Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]([NH2:7])=[O:6])=[N+:2]=[N-:3].[CH2:8]=[O:9].[OH-].[K+].Cl>>[N:1]([CH2:4][C:5]([NH:7][CH2:8][OH:9])=[O:6])=[N+:2]=[N-:3]
Reactant: C=O
Reactant: [N-]=[N+]=NCC(N)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: [N-]=[N+]=NCC(=O)NCO
Temperature: 0 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
A mixture of 2-azido-acetamide (1.40 g, 14 mmol), 30% aqueous (methanol free) formaldehyde (1.40 g, 14 mmol) and 1.0 N aqueous KOH (0.28 ml, 0.28 mmol) was stirred at 0° C for 4 hrs. To the reaction mixture 1.0 N aqueous HCl was added (pH=7) and the resulting mixture evaporated in vacuo. The residue was suspended in ethyl acetate (50 ml), the solution dried over magnesium sulfate, filtered and the filtrate concentrated to a volume of 5 ml. Chromatography on silica gel (63-200 μm, 18 g) with ethyl acetate afforded 2-azido-N-(hydroxymethyl)-acetamide as a colourless oil in 90% yield. NMR-spectrum in CDCl3: 3.6 (broad signal, 1H), 4.0 (s, 2H), 4.8 (d, 2H, J=6 Hz), 7.3 (broad signal 1H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].C(O)(=O)C.N1CCCCC1>O.C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:13]([C:14](=[O:15])[CH3:16])[C:12]([O:18][CH3:19])=[O:17])[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Temperature: 25 °C
Yield: 72.2 %

Procedure:
A solution of 151 g (1.00 mole) of 3-nitrobenzaldehyde, 116 g (1.00 mole) of methyl acetoacetate, 10 mL of glacial acetic acid, 4 mL of piperidine, and 400 mL of benzene was refluxed 2 hr during which time 21 mL of water was removed via a Dean-Stark trap. The dark yellow solution was cooled to ambient temperature and solidification occurred. Filtration followed by washing with ether afforded 180 g of product as a yellow solid. An additional 23 g product was obtained from the filtrate to yield a total of 203 g (82%) of product, m.p. 145°-146° C. (literature m.p. 158° C.; cf: Meyer, et al., Arzneim.-Forsch/Drug Research, 31, 407 (1981).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[N:16]1([CH2:21][C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:28][CH:27]=1
Reactant: Nc1ccc(CN2CCCC2)cc1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(CN2CCCC2)cc1
Yield: 24.7 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (200 mg, 0.83 mmol) was reacted with 4-(pyrrolidin-1-ylmethyl)aniline (310 mg, 1.24 mmol) to afford the desired product (78 mg, 25%) as a brown-orange solid: 1H NMR (300 MHz, CDCl3) δ 11.06 (s, 1H), 9.03 (s, 1H), 8.15 (d, J=8.7 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.41 (d, J=8.3 Hz, 2H), 7.13 (d, J=8.3 Hz, 2H), 3.85 (br s, 2H), 2.80 (br s, 4H), 2.60 (s, 3H), 1.92 (br s, 4H); ESI MS m/z 381 [M+H]+
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([Cl:9])[CH:3]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12](B(O)O)[CH:11]=1>>[Cl:9][C:4]1[CH:3]=[C:2]([C:12]2[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:5]=1[NH2:6]
Reactant: OB(O)c1cccnc1
Reactant: Nc1ccc(Br)cc1Cl
Product: Nc1ccc(-c2cccnc2)cc1Cl
Yield: 94 %

Procedure:
Prepared according to Method C (Preparation 85) using 4-bromo-2-chloroaniline and pyridin-3-ylboronic acid. Purified using Biotage silica gel column chromatography eluting with DCM/EtOH 99/1 to 97/3 and filtered on SCX-2 column to afford the title product as a yellow oil (93 mg, 94%). 1H NMR (500 MHz, CDCl3): δ 3.96 (br s, 2H), 6.87 (d, J=8.2 Hz, 1H), 7.32 (dd, J=8.2, 2.2 Hz, 1H), 7.35 (ddd, J=7.9, 4.8, 1.0 Hz, 1H), 7.51 (d, J=2.2 Hz, 1H), 7.80 (ddd, J=7.9, 2.3, 1.6 Hz, 1H), 8.54 (dd, J=4.8, 1.6 Hz, 1H), 8.79 (dd, J=2.3, 1.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]([CH3:16])[CH2:12][N+:13]([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]([CH3:16])[CH2:12][NH2:13]
