Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:18])[N:3]1[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1.IC.[C:33](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:1]=[C:2]1[N:6]([CH3:33])[C:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:18])[N:3]1[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:28])[F:29])[CH:20]=1
Reactant: C=CCOCC1(c2ccccc2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCOCC1(c2ccccc2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 0.86 g of 4-[2,5-dioxo-4-phenyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethyl-benzonitrile and 0.26 mL of iodomethane in 30 mL of DMF is added 430 mg of potassium carbonate. The mixture is stirred at rt for 5 hours, evaporated to dryness, diluted with water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by chromatography over silica gel while eluting with 70/30 heptane/ethyl acetate mixture to provide the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[O:31][CH2:32][CH2:33]O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:33][CH2:32][O:31][C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]=2)=[CH:7][CH:6]=1
Reactant: OCCOc1ccc2ccccc2c1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 59.7 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (3.62 g) in dimethylformamide (40 mL) under argon was treated with 55% sodium hydride (0.875 g), stirred for 15 minutes and treated with the mesylate of 2-(2-naphthyloxy)ethanol (5.48 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was crystallized from dichloromethane-hexane to provide 4.2 g of 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 155°-157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]2[C:6]([CH:17]=1)=[C:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[O:8][N:9]=2.[Br:19]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:18][C:4]1[C:5]2[C:6](=[C:7]([C:10]3[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=3)[O:8][N:9]=2)[CH:17]=[C:2]([Cl:1])[CH:3]=1
Reactant: Cc1cc(Cl)cc2c(-c3ccc(Cl)cc3)onc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2onc3c(CBr)cc(Cl)cc23)cc1
Yield: 81.5 %

Procedure:
A mixture of 12.2 g (0.044 mole) of 5-chloro-3-(4-chlorophenyl)-7-methyl-2,1-benzisoxazole, 8.0 g (0.045 mole) of N-bromosuccinimide, 0.1 g of dibenzoylperoxide and 500 ml of carbon tetrachloride was heated at reflux under white light illumination for 2 hr. The hot mixture was filtered and the filtrate was washed once with sodium bicarbonate solution, dried (sodium sulfate) and concentrated to give a solid as residue. The solid was recrystallized from acetonitrile to give 12.8 g (81%) of crude product. A portion of the solid was chromatographed on silica gel. The purified product was recrystallized from acetonitrile to yield an analytical sample of pale yellow solid, m.p. 145°-147° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:22])=[C:10]([N:14]3[CH2:19][CH2:18][NH:17][CH:16]([CH2:20][F:21])[CH2:15]3)[C:11]=2[F:13])[C:6](=[O:23])[C:5]([C:24]([OH:26])=[O:25])=[CH:4]1)[CH3:2].[C:27]([O-])(=O)C.[Na+].C=O>C(O)=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:22])=[C:10]([N:14]3[CH2:19][CH2:18][N:17]([CH3:27])[CH:16]([CH2:20][F:21])[CH2:15]3)[C:11]=2[F:13])[C:6](=[O:23])[C:5]([C:24]([OH:26])=[O:25])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(CF)C3)c(F)c21
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)C(CF)C3)c(F)c21
Yield: 70.7 %

Procedure:
A mixture of 150 mg of (-)-1-ethyl-6,8-difluoro-7-[3-(fluoromethyl)-1-piperazinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (Ex. 64) was reacted as described previously with 400 mg of sodium acetate, 3 ml of formic acid and 3 ml of formaldehyde, giving 110 mg of the desired product, mp 208°-210° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[CH3:16][O:17][C:18]([C:20]1[N:21]([CH2:26][C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=2)[N:22]=[C:23]([NH2:25])[CH:24]=1)=[O:19]>>[CH3:16][O:17][C:18]([C:20]1[N:21]([CH2:26][C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=2)[N:22]=[C:23]([NH:25][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]3)=[C:4]([O:14][CH3:15])[CH:3]=2)[CH:24]=1)=[O:19]
Reactant: COC(=O)c1cc(N)nn1Cc1cc(F)c(F)c(F)c1
Reactant: COc1cc(Br)ccc1-n1cnc(C)c1
Product: COC(=O)c1cc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nn1Cc1cc(F)c(F)c(F)c1

