Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([NH:8][C@H:9]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])[CH:3]([CH3:5])[CH3:4].CC1C=CC(S(O)(=O)=O)=CC=1.[NH:35]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@H:36]([C:39](O)=[O:40])[CH2:37][OH:38].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl.C(Cl)(Cl)Cl.O>[NH:35]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@H:36]([C:37]([NH:1][C@@H:2]([C:6]([NH:8][C@H:9]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:38])[CH2:39][OH:40]
Reactant: CC(C)C[C@H](NC(=O)[C@H](N)C(C)C)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@H](NC(=O)[C@H](CO)NC(=O)OC(C)(C)C)C(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of DVal-Leu-OBzl.p-TsOH(394 mg), Boc-Ser(164 mg), HOBT.H2O(129 mg) and N-methylmorpholine (88 μl) in dichloromethane(1.6 ml) was added EDCI.HCl (161 mg) under ice cooling. The reaction mixture was stirred at room temperature for 3 h. Saturated NaHCO, (2 ml) was added and the mixture was extracted with dichloromethane(15 ml×3). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by dry column flash chromatography on silica gel(Merck, KIESELGEL 60) with dichloromethane/methanol(50/1) for elution to give a solid. The solid was dissolved in chloroform and precipitated with hexane to give Boc-Ser-DVal-Leu-OBzl(355 mg) as a colorless powder. The tripeptide(330 mg) was dissolved in THF(3.3 ml) and 10% Pd/C(33 mg) was added. The mixture was vigorously stirred at room temperature under an atmosphere of hydrogen(under atmospheric pressure) for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Saturated NaCl (2 ml) was added to the residue and the mixture was extracted with EtOAc(20 ml×3). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give a solid. The solid was dissolved in chloroform and reprecipitated with hexane to give Boc-Ser-DVal-Leu(246 mg) as a colorless powder.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:46])[NH:6][C:7]2[CH:44]=[CH:43][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]6[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])[CH2:30][CH2:29]6)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:45])[CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO.C1COCC1>[CH:1]1([NH:4][C:5](=[O:46])[NH:6][C:7]2[CH:44]=[CH:43][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]6[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH2:32][CH2:33]6)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:45])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)CCCCN1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCCCN1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 73.8 %

Procedure:
To a stirred solution of 517 (94 mg, 0.145 mmol) in a mixture of MeOH/THF (5/5 mL) was added 1N NaOH (1.45 mL). The reaction mixture was heated at 60° C. for 1.5 h, then at rt. The reaction mixture was concentrated, diluted with water, neutralyzed with 1N HCl (pH around 5-6) until precipitation occurred. The suspension was shaken for 15 min and the gel was collected by filtration, rinsed with water, and dried under high vacuum to afford the desired product 518 (66 mg, 0.107 mmol, 73% yield) as a white fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): the carboxylic OH is missing, 8.78 (s, 1H), 8.56 (bd, J=1.4 Hz, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.33 (s, 1H), 8.25 (d, J=8.0 Hz, 1H), 7.86 (dd, J=8.2, 2.0 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.1 Hz, 1H), 7.20 (dd, J=8.9, 1.3 Hz, 1H), 6.65 (dd, J=5.4, 0.7 Hz, 1H), 6.60 (bd, J=2.5 Hz, 1H), 3.58 (s, 2H), 2.70-2.30 (m, 11H), 2.26-2.18 (m, 2H), 1.56-1.40 (m, 4H), 0.72-0.58 (m, 2H), 0.49-0.36 (m, 2H). MS (m/z): 619.5 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:20])[CH2:3][C@H:4]1[CH2:9][C@H:8]([C:10]2[O:14][NH:13][C:12](=[O:15])[CH:11]=2)[CH2:7][CH2:6][N:5]1[C:16]([O:18][CH3:19])=[O:17]>CCCCCCC.CC(O)C>[CH3:20][C:2]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([CH3:1])[CH2:3][C@@H:4]1[CH2:9][C@@H:8]([C:10]2[O:14][NH:13][C:12](=[O:15])[CH:11]=2)[CH2:7][CH2:6][N:5]1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1CC(C)(C)c1ccccc1
Solvent: CCCCCCC
Solvent: CC(C)O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1CC(C)(C)c1ccccc1
Yield: 44.3 %

