated aqueous sodium chloride solution, dried over sodium sulfate anhydride, and evaporated under reduced pressure for removing the solvent to give Compound IIbt-a (6.8 g, 87%) as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:8]([C:15]3[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=3)=[N:9][N:10]([CH3:14])[C:11]=2[CH:12]=[O:13])=[C:5]([CH3:23])[O:4][N:3]=1.[Li+].[BH4-].S(C)C>C(OCC)C>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:9][N:10]([CH3:14])[C:11]=2[CH2:12][OH:13])=[C:5]([CH3:23])[O:4][N:3]=1
Reactant: COc1ccc(-c2nn(C)c(C=O)c2-c2c(C)noc2C)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CSC
Product: Cc1noc(C)c1-c1c(-c2ccc(O)cc2)nn(C)c1CO
Temperature: 25 °C
Yield: 69.2 %

Procedure:
To a solution of 4-(3,5-dimethylisoxazol-4-yl)-3-(4-methoxyphenyl)-1-methyl-1H-pyrazole-5-carbaldehyde (4.1 mg, 0.013 mmol) in diethyl ether (3 mL) was added LiBH4 (12 mg, 0.55 mmol) and stirred at room temperature over night. The reaction was then quenched with water and extracted with EtOAc, filtered through a phase separator and concentrated. To the raw product in DCM (1 mL) was added BF3.Me2S (1 M solution in DCM, 0.2 mL, 0.2 mmol) and stirred over night at room temperature. The formed precipitate was twice washed with 0.5 mL DCM, dissolved in MeOH and purified on preparative HPLC to give E11 4-(4-(3,5-dimethylisoxazol-4-yl)-5-(hydroxymethyl)-1-methyl-1H-pyrazol-3-yl)phenol (2.8 mg, 0.009 mmol, 71%). ES/MS m/z: 299.6 (M+H), 297.7 (M−H); 1H NMR (MeOD, 500 MHz): 7.18 (m, 2H), 6.71 (m, 2H), 3.98 (s, 3H), 3.74 (s, 2H), 2.20 (s, 3H) and 1.87 (s, 3II).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1)[NH2:2].[C:15](Cl)(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>>[O:12]1[CH2:11][CH2:10][N:9]([C:6]2[CH:7]=[CH:8][C:3]3[N:4]([C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:2][N:1]=3)[N:5]=2)[CH2:14][CH2:13]1
Reactant: O=C(Cl)c1ccccc1
Reactant: NNc1ccc(N2CCOCC2)nn1
Agent: O=C([O-])O
Agent: [Na+]
Product: c1ccc(-c2nnc3ccc(N4CCOCC4)nn23)cc1

Procedure:
39 Grams of 3-hydrazino-6-morpholinopyridazine is added portionwise to 30 grams of benzoyl chloride. The mixture is heated at a temperature of 130°-140° C. for 1 hour. The mixture is then cooled and the residue of the reaction mixture is neutralized by the addition of aqueous sodium bicarbonate solution. The resulting aqueous mixture is then extracted with chloroform. The chloroform extract is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The 6-morpholino-3-phenyl-s-triazolo[4,3-b]pyridazine product is obtained as a residue from the evaporation. The product is crystallized twice from isopropanol and found to melt at 195°-196° C. 15 Grams of the named product are obtained. The structure of the product is confirmed by infrared spectroscopy and by nuclear magnetic resonance analysis.
Reaction SMILES: [C:1]([C:3]1[CH:35]=[CH:34][C:6]2[N:7]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][C:24]=3[CH3:33])[C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].N1C=CC=CC=1.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[C:42]([N:11]1[C@@H:10]([CH3:12])[C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:8](=[O:21])[N:7]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][C:24]=2[CH3:33])[C:6]2[CH:34]=[CH:35][C:3]([C:1]#[N:2])=[CH:4][C:5]1=2)(=[O:44])[CH3:43]
Reactant: CC(=O)Cl
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)Nc2cc(C#N)ccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1c2cc(C#N)ccc2N(Cc2c(C)ccc3ccccc23)C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To a 0° C. solution of tert-butyl(3S,4S)-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (364 mg, 774 μmol) in CH2Cl2 (7.74 ml) was added pyridine (306 mg, 315 μl, 3.87 mmol), followed by acetyl chloride (71.8 μl, 1.01 mmol), dropwise. The reaction was stirred at 0° C. for 1 h, then allowed to warm to rt and stirred for an additional 15 h, then quenched by the addition of H2O and extracted with CH2Cl2. The combined organic layers were washed with sat. aq. NaHCO3 and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(3S,4S)-5-acetyl-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (235 mg, 59%) as a white solid. MS m/z 535 (MNa)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])=O.[I-].[Na+].[N-:15]=[N+:16]=[N-:17].[Na+]>CS(C)=O>[N:15]([CH2:2][C:3]1[O:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=1)=[N+:16]=[N-:17]
Reactant: O=C(CCl)Nc1ccccc1O
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1nc2ccccc2o1
Reaction time: 0.5 h