Procedure:
Prepared in analogy to example 1b) starting with 1-(4-bromo-2-methoxy-phenyl)-4-methyl-1H-imidazole (WO2009076352) and 5-amino-2-(3,4,5-trifluoro-benzyl)-2H-pyrazole-3-carboxylic acid methyl ester from example 39b). The title compound was obtained as a yellowish solid (Yield=34%). MS ISP (m/e): 472.1 (100) [(M+H)+].
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:38]3[CH:37]=[N:36][C:35]([Cl:34])=[CH:40][CH:39]=3)[C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCCC2)CC1
Reactant: OB(O)c1ccc(Cl)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(Cl)nc1)N1CCC(N2CCCCC2)CC1
Yield: 57 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 168), 2-chloropyridine-5-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a brown oil (57%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:6][C:7]([C@@H:10]([NH:13]S(C(C)(C)C)=O)[CH2:11][CH3:12])=[CH:8][N:9]=1)(=[O:4])=[O:3].[ClH:20]>CO>[ClH:20].[CH3:1][S:2]([C:5]1[S:6][C:7]([C@@H:10]([NH2:13])[CH2:11][CH3:12])=[CH:8][N:9]=1)(=[O:3])=[O:4]
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1cnc(S(C)(=O)=O)s1
Agent: Cl
Solvent: CO
Product: CC[C@H](N)c1cnc(S(C)(=O)=O)s1
Reaction time: 1 h
Yield: 96.6 %

Procedure:
A solution of 2-methyl-propane-2-sulfinic acid [(S)-1-(2-methanesulfonyl-thiazol-5-yl)-propyl]-amide (80 mg, 0.25 mmol) in methanol (5 mL) was treated with hydrochloric acid (4 N in dioxane, 1 mL, 4 mmol). The mixture was stirred at room temp. for 1 h and then concentrated. The residue was taken up in dichloromethane (2 mL) and diluted with hexanes (10 mL). Concentration gave (S)-1-(2-Methanesulfonyl-thiazol-5-yl)-propylamine hydrochloride (62 mg, 98%) as a yellow hygroscopic solid, that was used without further purification.
Reaction SMILES: [CH:1]1([CH:4]([O:6][C:7](=[O:34])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:30]4[CH2:33][CH2:32][CH2:31]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][CH2:27][CH2:28]Cl)[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1.[I-].[Na+].[Na].[NH:38]1[CH:42]=[N:41][CH:40]=[N:39]1>CC#N.CN(C=O)C>[CH:1]1([CH:4]([O:6][C:7](=[O:34])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:30]4[CH2:33][CH2:32][CH2:31]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][CH2:27][CH2:28][N:38]3[CH:42]=[N:41][CH:40]=[N:39]3)[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCCl)cc3n2C2CCC2)cc1)C1CC1
Reactant: c1nc[nH]n1
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCn4cncn4)cc3n2C2CCC2)cc1)C1CC1

Procedure:
To a solution of {4-[6-(2-chloroethoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester (1.46 g, 3.05 mmol) in CH3CN (10 mL) is added sodium iodide (1.84 g, 12.22 mmol). The resulting mixture is stirred at reflux temperature overnight. The solvent is evaporated and the residue is diluted with anhydrous DMF (20 mL) and then used without further purification. To 1 mL of the DMF solution containing the iodoethyl intermediate (0.153 mmol) is added the sodium salt of 1,2,4-triazole (0.31 mmol) and the reaction is stirred at room temperature overnight. The reaction mixture is diluted with 0.5 mL DMF and the desired product is purified by preparative LC to give {4-[3-cyano-1-cyclobutyl-6-(2-[1,2,4]triazol-1-yl-ethoxy)-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester, compound 1329 (23 mg, 29%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH2:15].[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[C:16]([NH:24][C:25]([NH:15][C:4]1[CH:5]=[C:6]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(C2CCOCC2)cc1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: COc1ccc(C2CCOCC2)cc1NC(=S)NC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a stirred solution of 2.75 g (13.3 mmol) 2-methoxy-5-(tetrahydro-pyran-4-yl)-phenylamine in 60 ml acetone was added dropwise a solution of 2.04 ml (15.2 mmol) benzoyl isothiocyanate in 30 ml acetone and stirring continued for 30 minutes at room temperature. The mixture was then concentrated in vacuo. Flash chromatography (1/1 ethyl acetate/hexane) followed by trituration in ether afforded 3.25 g (66%) 1-benzoyl-3-[2-methoxy-5-(tetrahydro-pyran-4-yl)-phenyl]-thiourea as a white solid. ES-MS m/e (%): 371 (M+H+, 100).
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31]>>[CH3:29][N:30]([CH:32]=[C:9]1[CH2:10][C:11](=[O:14])[CH2:12][CH2:13][N:8]1[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:31]
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: COC(N(C)C)N(C)C
Product: CN(C)C=C1CC(=O)CCN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 64 %