Procedure:
Racemic trans-methyl 2-(2-methyl-2-phenylpropyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (0.82 g, 2.28 mmol) was subjected to chiral separation using Chiralcel IC, mobile phase heptane/IPA 80/20 at 40° C. which resulted in (2S,4S)-methyl 2-(2-methyl-2-phenylpropyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.361 g, 1.01 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[CH:7][C:6]([CH3:13])=[CH:5]2.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[O:16]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[C:7]([CH:15]([OH:16])[C:14]([O:18][CH2:19][CH3:20])=[O:17])[C:6]([CH3:13])=[CH:5]2
Reactant: Cc1cc(O)c2ccc(Br)cc2c1
Reactant: CCOC(=O)C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(O)c1c(C)cc2cc(Br)ccc2c1O
Reaction time: 0.75 h

Procedure:
To a mixture of 6-bromo-3-methylnaphthalen-1-ol (3.79 g, 15.98 mmol) in anhydrous dichloromethane (150 mL) at −40° C. was added a 1M titanium(IV) chloride solution in dichloromethane (20.78 mL, 13.78 mmol) and stirred for 45 min. Ethyl glyoxalate (2.45 g, 23.97 mmol) dissolved in dichloromethane (10 mL) was added over 15 minutes and stirred for 1 hour at −40° C. The reaction was quenched by the addition of Rochelle's salt solution and stirred at room temperature for 2.5 hours. The resulting mixture was washed with water and aqueous layer back-extracted with dichloromethane (2×). The combined organic layer was dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 5 to 30% ethyl acetate/hexanes) to give the desired compound. LCMS-ESI− (m/z): [M−H]− calcd for C15H15BrO4: 338.18. Found: 338.8.
Reaction SMILES: [ClH:1].Cl.O[CH2:4][CH:5]1[CH2:10][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7][N:6]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>S(Cl)(Cl)=O>[Cl:1][CH2:4][CH:5]1[CH2:10][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7][N:6]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cl
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Yield: 99.4 %

Procedure:
A suspension of 23 g (62.3 mmol) of 2-hydroxymethyl-1,4-di-phenylmethyl piperazine, dihydrochloride in 79 ml thionyl chloride was heated 4 hours under reflux. The solution was cooled and excess thionyl chloride was evaporated under reduced pressure. The residue was crystallized in ethanol, dried with acetone to yield 19.5 g of title compound dihydrochloride M.P. 234° C. dec. A suspension of this dihydrochloride in 130 ml 1N aqueous sodium hydroxyde was stirred with 75 ml dichloromethane, the aqueous layer back washed three times with 75 ml dichloromethane. The organic layers were collected and dried over magnesium sulfate to give after evaporation 15.44 g (78%) of title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)N)=[CH:6][CH:5]=1.[CH3:20][CH2:21][O:22][C:23]([CH2:25][CH:26]1[C:31](=O)[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:24]>>[CH3:2][O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]2[C:27]3[CH:26]([CH2:25][C:23]([O:22][CH2:21][CH3:20])=[O:24])[CH2:31][CH2:30][CH2:29][C:28]=3[C:16]3[C:11]2=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: COc1ccc(CN(N)c2ccc(F)cc2)cc1
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(OC)cc1)c1ccc(F)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-methoxybenzyl)-1-(4-fluorophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].CN(C)C=O.Br[CH2:29][CH:30]1[CH2:32][CH2:31]1>O>[CH:30]1([CH2:29][N:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]4[N:6]([C:2]([CH3:1])=[N:3][N:4]=4)[N:7]=3)[CH:12]=2)[C:18](=[O:20])[CH3:19])[CH2:32][CH2:31]1
Reactant: CC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(CC1CC1)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
A mixture of 3.0 g of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide, 0.6 g of sodium hydride (50% in oil) and 250 ml of dimethylformamide was stirred under argon for 1 hour, then 1.2 ml of (bromomethyl)cyclopropane was added. This mixture was stirred overnight, then poured into 200 ml of water and extracted with 150 ml portions of dichloromethane. The extracts were combined, dried and evaporated. The residue was chromatographed on a silica gel column, eluting with dichloromethane:methanol (95:5). The active fractions were combined, evaporated and the solid recrystallized from ethyl acetate-hexane, giving 1.5 g of the desired product as pink crystals, mp 118°-121° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[S:5][C:6]=1[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][CH:10]=1.[C:29]1([O:35]C(Cl)=O)C=CC=CC=1.N1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>ClCCl.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][CH:20]=2)[S:5][C:6]=1[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[O:14][C:29](=[O:35])[NH:16][N:15]=2)=[CH:17][CH:18]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C(=O)NN)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(-c2n[nH]c(=O)o2)cc1
Temperature: 25 °C
Yield: 21.5 %

