Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:18][CH2:17][CH2:16][C@@H:15]3[N:10]2[C:11](=[O:19])[CH2:12][CH:13]=[CH:14]3)=[CH:5][CH:4]=1.[H][H]>CO.[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:18][CH2:17][CH2:16][C@@H:15]3[N:10]2[C:11](=[O:19])[CH2:12][CH2:13][CH2:14]3)=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: COc1ccc([C@H]2CCC[C@H]3C=CCC(=O)N32)cc1
Agent: O=[Pt]
Solvent: CO
Product: COc1ccc([C@H]2CCC[C@H]3CCCC(=O)N32)cc1
Yield: 81.5 %

Procedure:
Platinum oxide (2 mg) was added to a solution of (6R*,9aS*)-6-(4-methoxyphenyl)-3,6,7,8,9,9a-hexahydroquinolizin-4-one (28 mg) in methanol (5 mL), and the reaction solution was stirred in a hydrogen stream at room temperature for 13 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 23 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[N:11]=[N:12][C:13]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:14][C:15]=1[C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.[I:31]N1C(=O)CCC1=O>CC(C)=O>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[I:31][C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][C:16]=1[C:15]1[CH:14]=[C:13]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:12]=[N:11][C:10]=1[O:9][CH3:8]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: COc1nnc(-c2ccncc2)cc1-c1[nH]c2ccccc2c1I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 2 g 2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-1H-indole trifluoroacetate and 1.3 g N-Iodosuccinimide (NIS) in acetone is stirred for 4 h at ambient temperature. The product is isolated by filtration, washed with acetone and used without further purification
Reaction SMILES: [CH2:1]([Si:3]1([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([Mg]Br)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH:6]3[CH2:7][CH2:8][Si:3]([CH2:1][CH3:2])([C:10]4[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=4)[CH2:4][CH2:5]3)=[CH:26][CH:25]=2)=[CH:22][CH:23]=1
Reactant: Fc1ccc(-c2ccc([Mg]Br)cc2)cc1
Reactant: CC[Si]1(c2ccc(C)cc2)CCC(=O)CC1
Product: CC[Si]1(c2ccc(C)cc2)CCC(c2ccc(-c3ccc(F)cc3)cc2)CC1

Procedure:
Using the same method as Example 14, 23.2 g of 4-ethyl-4-p-tolyl-4-silacyclohexanone was reacted with 4-(4-fluorophenyl)phenyl magnesium bromide; the alcohol generated was treated with a dehydration reaction followed by catalytic reduction to obtain 4-(4-(4-fluorophenyl)phenyl)-1-ethyl-1-p-tolyl-1-silacyclohexane; this was then reacted with iodine monochloride; and then the product was reduced using lithium aluminum hydride to obtain 2.12 g (yield 71%) of the target product.
Reaction SMILES: NCC(O)=O.[OH-].[Na+].[CH:8]1([CH:14]([CH2:17][CH2:18][OH:19])[CH2:15][OH:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)([O-])=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.COC1C=CC(C=O)=CC=1>O.CC(C)=O.C(O)C.C(Cl)Cl>[CH:8]1([C@H:14]2[CH2:17][CH2:18][O:19][C:15]2=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: OCCC(CO)C1CCCCC1
Agent: COc1ccc(C=O)cc1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: NCC(=O)O
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C1OCC[C@@H]1C1CCCCC1