Procedure:
1-Triphenylmethyl-4-piperidone (0.239 g, 0.70 mmol) was added to methoxybis(dimethylamino)methane (1.75 ml) and the reaction mixture was stirred at 50° for sixteen hours. Volatiles were then removed in vacuo to provide a yellow solid, which was triturated with ether, and air dried to give the title product as a light yellow solid (0.179 g, 0.45 mmol, 64% yield).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[N:2]1.[N:13]1([CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([NH2:32])=[CH:24][CH:23]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[N:13]1([CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([NH:32][C:10]([C:8]3[CH:7]=[CH:6][C:5]4[S:1][N:2]=[N:3][C:4]=4[CH:9]=3)=[O:12])=[CH:24][CH:23]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C(O)c1ccc2snnc2c1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccc2snnc2c1

Procedure:
Compound is prepared from benzo[1,2,3]thiadiazole-5-carboxylic acid and 4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-ylamine according to conditions described in general procedure G. Mp: 188-190° C.; 1H NMR (300 MHz, CDCl3) δ 2.70 (t, 4H), 3.00 (t, 2H), 3.78 (t, 4H), 4.30 (t, 2H), 6.82 (d, 1H), 7.58 (m, 2H), 7.65 (d, 1H), 7.88 (d, 1H), 8.15 (d, 1H), 8.25 (d, 2H), 8.40 (s, 1H), 9.18 (s, 1H); MS 435 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:19]([O:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:15]([F:16])([F:17])[F:18])[CH:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(O)cc1C(F)(F)F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])c(OCc2ccccc2)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 6 h
Yield: 52.2 %

Procedure:
Methyl 4-hydroxy-5-nitro-2-(trifluoromethyl)benzoate (3.0 g) was dissolved in N,N-dimethyl-formamide (50 ml), and thereto were added benzyl bromide (2.3 g) and potassium carbonate (2.3 g), and the mixture was stirred at 80° C. for 6 hours. The reaction mixture was cooled, and water was added thereto. The mixture was extracted with ethyl acetate, and the organic layer was washed twice with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (the developing solvent: hexane/ethyl acetate=8:1→5:1→3:1) to give methyl 4-(benzyloxy)-5-nitro-2-(trifluoromethyl)benzoate (2.1 g), which was treated in a similar manner to Reference Example 5 to give the title compound (1.9 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].Br[CH2:37][C:38]([NH2:40])=[O:39]>>[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[C:23]4[CH:26]=[CH:27][C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:37][C:38]([NH2:40])=[O:39])[CH2:32][CH2:31]5)=[CH:29][C:22]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Reactant: NC(=O)CBr
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(CC(N)=O)CC3)cc1OCC2