Procedure:
To a suspension of 4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzoic acid hydrazide (Example 8, 271 mg, 0.74 mmol) in dichloromethane (7 mL) add phenylchloroformate (94 μL, 0.75 mmol) followed by pyridine (132 μL, 1.63 mmol). Stir the resulting mixture at room temperature until all the starting material is consumed (by TLC analysis). Concentrate the mixture, and then take the residue up in acetonitrile (10 mL). To this mixture, add DBU (220 μL, 1.5 mmol). Seal the resulting solution; warm it to 180° C. in a Personal Chemistry™ microwave oven and stir at this temperature for 15 min. Cool the reaction to room temperature, dilute with ethyl acetate, wash with 1 M HCl solution (or saturated NaH2PO4 solution) dry over MgSO4 and concentrate. Triturate the resulting residue with dichloromethane several times to give the title compound as a tan solid (69 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1F)([O-:9])=[O:8]>>[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1cccs1
Product: O=[N+]([O-])c1ccccc1Nc1cccs1

Procedure:
Both paths start with a Gewald reaction to form appropriately substituted 2-amino-thiophenes (a). This type of reaction is described in Chem. Ber. 1965, 98, 3571-3577; Chem. Ber. 1966, 99, 94-100. The second step involves the reaction of 2-aminothiophene with 2-nitro-1-fluorobenzene (b), to give a 2-(2-nitro-anilino)thiophene.
Reaction SMILES: [C:1]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8]C=2)[CH2:4][CH2:3][CH2:2]1.[CH:12](OC)([O:15][CH3:16])[O:13][CH3:14].F[P-](F)(F)(F)(F)F.[H+].C([O-])(O)=O.[Na+]>CO>[CH3:14][O:13][C:12]1([O:15][CH3:16])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: COC(OC)OC
Reactant: O=C1CCCc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [H+]
Solvent: CO
Product: COC1(OC)CCCc2ccccc21
Temperature: 25 °C

Procedure:
In a round bottom flask, (10 g) 1-tetralone in 20 ml methanol, 15 ml (2 equiv.) trimethyl orthoformate was taken and the mixture was stirred at room temperature. 0.2 ml hexafluoro phosphoric acid (catalytic amount) was added and the mixture was refluxed for 5.5 hrs. The mixture was then cooled at 25-30° C. After completion of reaction dilute the reaction mass by adding 10% NaHCO3 solution and extract with ethyl acetate. The organic layer was washed with NaHCO3 solution. Dry it by adding sodium sulfate, concentrate it on rotavapour to give dark brown colored oily product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2.[C:24]([Cu])#[N:25].CCOC(C)=O>CN1CCCC1=O.[Cu]I>[CH:17]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6](=[CH:5][C:4]3[CH:21]=[C:22]([CH:23]=[CH:2][CH:3]=3)[C:24]#[N:25])[C:7]=2[CH:20]=[CH:19][CH:18]=1
Reactant: N#C[Cu]
Reactant: Brc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Agent: [Cu]I
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Reaction time: 1 h
Yield: 71.5 %

Procedure:
Purge a solution of 5-(3-bromo-benzylidene)-10,11-dihydro-5H-dibenzo-[a,d]cycloheptene (4.2 g, 11.6 mmol) in N-methylpyrrolidinone (80 mL) with nitrogen for 10 minutes. Add CuI (6.7 g, 35 mmol) and CuCN (3.1 g, 35 mmol) and heat to 130° C. After 1 hour, cool the reaction to ambient temperature and shake with aqueous FeCl3 (200 mL) and EtOAc (200 mL). Wash the organic layer with water, dry with MgSO4 and concentrate to obtain 6.4 g crude product. Purify on silica gel using EtOAc/hexane to obtain 2.55 g (71%) title compound as a white solid, mp 115.7° C. 1H NMR (CDCl3) δ 3.02 (br d, 2H), 3.40 (br d, 2H), 6.77 (s, 1H), 6.93 (dd, 1H), 7.02-7.49 (m,11H); MS (EI) 307. HPLC shows 98% purity.
Reaction SMILES: S(=O)(=O)(O)O.CO[CH:8](OC)[C:9]([NH:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])=[O:10]>>[CH3:13][C:12]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[C:9]([OH:10])[N:11]=1
Reactant: COC(OC)C(=O)NC(C)c1ccccc1
Agent: O=S(=O)(O)O
Product: Cc1nc(O)cc2ccccc12
Temperature: 60 °C
Reaction time: 1.75 h