Procedure:
To a mixture of 8.34 g (49.8 mmol) of 2-chloro-N-(2-hydroxyphenyl)acetamide (PREPARATION 4) and 0.75 g (5 mmol) of sodium iodide in 25 ml of DMSO were added 3.56 g (5.47 mmol) of sodium azide. A moderate exotherm ensued. After stirring for 30 min the reaction was partitioned between ethyl ether and saline. The organic layers were dried over magnesium surfate and concentrated. The crude product was chromatographed on silica gel (700 ml) eluting with ethyl acetate/hexane (5/95), the appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 4.60, 7.39, 7.56, 7.76 δ.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[CH2:10]([SH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:10]([S:17][CH:1](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: C#Cc1ccc(C)cc1
Agent: [Na]
Product: Cc1ccc(/C=C\C(SC(/C=C\c2ccc(C)cc2)c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of 4-methylphenylacetylene (0.02 mol) and benzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-methylstyryl benzylsulfide. The title compound was obtained in 70% yield following oxidation. 1HNMR (CDC13) δ 2.48 (3H, s), 4.60 (2H, s), 6.68 (1H, d, JH,H=11.94), 7.20-7.65 (9H aromatic+1H ethylenic).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([OH:17])=O.[NH2:18][C:19](N)=[O:20]>O>[OH:20][C:19]1[N:1]=[C:2]2[N:6]([CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:5]=[CH:4][C:3]2=[C:15]([OH:17])[N:18]=1
Reactant: NC(N)=O
Reactant: Nc1c(C(=O)O)cnn1CCc1ccccc1
Solvent: O
Product: Oc1nc(O)c2cnn(CCc3ccccc3)c2n1
Temperature: 180 °C
Yield: 105 %

Procedure:
A mixture of 5-amino-1-(2-phenylethyl)-1H-pyrazole-4-carboxylic acid (1.87 g, 8.1 mmol) and urea (1.46 g, 24 mmol) was heated at 180° C. for 5 h, cooled and the resulting solid suspended in boiling water, filtered and washed with water to give the impure title compound (2.18 g, 105%,) as a cream solid.
Reaction SMILES: N#N.[NH:3]1[C:11]2[C:6](=[CH:7][C:8](/[C:12](/[C:24]3[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33])=[CH:26][CH:25]=3)=[C:13](/[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[CH:17]=3)\[CH2:14][CH3:15])=[CH:9][CH:10]=2)[CH:5]=[N:4]1.B(Br)(Br)Br>C(Cl)Cl>[OH:22][C:18]1[CH:17]=[C:16](/[C:13](/[CH2:14][CH3:15])=[C:12](\[C:24]2[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33])=[CH:26][CH:25]=2)/[C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[NH:3][N:4]=[CH:5]3)[CH:21]=[CH:20][CH:19]=1
Reactant: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1ccc2[nH]ncc2c1)c1cccc(OC)c1
Agent: BrB(Br)Br
Agent: N#N
Solvent: ClCCl
Product: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1ccc2[nH]ncc2c1)c1cccc(O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 10-mL recovery flask equipped with a magnetic stir bar, a rubber septum and N2 inlet was charged with (E)-3-(4-((E)-1-(1H-indazol-5-yl)-2-(3-methoxyphenyl)but-1-en-1-yl)phenyl)acrylic acid (30 mg, 0.07 mmol, Compound 5) and DCM (1.4 mL). This solution was cooled down to 0° C. in an ice-bath. Then, BBr3 (88 mg, 0.35 mmol) was added dropwise via a syringe. The reaction mixture was stirred at 0° C. for 1 h. Upon completion, the reaction was quenched with methanol (5 mL) at 0° C. The resulting mixture was concentrated under reduced pressure to give the crude product that was directly purified on a reversed phased C-18 column eluted with 40-100% acetonitrile in water in the presence of 0.1% TFA affording the title compound as an off-white solid (11 mg). 1H NMR (300 MHz, DMSO-d6): δ 13.11 (s, 1H), 12.32 (br, 1H), 9.23 (s, 1H), 8.08 (s, 1H), 7.62 (s, 1H), 7.52 (d, 1H), 7.45-7.35 (m, 3H), 7.12 (d, 1H), 7.00 (t, 1H), 6.90 (d, 2H), 6.59-6.53 (m, 3H), 6.36 (d, 1H), 2.37 (q, 2H), 0.89 (t, 3H); LCMS: 411 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[N+]([O-])(O)=[O:13]>OS(O)(=O)=O>[NH2:1][CH:2]1[CH:3]2[CH2:11][CH:7]3[CH2:6][C:5]([OH:13])([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: NC1C2CC3CC1CC(O)(C3)C2