Reactant: CC(C[N+](=O)[O-])c1c[nH]c2ccc(Br)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CN)c1c[nH]c2ccc(Br)cc12
Yield: 55.9 %

Procedure:
A solution of 5-bromo-3-(1-methyl-2-nitroethyl)-1H-indole (7.0 g) in dry tetrahydrofuran (100 ml) was added to a stirred suspension of lithium aluminium hydride (1.88 g) in dry tetrahydrofuran (50 ml) under a stream of nitrogen. The mixture was heated under reflux for 8 h, cooled in an ice bath and 2N sodium hydroxide solution (6 ml) was added cautiously. Filtration of the suspension through Hyflo and evaporation of the filtrate gave an amber oil which was chromatographed on kieselgel 60 eluted with methanol to give the title amine as a yellow gum (3.5 g) T.L.C. silica, methanol/ammonia (79:13) Rf 0.27.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[C:11]([CH2:13][C:14]1([N:25]2[CH:29]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=[N:26]2)[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1)#[N:12].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]([CH2:13][C:14]1([N:25]2[CH:29]=[C:28]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[NH:8][CH:9]=[CH:10][C:3]=34)[CH:27]=[N:26]2)[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1)#[N:12]
Reactant: Brc1ccnc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ccnc4[nH]ccc34)cn2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (1.1 g, 5.7 mmol), tert-butyl 3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (2.00 g, 5.15 mmol) (Example 40, Step 1), tetrakis(triphenylphosphine)palladium(0) (0.30 g, 0.26 mmol) and sodium carbonate (1.64 g, 15.4 mmol) in 1,4-dioxane (100 mL) and water (50 mL) under N2(g) was stirred at 100° C. overnight. The reaction mixture was extracted with ethyl acetate (3×20 mL), The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure until 5 mL of solvent was left. The resulting precipitate (0.90 g) was collected by filtration and washed with ether. The filtrate was further concentrated under reduced pressure to a volume of about 3 mL. The precipitate formed was filtered, and washed with ether to afford additional product (0.50 g). The filtrate was concentrated under reduced pressure again. The residue was purified by flash chromatography on a silica gel column with methanol in dichloromethane (0-5%) to afford additional desired product (0.55 g). Total amount of product was 1.95 g (yield: 92.3%). LCMS (M+H)+: m/z=379.1.
Reaction SMILES: [Li][CH2:2]CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[F:23]>C1COCC1.CCOC(C)=O>[Br:13][C:14]1[CH:22]=[CH:21][C:17]2[C:18](=[O:20])[O:19][CH2:2][C:16]=2[C:15]=1[F:23]
Reactant: [Li]CCCC
Reactant: O=C(O)c1ccc(Br)c(F)c1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C1OCc2c1ccc(Br)c2F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of n-BuLi (40 mL, 100 mmol) was added dropwise to a solution of diisopropylamine (10.6 g, 105 mmol) in 150 mL of THF at −70° C. The mixture was stirred at 0° C. for 15 minutes and then cooled to −70° C. again. A solution of 4-bromo-3-fluorobenzoic acid (10 g, 45.7 mmol, in 50 mL of THF) was added dropwise. The resulting mixture was stirred at −70° C. for 1 hour then CH2O