Procedure:
Concentrated sulfuric acid (18 M; 6.0 mL) was added to 2,2-dimethoxy-N-(1-phenylethyl)-acetamide (2.49 g, 11.2 mmol), and the resulting solution was stirred at 60° C. for 105 min. The reaction mixture was added to ≈100 mL of ice, and the yellow precipitate was filtered off. The pH of the filtrate was adjusted to 7-8 with NaHCO3 solution, the initial yellow solid was added, and the yellow precipitate was filtered off, washed with water, and dried in vacuo, giving the title compound as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=10.68 (brs, 1H), 8.00 (dd, J=1.0, 8.6 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.53 (dt, J=1.0, 8.0 Hz, 1H), 7.28 (dt, J=0.8, 8.0 Hz, 1H), 6.69 (s, 1H), 2.78 (s, 3H). MS(ES+): m/z=160.10 (100) [MH+]. HPLC: tR=2.13 min (polar—5 min, ZQ3).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=2)[N:7]=1.[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:18][O:17][C:12]1[C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: COc1ncccc1-c1cnc2ccc(Cl)nn12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ncccc1-c1cnc2ccc(N[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)nn12
Temperature: 110 °C
Yield: 42.6 %

Procedure:
A mixture of 6-chloro-3-(2-methoxypyridin-3-yl)imidazo[1,2-b]pyridazine (Preparation 2, 0.15 g, 0.58 mmol), tert-butyl (3R)-3-aminopiperidine-1-carboxylate (0.23 g, 1.15 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (0.03 g, 0.09 mmol), sodium tert-butoxide (0.08 g, 0.81 mmol) and toluene (4 mL) in a Schlenk vial was subjected to three cycles of evacuation backfilling with argon. Tris(dibenzylidene acetone)dipalladium(0) (0.04 g, 0.04 mmol) was then added and the resulting mixture was subjected to three further cycles of evacuation backfilling before being heated at 110° C. for 20 hours. Subsequently, the reaction was cooled down, filtered through Celite® eluting with ethyl acetate and dichloromethane, and the filtrate was evaporated to dryness. The crude was purified by flash chromatography (1:1 hexanes/ethyl acetate to 100% ethyl acetate) to give the title compound (0.105 g, 42%) as a solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([Br:10])[CH:9]=1.[CH3:12][O:13][CH2:14]Cl>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]([O:11][CH2:12][O:13][CH3:14])[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: COCCl
Reactant: Oc1cc(Br)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a suspension of sodium hydride (693 mg, 17.33 mmol, 60%, oil was washed with pentane) in THF (15 mL) was added 3, 5-dibromophenol (3.0 g, 11.55 mmol) at 0° C. and the suspension was stirred for 30 minutes. Then, methoxymethyl chloride (1.4 g, 17.33 mmol) was added at 0° C. The resulting suspension was allowed to warm to room temperature and stirred for 2 days at which time TLC analysis of the mixture indicated the absence of starting material. Then, the reaction mixture was poured into an ice-water (50 mL) and the organic compound was extracted into ethyl acetate (2×100 mL). The combined extracts were washed with brine solution (250 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and the concentration of the solution under reduced pressure gave the crude residue which was purified by using an ISCO 120 g column chromatography, eluting with 5-20% ethyl acetate in hexanes to obtain 1,3-dibromo-5-methoxymethoxy-benzene (2.94 g, 86%) as a white solid: EI(+)-HRMS m/e calcd for C8H8Br2O2 (M)+ 293.8891, found 293.8893.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.O.[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:8][C:6]1[CH:5]=[C:4]([OH:11])[CH:3]=[C:2]([Br:1])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(O)cc(Br)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(O)cc(Br)c1

Procedure:
To a solution of 3-bromo-5-nitro-phenol (16.9 g, 77.52 mmol, commercially available [CAS 116632-23-6 {Specs}]) in ethanol (300 ml) and water (100 ml) was added solid ammonium chloride (16.59 g, 310 mmol) and then powdered electrolytic iron (34.4 g, 698 mmol). The material was heated from ambient to reflux temperature (oil bath). The material was refluxed for 3 hours and then filtered, hot, through a plug of celite, washing well with several volumes of hot EtOAc. The solvent was stripped and the remainder was taken up in EtOAc (150 ml) and water (150 ml) and the material shaken. The organic phase was collected and washed with brine (150 ml). The aqueous phases were back extracted with EtOAc (2×100 ml). The organics were combined, dried (MgSO4), filtered and stripped to provide a crude oil. The material was adsorbed onto silica (50 g) and purified by silica gel chromatography, eluting with 15% to 50% ethyl acetate in hexanes to afford 10.35 g of 3-amino-5-bromo-phenol as a dark golden-brown viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([CH2:15][C:16](=[O:26])[NH:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:9]=1[CH3:27])[CH3:6])=[O:4].N1C=CC=CC=1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH:5]([N:7]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([CH2:15][C:16](=[O:26])[NH:17][C:18]2[CH:19]=[C:20]([Cl:25])[CH:21]=[C:22]([Cl:24])[CH:23]=2)[C:9]=1[CH3:27])[CH3:6])=[O:4]
Reactant: COC(=O)C(C)Nc1c(C)ccc(CC(=O)Nc2cc(Cl)cc(Cl)c2)c1C
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COCC(=O)N(c1c(C)ccc(CC(=O)Nc2cc(Cl)cc(Cl)c2)c1C)C(C)C(=O)OC
Temperature: 25 °C