Procedure:
Glycine (18.8 grams) is dissolved in 2 liters of deionized water, and the pH is adjusted by the addition of 10% sodium hydroxide to 9.0. 2-Cydohexyl-1,4-butanediol (10.0 grams) is dissolved in 150 ml of acetone added to the glycine solution with stirring, followed by the addition of β-NAD+ (Sigma, 0.5 grams). To the resulting solution is added horse liver alcohol dehydrogenase (Sigma, 250 mg, approximately 400 units). After the enzyme has dissolved the pH is readjusted to 9.0 with 10% sodium hydroxide, and the reaction mixture is stirred at 30° C. During the reaction, the pH is maintained at 9.0 with a pH-stat by the addition of 10% sodium hydroxide. Progress of the reaction is monitored by thin layer chromatography (Silica gel plates, eluent methylene chloride; visualization by dipping in a solution of 5% anisaldehyde in ethanol and heating). When the reaction is complete as judged by thin layer chromatography, the reaction mixture is adjusted to a pH of 13 with 10 M sodium hydroxide and then extracted 3 times with 250 ml of methylene chloride. The pH of the aqueous mixture is then adjusted to 3 with concentrated HCl, followed by continuous extraction with 1 liter of ethyl acetate for 24 hours. The ethyl acetate extract is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to yield (2R)-2-cydohexylbutyrolactone as a yellowish solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:17]([O-])=O.C([O-])=O.[NH4+].[CH:24]1([C:27]2[N:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][N:28]=2)[CH2:26][CH2:25]1.C(O)(=O)C>CN(C)C=O.O.[Zn]>[CH:24]1([C:27]2[N:32]=[C:31]([C:33]3[NH:1][C:2]4=[N:7][C:6]([N:8]5[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=[O:15])[CH2:9]5)=[CH:5][CH:4]=[C:3]4[N:17]=3)[CH:30]=[CH:29][N:28]=2)[CH2:26][CH2:25]1
Reactant: O=Cc1ccnc(C2CC2)n1
Reactant: Nc1nc(N2CCC[C@@H](C(=O)O)C2)ccc1[N+](=O)[O-]
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)[C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1
Temperature: 45 °C
Reaction time: 16 h
Yield: 28.6 %

Procedure:
(R)-1-(6-amino-5-nitropyridin-2-yl)piperidine-3-carboxylic acid, prepared during the previous step, was dissolved in a mixture of N,N-dimethylformamide (45.5 mL) and water (4.9 mL). Ammonium formate (1.925 g, 30.625 mmol) was added followed by zinc dust (1.05 g, 15.3 mmol). The reaction mixture was stirred at 45° C. for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. To the residue was added N,N-dimethylformamide (24.5 mL) followed by a solution of 2-cyclopropylpyrimidine-4-carbaldehyde in N,N-dimethylformamide (24.5 mL, 6.125 mmol, 0.25M) and acetic acid (3.675 mL, 61.25 mmol). The reaction mixture was stirred at 60° C. for 16 h. The solvent was removed under reduced pressure and the residue was purified via preparative HPLC to afford the title compound (0.637 g, 28.6%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:34](=[O:39])[C:35]([O:37][CH3:38])=[O:36].C(N(CC)CC)C.O>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([C:34](=[O:39])[C:35]([O:37][CH3:38])=[O:36])[CH2:29][CH2:28]3)=[CH:23][CH:24]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(=O)Cl
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(OCC3CCNCC3)cc2)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(=O)N1CCC(COc2ccc(C(=O)N3CCN(c4ccccc4C(C)(C)C)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)-4-{[4-(piperidin-4-ylmethoxy)phenyl]carbonyl}piperazine (0.44 g, 1.01 mmol), methyl chloro(oxo)acetate (0.153 g, 1.25 mmol) and triethylamine (0.279 mL, 2.0 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford a solid (0.527 g, 100%).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12](Br)[C:11]2[C:15]([CH3:18])=[N:16][S:17][C:10]=2[C:9]=1[OH:19])=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:20]([Sn](CC)(CC)CC)[CH3:21]>>[CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([CH2:20][CH3:21])[C:11]2[C:15]([CH3:18])=[N:16][S:17][C:10]=2[C:9]=1[OH:19])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2c(C)nsc2c1O
Reactant: CC[Sn](CC)(CC)CC
Product: CCCCOC(=O)c1nc(CC)c2c(C)nsc2c1O