gas (generated by heating 5.1 g of Para formaldehyde to 200° C.) was bubbled into the mixture. The resulting mixture was stirred at −70° C. for 1 hour then allowed to warm to room temperature and stirred for another 2 hours. HCl gas was bubbled into the suspension for 15 minutes to give a solution. The mixture was diluted with 1 L of EtOAc and washed subsequently with water, saturated Na2CO3 and brine, dried over anhydrous Na2SO4 and concentrated to give 5-bromo-4-fluoro-2-benzofuran-1(3H)-one. 1H-NMR (400 MHz, CDCl3) δ ppm 7.72-7.75 (m, 1H), 7.58 (d, J=8.0 Hz, 1H), 5.36 (s, 2H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[C:11]3[N:16]=[CH:15][S:14][C:12]=3[N:13]=2)[CH2:4]1.[O:28]=[C:29]1[NH:33][C:32]2[CH:34]=[CH:35][C:36]([C:38](O)=[O:39])=[CH:37][C:31]=2[NH:30]1.CCN=C=NCCCN(C)C.CN1C=CN=C1>C(Cl)Cl>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([NH:17][C:10]2[C:11]3[N:16]=[CH:15][S:14][C:12]=3[N:13]=[C:8]([N:5]3[CH2:6][CH2:7][CH:3]([NH:2][C:38]([C:36]4[CH:35]=[CH:34][C:32]5[NH:33][C:29](=[O:28])[NH:30][C:31]=5[CH:37]=4)=[O:39])[CH2:4]3)[N:9]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: COc1ccc(Nc2nc(N3CCC(N)C3)nc3scnc23)cc1OC
Reactant: O=C(O)c1ccc2[nH]c(=O)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2nc(N3CCC(NC(=O)c4ccc5[nH]c(=O)[nH]c5c4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.2 %

Procedure:
A mixture of 5-(3-aminopyrrolidin-1-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine hydrochloride (100 mg, 0.245 mmol), 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (48 mg, 0.27 mmol), EDCI (97 mg, 0.49 mmol) and N-methylimidazole (60 mg, 0.735 mmol) in 10 mL of DCM was stirred at room temperature for 16 hours. The mixture was washed with water (5 mL), The organic layer was dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography on silica gel eluting with a mixture of CH2Cl2 and methanol (100:1: to 20:1, V/V) to give N-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide (25 mg, 19%) as white solid. 1H NMR (300 MHz, DMSO): δ 9.57 (s, 1H), 8.81 (s, 1H), 8.475-8.46 (m, 1H), 8.27-8.25 (m, 2H), 7.60-7.25 (m, 2H), 6.92 (d, 1H, J=8.7 Hz), 6.47-6.39 (m, 3H), 4.54-4.52 (m, 1H), 3.76-3.58 (m, 10H), 2.27-2.05 (m, 2H). LC-MS: 247 [M/2+H]+, 493 [M+H]+, 491 [M−H]−, tR=1.22 min. HPLC: 95.20% at 214 nm, 95.06% at 254 nm, tR=5.64 min.
Reaction SMILES: [CH:1]1([C:5]2[NH:10][C:9](=[O:11])[C:8]([CH2:12][NH:13]C(=O)OC(C)(C)C)=[C:7]([CH3:21])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[ClH:22]>>[NH2:13][CH2:12][C:8]1[C:9](=[O:11])[NH:10][C:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)=[CH:6][C:7]=1[CH3:21].[ClH:22]
Reactant: Cc1cc(C2CCC2)[nH]c(=O)c1CNC(=O)OC(C)(C)C
Agent: Cl
Product: Cc1cc(C2CCC2)[nH]c(=O)c1CN
Temperature: 25 °C

Procedure:
A solution of 1,1-dimethylethyl [(6-cyclobutyl-4-methyl-2-oxo-1,2-dihydro-3pyridinyl)methyl]carbamate (2.1 g, 7.2 mmol) in 4N HCl (in 15 mL 1,4 dioxane) was heated to 60° C. for 1 h. The mixture was cooled to room temperature. The mixture was filtered and dried to give 3-(aminomethyl)-6-cyclobutyl-4-methyl-2(1H)-pyridinone as an HCl salt (1.95 g, 90%). LCMS MH+=193.1 1H NMR (400 MHz, DMSO-d6) δ 11.70 (br s, 1H), 8.01 (s, 3H), 6.04 (s, 1H), 3.74 (d, 2H), 3.32-3.39 (m, 1H), 2.22 (s, 3H), 2.17-2.20 (m, 2H), 2.06-2.11 (m, 2H), 1.85-1.95 (m, 1H), 1.71-1.79 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[N:4][N:5]([C:7]([CH3:12])([CH3:11])[C:8]([NH2:10])=[O:9])[CH:6]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][CH3:22])[C:18]([C:23]([F:26])([F:25])[F:24])=[CH:17][N:16]=1.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>COCCO.O>[CH3:12][C:7]([N:5]1[CH:6]=[C:2]([NH:1][C:15]2[N:20]=[C:19]([NH:21][CH3:22])[C:18]([C:23]([F:26])([F:24])[F:25])=[CH:17][N:16]=2)[C:3]([CH3:13])=[N:4]1)([CH3:11])[C:8]([NH2:10])=[O:9]