Procedure:
16.2 g of N-(1'-methoxycarbonyl-ethyl)-2,6-dimethyl-3-(3',5'-dichlorophenylcarbamoylmethyl)-aniline and 3.2 g of pyridine were placed into 120 ml of toluene; and within 15 minutes were added 4.7 g of methoxyacetic acid chloride, dissolved in 30 ml of toluene. After the exothermic reaction had subsided, stirring was maintained for 4 hours at room temperature, and the reaction suspension was then filtered with suction. The yellow filtrate was washed with water, dried over sodium sulfate, and concentrated in a rotary evaporator. The solid residue was digested with ether, and the white crystals were filtered off with suction; m.p. 126°-128° C.
Reaction SMILES: [OH-].C([N+](C)(C)C)C1C=CC=CC=1.[OH:13][CH2:14][CH2:15][C:16]1[CH:45]=[CH:44][CH:43]=[CH:42][C:17]=1[O:18][CH2:19][CH2:20][N:21]1[CH2:41][CH2:40][C:24]2([O:29][CH2:28][CH2:27][N:26]([C:30]([C:32]3[N:33]=[C:34]([CH:37]([CH3:39])[CH3:38])[S:35][CH:36]=3)=[O:31])[CH2:25]2)[CH2:23][CH2:22]1.[C:46]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])(=[O:49])[CH:47]=[CH2:48]>C1(C)C=CC=CC=1>[CH:37]([C:34]1[S:35][CH:36]=[C:32]([C:30]([N:26]2[CH2:25][C:24]3([CH2:40][CH2:41][N:21]([CH2:20][CH2:19][O:18][C:17]4[CH:42]=[CH:43][CH:44]=[CH:45][C:16]=4[CH2:15][CH2:14][O:13][CH2:48][CH2:47][C:46]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:22][CH2:23]3)[O:29][CH2:28][CH2:27]2)=[O:31])[N:33]=1)([CH3:39])[CH3:38]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCOc4ccccc4CCO)CC3)C2)cs1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCOc4ccccc4CCOCCC(=O)OC(C)(C)C)CC3)C2)cs1
Reaction time: 16 h
Yield: 68.2 %

Procedure:
benzyltrimethylammonium hydroxide (0.2 mL) was added to (9-(2-(2-(2-hydroxyethyl)phenoxy)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (0.60 g) (example 178 step b) and tert-butyl acrylate (0.244 g) in toluene (1 mL) and the reaction mixture stirred vigorously. After 16 h, more benzyltrimethylammonium hydroxide (0.2 mL) and tert-butyl acrylate (0.244 g) was added. After a further 48 h the reaction mixture was evaporated in vacuo and applied to a silica gel column eluting with 5% methanol in DCM. Yield as a gum 0.52 g.
Reaction SMILES: [N:1]([CH:4]1[C:9]2[CH:10]=[C:11]([C:14]#[N:15])[CH:12]=[CH:13][C:8]=2[O:7][C:6]([CH3:17])([CH3:16])[CH2:5]1)=[N+]=[N-].Cl>CC(C)=O.O.[Zn]>[NH2:1][CH:4]1[C:9]2[CH:10]=[C:11]([C:14]#[N:15])[CH:12]=[CH:13][C:8]=2[O:7][C:6]([CH3:17])([CH3:16])[CH2:5]1
Reactant: CC1(C)CC(N=[N+]=[N-])c2cc(C#N)ccc2O1
Agent: Cl
Agent: [Zn]
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)CC(N)c2cc(C#N)ccc2O1
Yield: 84.6 %

Procedure:
To a solution of 4-azido-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (0.92g) in acetone (20 ml) was added concentrated hydrochloric acid (3 ml) and zinc dust (0.6g) in portions, with vigorous stirring. After 15 min the reaction was diluted with water, filtered and the filtrate extracted with ethyl acetate. The aqueous phase was made basic with 10% (w/v) aqueous sodium hydroxide solution and further extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulphate, filtered and the solvent evaporated in vacuo to give the title compound (0.69g).