Procedure:
The title compound was synthesized in analogy to Example 28 from 4-bromo-7-hydroxy-3-methyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester and tetraethyltin: MS (m/z) 295.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([NH2:14])[C:12]#[CH:13].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:14][CH2:11][C:12]#[CH:13])=[O:7])=[CH:4][CH:3]=1
Reactant: C#CCN
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCNC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To 4-bromobenzoyl chloride (4.39 g, 20 mmol) in 40 mL dichloromethane at 0° C., propargylamine (1.10 g, 20 mmol) was added, followed by triethylamine (4.05 g, 40 mmol). The mixture was stirred at room temperature for 40 minutes. 150 mL ethyl acetate was added and filtered. The filtrate was washed with 2×40 mL water and 40 mL brine, dried and concentrated to give 4-Bromo-N-(2-propynyl)benzamide. 4-Bromo-N-(2-propynyl)benzamide was added into ice cooled 47 mL concentrated sulfuric acid. The reaction was stirred at 5°-10° C. for 3 hours and at room temperature overnight. The mixture was poured into 500 mL ice water, neutralized with sodium carbonate to pH 8 and extracted with 3×250 mL ethyl acetate. The combined organic extracts were washed with 200 mL water and 100 mL brine, dried and concentrated to afford compound A (4.5 g, 95%) as a light yellow solid.
Reaction SMILES: [CH:1]1([N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9](B4OC(C)(C)C(C)(C)O4)[CH:10]=3)[C:5]2=[O:22])[CH2:3][CH2:2]1.Br[C:24]1[CH:38]=[CH:37][C:27]([CH2:28][N:29]2[C:33](=[O:34])[CH2:32][N:31]([CH3:35])[C:30]2=[O:36])=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(Cl)Cl.O>[CH:1]1([N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:24]4[CH:38]=[CH:37][C:27]([CH2:28][N:29]5[C:33](=[O:34])[CH2:32][N:31]([CH3:35])[C:30]5=[O:36])=[CH:26][CH:25]=4)[CH:10]=3)[C:5]2=[O:22])[CH2:2][CH2:3]1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CC2)C3=O)OC1(C)C
Reactant: CN1CC(=O)N(Cc2ccc(Br)cc2)C1=O
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CN1CC(=O)N(Cc2ccc(-c3ccc4c(c3)CN(C3CC3)C4=O)cc2)C1=O
Yield: 2280.8 %

Procedure:
2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (1A5) (0.08 mmol, 26.4 mg), 3-(4-bromobenzyl)-1-methylimidazolidine-2,4-dione (3D3) (0.08 mmol, 25.0 mg), tris(dibenzylidineacetone)dipalladium (0.004 mmol, 4.12 mg), tricyclohexylphosphine (0.096 mmol, 3.1 mg) and potassium phosphate (0.16 mmol, 39.0 mg) were suspended in dioxane (1 ml) and water (0.5 ml) and heated at 120° C. in the microwave for 20 min. The reaction was diluted with DCM (2 ml) and water (2 ml) then passed through a hydrophobic fritted tube. The organic phase was concentrated and the residue purified on basic HPLC to give 3-(4-(2-cyclopropyl-1-oxoisoindolin-5-yl)benzyl)-1-methylimidazoline-2,4-dione (Example 3a) (685 mg, 55%) 1H NMR (400 MHz, CDCl3) δ 7.87 (d, 1H) 7.64 (d, 1H) 7.57-7.50 (m, 5H) 4.71 (s, 2H) 4.37 (s, 2H) 3.89 (s, 2H) 3.01 (s, 3H) 2.95 (m, 1H) 0.95-0.88 (m, 4H) LCMS m/z (M+H) 376.0.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[N:3]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc2c(-c3ccc(OC)c(OC)c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3,4-dimethoxy-phenylboronic acid to give [1-(3,4-dimethoxy-phenyl)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 377(MH+).
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5]Cl.[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.[K]>>[Cl:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:11]1[C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]2[C:7]1=[O:17]
Reactant: ClC/C=C/CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1C/C=C/CCl
Temperature: 20 °C
Yield: 61 %

Procedure:
Ex-7a) Under argon, to 65.8 g of trans-1,4-dichloro-2-butene was added in portions 47 g of potassium phthalimide with mechanical stirring maintaining the temperature between 100° C. and 110° C. The reaction mixture was then stirred for 2 h keeping the temperature between 145° C. to 150° C. It was then cooled to 20° C. and extracted with 3×400 mL of ether. The ether layer was separated and stripped to give a solid. This solid was recrystallized from ethanol to yield yellow crystals of N-(trans-4-Chloro-2-butenyl)phthalimide, wt. 36 g, 61% yield. Analysis calcd. for C12H10ClNO2 (MW 237.25): C, 61.26; H, 4.29; N, 6.02; Cl, 14.94; Found C, 61.18; H, 4.30; N, 5.98; Cl, 14.62.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([NH:10][C:8]([C:3]1[C:2]([OH:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:9])(=[O:13])[CH3:12]
Reactant: NC(=O)c1nccnc1O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NC(=O)c1nccnc1O
Temperature: 110 °C
Reaction time: 1 h