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Reactant: Cc1nn(C(C)(C)C(N)=O)cc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCO
Solvent: O=C(O)C(F)(F)F
Product: CNc1nc(Nc2cn(C(C)(C)C(N)=O)nc2C)ncc1C(F)(F)F
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
To a solution of 2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanamide (250 mg, 1.37 mmol) in 2-methoxyethanol (5 mL) was added 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (290 mg, 1.37 mmol) and trifluoroaceticacid (156 mg, 1.37 mmol), the reaction was stirred at 70° C. for about 0.5 h. The reaction mixture was cooled to ambient temperature followed with the addition of water (10 mL) and the pH of solution was adjusted to 8 with sat. Na2CO3 The aqueous phase was extracted with ethyl acetate (10 mL×3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to dry to give a residue which was purified by column chromatography on silica gel (CH2Cl2:MeOH=20:1) to give 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide (250 mg, 51%) as white solid. LCMS (m/z) ES+358 (m+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:19]>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][CH2:17][C:18]([NH:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(CNC(=O)CBr)cc1
Reactant: Cc1c(N)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)CNc2cccc(Cl)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
3.93 g of 3-chloro-2-methylaniline was dissolved in 10 mL of DMF, and 2.00 g of potassium carbonate was added thereto, followed by portionwise addition of 3.55 g of 2-bromo-N-(4-methoxybenzyl)acetamide over 1 hour. The mixture was stirred at room temperature overnight, and ice water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30 to 30:70) to obtain 2.89 g of N2-(3-chloro-2-methylphenyl)-N-(4-methoxybenzyl)glycinamide.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH:11]=[O:12].[Cl:24][C:25](Cl)(Cl)[C:26](F)([F:28])[F:27].[Cl-].[Al+3].[Cl-].[Cl-]>CN(C)C=O.[Zn]>[Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH:11]([OH:12])[C:25]([Cl:24])=[C:26]([F:28])[F:27]
Reactant: FC(F)(F)C(Cl)(Cl)Cl
Reactant: O=CCOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [Zn]
Solvent: CN(C)C=O
Product: OC(COCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)C(Cl)=C(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.8 %

Procedure:
Then, 19.54 g of 4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyloxyacetaldehyde was dissolved in 200 ml of N,N-dimethylformamide, to which 25.3 g of 1,1,1-trichlorotrifluoroethane, 17.6 g of zinc dust and 2.0 g of aluminum chloride were added. After stirring at room temperature for 1.5 hours, the reaction mixture was filtered. The filtrate was poured into diluted hydrochloric acid and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over magnesium sulfate and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 8.46 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(3-chloro-4,4-difluoro-2-hydoxy-3-butenyloxy)butyloxy)benzene (yield, 38%), nD22.5 1.5302.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH:8]([C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])=[O:10])=[CH:5][C:4]=1[C:30]([F:33])([F:32])[F:31])#[N:2].[CH3:34][S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH:8]([C:9](=[O:10])[NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[C:23]([CH3:27])([CH3:26])[CH2:24][O:25][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:5][C:4]=1[C:30]([F:32])([F:31])[F:33])#[N:2]