Procedure:
Following the procedure for 143, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetic acid salt was reacted with 2-bromo acetamide to give 226 as a white solid. 1H NMR δ (ppm) (DMSO-d): 8.27 (1H, d, J=8.27 Hz), 7.84 (2H, d, J=2.70 Hz), 7.15 (1H, s), 7.06 (1H, s), 7.01 (1H, d, J=8.43 Hz), 6.87 (1H, s), 5.87-5.78 (1H, m), 4.44 (4H, d, J=6.92 Hz), 2.90-2.78 (4H, m), 2.15-2.06 (2H, m), 1.68 (5H, s), 1.42 (6H, d, J=6.59 Hz). LCMS: RT=2.57 min, M+H+=436
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)(O)[O-].[Na+].Cl[CH2:20][C:21](Cl)=[O:22]>CC(CC(C)C)=O.O>[I:13][C:10]1[C:11]2[O:12][CH2:20][C:21](=[O:22])[NH:1][C:2]=2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=1
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1cc(N)c(O)c(I)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: COC(=O)c1cc(I)c2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To an ice-cold, stirred solution of Methyl 3-amino-4-hydroxy-5-iodobenzoate (2.3 g) and sodium bicarbonate (1.5 g) in 1:1 isobutyl methyl ketone/water (80 mL) was added chloroacetyl chloride (1.1 g), and the reaction mixture was stirred for 1 h. The mixture was warmed to room temperature and heated at reflux for 18 h. After overnight, a beige solid formed. The mixture was filtered, and washed with water and hexanes to give 2.4 g of the title compound: 1H NMR (300 MHz, DMSO-d6) δ 10.98, 7.89, 7.47, 4.79, 3.82.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH2:18][C@@H:17]([NH:20]C(N2CCC(N3C4C(=NC=CC=4)N(COCC[Si](C)(C)C)C3=O)CC2)=O)[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C@H:10]1[NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:20][C@H:17]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C@@H:10]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[C@H:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2[C@H](NC(=O)N2CCC(n3c(=O)n(COCC[Si](C)(C)C)c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2[C@H](N)CC[C@H]1c1cccc(F)c1F

Procedure:
A Methylene chloride (1 mL) solution of tert-butyl (5S,6S,9R)-6-(2,3-difluorophenyl)-9-(4-(2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamido)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ylcarbamate (12 mg, 0.016 mmol) in TFA (0.5 ml, 6.5 mmol) was stirred at room temperature overnight. The solvent was removed via vacuum and the crude residue was partitioned between ethyl acetate and Sodium bicarbonate (sat). The ethyl acetate layer was separated, dried (sodium sulfate) and concentrated. The desired product was obtained by prep TLC eluting with 10% methanol in methylene chloride:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[Na].Br[CH2:12][C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14]>>[CH:15]1([C:13](=[O:14])[CH2:12][O:8][CH2:7][CH:5]2[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]2)[CH2:17][CH2:16]1
Reactant: CC1(C)OCC(CO)O1
Reactant: O=C(CBr)C1CC1
Agent: [Na]
Product: CC1(C)OCC(COCC(=O)C2CC2)O1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Charge a flask with (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (10 g, 75.7 mmol), heat to 85° C. and add freshly cut sodium (465 mg, 20.23 mmol) Heat to 85° C. and stir for 1 hour. Add 2-bromo-1-cyclopropylethanone (3.0 g, 18.4 mmol) maintain the temperature at 85° C. and stir for 30 minutes. Filter and wash the solid with ACN (20 mL). Collect the filtrate and concentrate under reduced pressure. Purify via HPLC conditions Z to give the title compound as a colorless oil. (650 mg, 16.5%). MS (m/z): 215 (M+1).
Reaction SMILES: C1([C@H]2[O:17][C:16](=[O:18])[C@@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:9]3[C@H]2C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCO.[Pd](Cl)Cl>[NH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[C:16]([OH:18])=[O:17]
Reactant: O=C1O[C@H](c2ccccc2)[C@H](c2ccccc2)N2CCCCC[C@@H]12
Agent: Cl[Pd]Cl
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)[C@@H]1CCCCCN1
Reaction time: 12 h

Procedure:
Palladium (II) chloride (800 mg, 4.51 mmol) is added to a solution of (3R,4S,9aS)-3,4-diphenyl-octahydro-2-oxa-4a-aza-benzocyclohepten-1-one (4.5 g, 14.0 mmol) in THF (140 mL) and EtOH (160 mL). The reaction mixture is stirred for 12 hours under H2 atmosphere at 50 psi, then filtered through celite that is washed with EtOH. Removal of the solvent under reduced pressure affords the title compound m/z 144 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:18]([CH2:21][CH3:22])([CH2:19][CH3:20])[C:17]2[CH:16]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:13][C:12]=2[CH2:11][CH:10]1[O:31][CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][N:34](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[C@H:10]([O:31][CH3:32])[CH2:11][C:12]2[C:17](=[CH:16][C:15]([C:33]#[N:34])=[CH:14][CH:13]=2)[C:18]1([CH2:19][CH3:20])[CH2:21][CH3:22])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCC1(CC)c2cc(OS(=O)(=O)C(F)(F)F)ccc2CC(OC)C1NC(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CCC1(CC)c2cc(C#N)ccc2C[C@@H](OC)[C@@H]1NC(=O)OC(C)(C)C
Temperature: 110 °C
Yield: 93.9 %