Procedure:
This know material (CAS 62058-13-3) was made according to Klimova et al., Khimiko-Farmatsevticheskii Zhurnal (1986), 20(7), 810-815 by hydroxylation of 2-aminoadamantane with HNO3 in H2SO4. 2-amino-5-hydroxyadamantane was obtained as a 2:1 mixture of the (Z) and (E) diasteromers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:10]([C:19]3[N:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:27][C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:29])[CH2:15][CH2:14]3)[N:10]([C:19]3[N:20]=[CH:21][CH:22]=[CH:23][N:24]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Fc1ccc(-c2nc(C3CCNCC3)n(-c3ncccn3)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CCC(c2nc(-c3ccc(F)cc3)nn2-c2ncccn2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of INTERMEDIATE 9 HCl salt (72.4 mg, 0.17 mmol) in DMF (1.0 ml) was added 2-bromoacetophenone (83.0 mg, 0.42 mmol), followed by the portionwise addition of potassium carbonate (138.0 mg, 1.00 mmol). After stirring at ambient temperature overnight, the reaction mixture was quenched with a saturated solution of ammonium chloride, extracted with EtOAc, and washed with water and brine. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified using a silica gel cartridge using a gradient of 0-50% ethyl acetate in hexanes, followed by a gradient of 0-10% methanol in dichloromethane to give the title compound as a yellow oil, which solidified on standing. LC-MS (m/z): 443.10 [M+H]+. 1H NMR (CDCl3, 500 MHz): δ 8.92 (d, J=4.8 Hz, 2H), 8.25-8.27 (in, 2H), 8.10 (d, J=8.1 Hz, 2H), 7.60-7.62 (m, 1H), 7.50 (t, J=7.6 Hz, 2H), 7.37 (t, J=4.8 Hz, 1H), 7.15 (t, J=8.6 Hz, 2H), 3.88 (s, 2H), 3.80-3.86 (in, 1H), 3.13-3.15 (br, 2H), 2.41-2.45 (br, 2H), 2.07-2.27 (br, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([NH:8][C:9]2[S:10][C:11]([C:15](=[O:17])[CH3:16])=[C:12]([CH3:14])[N:13]=2)[CH:7]=1.[Br-:20].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>Br.CC(O)=O>[Br:20][CH2:16][C:15]([C:11]1[S:10][C:9]([NH:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:18][CH3:19])=[N:13][C:12]=1[CH3:14])=[O:17]
Reactant: COc1ccc(Cl)cc1Nc1nc(C)c(C(C)=O)s1
Reactant: [Br-]
Agent: Br
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: COc1ccc(Cl)cc1Nc1nc(C)c(C(=O)CBr)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.2 %

Procedure:
To a solution of 5z (0.15 g, 0.5 mmol) in HBr/HOAc (33% wt HBr in HOAc; 2.5 mL) was added pyridinium tribromide (0.18 g, 0.55 mmol). The reaction mixture was stirred at room temperature for 24 h and poured onto ice-water. The precipitated product was collected by filtration, washed with cold water, and dried to afford 6z (0.19 g, 99%). Rf=0.714 in Hexane:EtOAc:1:1. 1H NMR (600 MHz, DMSO-d6): δ 8.38 (d, J=2.4 Hz, 1H), 7.07-7.12 (m, 2H), 4.58 (s, 2H), 3.86 (s, 3H), 2.57 (s, 3H). 13C NMR (150 MHz, DMSO-d6): δ 183.1, 166.1, 158.1, 147.8, 129.8, 124.1, 123.1, 119.6, 119.4, 112.7, 56.2, 36.0, 18.7. MS m/z (ESI) 376.92 (M+H)+.