Reactant: COc1ccc(CNC(=O)C(Oc2ccc(C#N)c(C(F)(F)F)c2)C(C)(C)CO)c(OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(CNC(=O)C(Oc2ccc(C#N)c(C(F)(F)F)c2)C(C)(C)COS(C)(=O)=O)c(OC)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 116.8 %

Procedure:
To a clear, colorless solution comprised of 2-(4-cyano-3-trifluoromethyl-phenoxy)-N-(2,4-dimethoxy-benzyl)-4-hydroxy-3,3-dimethyl-butyramide (116.42 g; 250 mmol) in pyridine (160 mL) cooled to 0° C. under a nitrogen atmosphere was added methanesulfonyl chloride (30.2 g; 262 mmol). The mixture turned cloudy yellow with precipitate within 5 minutes of methanesulfonyl chloride addition. The reaction mixture was stirred cold for 1 hour, 20 minutes. The reaction flask was then loaded onto the rotary evaporator over a water bath warmed to 40° C. and the high vacuum was applied. After two hours of rotation, a negligible volume of pyridine had been distilled off and the water bath temperature was raised to 54° C. The pyridine was distilled off as the solution turned to a darker orange color and yielded a dark orange oil. To avoid decomposition, the flask was removed and the contents were partitioned between dichloromethane (1500 mL) and 2N aqueous hydrochloric acid (500 mL.) The unseparated aqueous (top) layer was tested with pH paper to show a pH of 4. The aqueous phase was acidified to pH 0 by the addition of concentrated aqueous hydrochloric acid (10 mL) to the biphasic mixture. The layers were separated and the organic phase was dried over anhydrous magnesium sulfate and vacuum filtered. The vacuum flask containing the clear orange filtrate solution was covered and left at ambient temperature for three days. The solution turned to dark red. Thin layer chromatography analysis of this solution (solvent system: 1:1 v/v hexanes-ethyl acetate) showed the major presence of desired material along with a baseline (Rf=0) species and two higher Rf species. The solution was concentrated in vacuo, keeping the water bath temperature at 35° C., to obtain 159 g of a red foam; 1H-NMR (400 MHz; CDCl3) δ 7.59 (d, 1H, J=2.1 Hz), 7.23 (d, 1H, J=2.5 Hz), 7.05 (d, 1H, J=2.1 Hz), 6.93 (dd, 1H, J=2.2, 0.7 Hz), 6.50 (t, 1H, J=1.5 Hz), 6.36 (dd, 1H, J=2.1, 0.6 Hz), 6.26 (d, 1H, J=0.6 Hz), 5.28 (s, 1H), 4.45 (s, 1H), 4.36-4.24 (m, 2H), 4.11 (dd, 2H, J=6.7, 2.4 Hz), 3.77 (s, 3H), 3.57 (s, 3H), 2.99 (s, 3H), 1.13 (s, 3H), 1.12 (s, 3H); 19F-NMR (376 MHz; CDCl3) δ −62.69 (s, 3F).
Reaction SMILES: [O:1]1[N:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[N:2]1.C1C=CC2N(O)N=NC=2C=1.N=C=N.[NH2:22][C@@H:23]([CH3:39])[CH2:24][N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([Cl:38])[CH:31]=2)=[N:26]1>C(Cl)Cl>[Cl:38][C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][N:25]([CH2:24][C@@H:23]([NH:22][C:6]([C:3]3[CH:4]=[N:5][O:1][N:2]=3)=[O:8])[CH3:39])[N:26]=2)[CH:37]=[CH:36][C:33]=1[C:34]#[N:35]