Procedure:
Trifluoro-methanesulfonic acid 7-tert-butoxycarbonylamino-8,8-diethyl-6-methoxy-5,6,7,8-tetrahydro-naphthalen-2-yl ester (236.6 g, 0.49 mol) was dissolved in N,N-dimethylformamide (851 mL, 10.99 mol) and water (23.8 mL, 1.32 mol) at room temperature. The solution was purged with nitrogen for 5 min, and then connected to house vacuum for 5 min. Nitrogen purging and exposure to vacuum was repeated twice. To the reaction mixture was added zinc cyanide (34.2 g, 0.29 mol), tris(dibenzylideneacetone)dipalladium(0) (4.4 g, 4.8 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (5.4 g, 9.7 mmol) with stirring. The reaction mixture was purged with nitrogen for 5 min, heated under nitrogen at 110° C. for 1 h, cooled to room temperature and then filtered through celite. The filtered reaction mixture was added slowly to water (3 L), cooled to 0° C. with stirring, stirred for 30 min at 0° C., and then filtered. The filter cake was washed with water (500 mL) and dried in air for 2 h, slurried in ethanol (1 L) with stirring over 1 h, and then filtered to give the title compound (165.0 g, >96% purity). The filtrate was dried (21.6 g) and dissolved in ethanol (110 mL) with stirring over 1 h, and the resulting slurry was filtered and dried under vacuum to give additional product (10.2 g, >98% purity).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[CH2:6][N:5]([C@H:15]([CH:28]([CH3:30])[CH3:29])[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:17])[CH2:4]1.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.[Si](OC[C@@H]1[C@@H](C2C=CC=CC=2)CNC1)(C(C)(C)C)(C)C>C(Cl)Cl.C(OCC)(=O)C.CS(C)=O>[CH:2]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[CH2:6][N:5]([C@H:15]([CH:28]([CH3:30])[CH3:29])[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:17])[CH2:4]1)=[O:1]
Reactant: COc1ccc(COC(=O)[C@@H](C(C)C)N2C[C@@H](CO)[C@@H](c3cccc(F)c3)C2)cc1
Agent: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc(COC(=O)[C@@H](C(C)C)N2C[C@H](c3cccc(F)c3)[C@@H](C=O)C2)cc1
Yield: 94.5 %

Procedure:
The title compound was prepared from 3.53 g of α-(R)-(3-(S)-(hydroxymethyl)-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-isopropylacetic acid, para-methoxybenzyl ester (from Step C), 0.89 mL of oxalyl chloride, 1.448 mL DMSO, and 5.924 mL of diisopropylethylamine in 150 mL of CH2Cl2 using a procedure analogous to that described for Aldehyde 1, Step C to provide 3.32 g of the title compound as a yellowish viscous oil (94%) after flash chromatography on silica gel eluting with 15˜35% ethyl acetate in hexanes. RF: 0.38 (20% EtOAc in hexanes). 1H NMR (500 MHz, CDCl3): δ9.64 (d,1.8 Hz, 1H), 7.32˜7.34 (m, 2H), 7.23˜7.28 (m, 1H), 6.87˜6.97 (m, 5H), 5.13 (s, 2H), 3.82 (s, 3H), 3.55 (dd, 7.1 & 14.4 Hz, 1H), 3.25˜3.28 (m, 1H), 3.13˜3.20 (m, 2H), 3.07 (d, 9.6 Hz, 1H), 2.88˜2.93 (m, 1H), 2.66˜2.70 (m, 1H), 2.03˜2.10 (m, 1H), 1.00 (d, 6.4 Hz, 3H), 0.91 (d, 6.6 Hz, 3H).