Reactant: O=C(O)c1cnon1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cnon1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of 1,2,5-oxadiazole-3-carboxylic acid (66 mg, 0.58 mmol) in 5 ml of DCM were added anhydrous HOBt (88 mg, 0.65 mmol) and PS-carbodiimide (590 mg, 0.77 mmol). After 10 min (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (100 mg, 0.38 mmol) was added and the reaction mixture was stirred at RT overnight. Resin was filtered and washed twice with DCM. Filtrate was washed with 10% citric acid, 1 M NaHCO3-solution, brine and water. Organic phase was dried over Na2SO4, filtered and evaporated to give 111 mg (81%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 4.25 (dd, 1H), 4.48 (dd, 1H), 4.58-4.70 (m, 1H), 6.66 (d, 1H), 7.51 (d, 1H), 7.71 (dd, 1H), 7.83 (dd, 1H), 8.01 (dd, 1H), 8.31 (d, 1H), 8.65 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:23]([CH3:24])=[C:22]([CH3:25])[S:21][C:10]=3[NH:11][C:12](=O)[C@@:13]3([CH2:16][C@H:15]3[CH2:17][O:18][CH3:19])[N:14]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].P(Cl)(=O)(OCC)OCC.[C:41]([NH:44][NH2:45])(=O)[CH3:42]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:23]([CH3:24])=[C:22]([CH3:25])[S:21][C:10]=3[N:11]3[C:41]([CH3:42])=[N:44][N:45]=[C:12]3[C@@:13]3([CH2:16][C@H:15]3[CH2:17][O:18][CH3:19])[N:14]=2)=[CH:4][CH:3]=1
Reactant: COC[C@@H]1C[C@]12N=C(c1ccc(Cl)cc1)c1c(sc(C)c1C)NC2=O
Reactant: CC(=O)NN
Agent: CC(C)(C)[O-]
Agent: CCOP(=O)(Cl)OCC
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: COC[C@@H]1C[C@]12N=C(c1ccc(Cl)cc1)c1c(sc(C)c1C)-n1c(C)nnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a solution of (1S,2R)-5′-(4-chlorophenyl)-2-(methoxymethyl)-6′,7′-dimethylspiro-[cyclopropane-1,3′-thieno[2,3-e][1,4]diazepin]-2′(1′H)-one (3.7, 9.87 mmol) in anhydrous THF (200 mL) at −78° C. was slowly added a solution of potassium tert-butoxide (12.34 mL, 12.34 mmol). The resulting dark brown solution was warmed to rt and stirred for 30 min. The reaction was cooled to −78° C. before diethyl phosphorochloridate (2.85 mL, 19.74 mmol) was slowly added. Once the addition was completed, the reaction was warmed to rt for 60 to 90 min before acetohydrazide (2.193 mg, 29.6 mmol) was added. The reaction was then heated to 60° C. for 2 h before MeOH (5 mL) and silica gel were sequentially added. The solvent was removed under vacuum, the dry silica gel was packed, and the product was purified by flash chromatography (EtOAc/hexane 3:7 to 100:0) to give (1S,2R)-4′-(4-chlorophenyl)-2-(methoxymethyl)-2′,3′,9′-trimethylspiro[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine] as a solid (3.54 g). LRMS (M+H)+: 413 m/z. 1H NMR (two conformers detected in ˜1:1 ratio) (400 MHz, DMSO-d6) δ 7.42-7.55 (m, 4H), 3.82 (dd, J=7.32, 10.99 Hz, 0.5H), 3.71 (dd, J=6.41, 11.22 Hz, 0.5H), 3.39 (s, 1.5H), 3.21 (dd, J=6.29, 10.87 Hz, 0.5H), 3.04 (dd, J=7.67, 10.87 Hz, 0.5H), 2.97 (s, 1.5H), 2.60 (s, 3H), 2.39 (s, 1.5H), 2.38 (s, 1.5H), 2.16-2.27 (m, 0.5H), 2.05 (dd, J=5.26, 9.38 Hz, 0.5H), 1.58 (s, 1.5H), 1.54 (s, 1.5H), 1.43-1.51 (m, 0.5H), 1.33-1.40 (m, 0.5H), 1.03 (dd, J=5.38, 9.27 Hz, 0.5H), 0.61 (t, J=6.07 Hz, 0.5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[C:19]([Cl:24])[CH:18]=1)(=[O:16])=[O:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([O:8][C:20]2[CH:21]=[CH:22][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[CH:18][C:19]=2[Cl:24])[CH:7]=1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Product: CS(=O)(=O)c1ccc(Oc2cc(Cl)cc(CC(=O)O)c2)c(Cl)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of step (iv) and 3-chloro-4-fluorophenyl methyl sulfone.