Procedure:
In 5 mL of acetic anhydride is suspended 0.5 g of 3-hydroxy-2-pyrazinecarboxamide. The resulting solution is stirred at 110° C. for 1 hour. The deposited crystals are collected by filtration to obtain 0.5 g of N2-acetyl-3-hydroxy-2-pyrazinecarboxamide.
Reaction SMILES: [F:1][C:2]([F:32])([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])=[CH:21][CH:20]=1)[C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:5][C:4]=1[F:17]>C1COCC1>[F:32][C:2]([F:1])([O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])=[CH:23][CH:24]=1)[C:3]1[C:4]([F:17])=[CH:5][C:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:7][C:8]=1[F:9]
Reactant: OCCCCC#Cc1ccc(OC(F)(F)c2c(F)cc(C#CCCCCO)cc2F)cc1
Solvent: C1CCOC1
Product: OCCCCCCc1ccc(OC(F)(F)c2c(F)cc(CCCCCCO)cc2F)cc1

Procedure:
6-(4-{Difluoro[4-(6-hydroxyhex-1-ynyl)phenoxy]methyl}-3,5-difluorophenyl)-hex-5-yn-1-ol is hydrogenated to completion on palladium/active carbon catalyst in THF. The catalyst is filtered off, the solvent is removed in vacuo, and the crude product is chromatographed on silica gel with toluene/ethyl acetate (1:2), giving 6-(4-{difluoro[4-(6-hydroxyhexyl)-phenoxy]methyl}-3,5-difluorophenyl)hexan-1-ol as a colourless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](N)[CH:3]=1.[C:9](=[O:12])([O-])[O-].[K+].[K+].CI>OS(O)(=O)=O.CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:6])[C:9](=[O:12])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1cc(Br)ccn1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1ccc(Br)cc1=O
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
A solution of 4-bromopyridin-2-amine (600 mg, 3.5 mmol) in a mixture of 2M H2SO4 (20 mL) and 2M Na2NO2 (10 mL) was stirred at 0-5° C. for 2 h. The reaction mixture was extracted with CH2Cl2, and the organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude product was used in next step without further purification. The crude product 15a, potassium carbonate (3.6 mmol) and methyl iodide (3.7 mmol) were refluxed in acetone (100 mL) in a sealed tube for 4 h. The reaction mixture was cooled, and potassium carbonate was filtered off. The acetone was evaporated off and a small amount of water was added to the residue. This solution was extracted with CH2Cl2. The organic layer was dried, concentrated and purified with column chromatography to afforded 17a (355 mg, 57%). 1H NMR (CDCl3,): δ 3.49 (s, 3H), 6.31 (d, J=6.0 Hz, 1H), 6.82 (s, 1H), 7.14 (d, J=6.0 Hz, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].[C:13]([O:17][C:18](=[O:40])[CH:19]([NH:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=2)=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH:20]([CH3:22])[CH3:21])([CH3:16])([CH3:15])[CH3:14]>ClCCl.CN(C)C1C=CN=CC=1>[C:13]([O:17][C:18]([CH:19]([NH:23][S:24]([C:27]1[CH:28]=[CH:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([O:11][C:10]([C:2]3[O:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[CH:3]=3)=[O:12])=[CH:35][CH:34]=2)=[CH:31][CH:32]=1)(=[O:25])=[O:26])[CH:20]([CH3:22])[CH3:21])=[O:40])([CH3:15])([CH3:16])[CH3:14]
Reactant: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(O)cc2)cc1)C(=O)OC(C)(C)C
Reactant: O=C(O)c1cc2ccccc2o1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(OC(=O)c3cc4ccccc4o3)cc2)cc1)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 23.9 %

Procedure:
To benzofuran-2-carboxylic acid (0.401 g, 2.47 mmol, 1 equiv.) dissolved in dry dichloromethane (50 mL) was added dicyclohexylcarbidiimide (1.019 g, 4.94 mmol, 2 equiv) and the mixture was stirred under nitrogen for 15 minutes. Then 2-(4′-hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester (1.0 g, 2.47 mmol, 1 equiv., Example 134, Step 1) was introduced to the reaction mixture, followed by the addition of 4-dimethylamino pyridine (0.050 g, 0.41 mmol). The mixture was allowed to stir at room temperature overnight. The reaction mixture was then diluted with dichloromethane, washed with water and brine. The organic layer was dried over magnesium sulfate and the solvent was concentrated in vacuo. The residue was dissolved in ethyl acetate and purified by column chromatography on silica gel eluting with 20% ethyl acetate/hexane to afford 325 mg of benzofuran-2-carboxylic acid 4′-(1-tert-butoxycarbonyl-2-methyl-propylsulfamoyl)-biphenyl-4-yl ester in 31% yield. 1H NMR (400 MHz, CDCl3) δ ppm 0.87 (d, J=6.82 Hz, 3 H) 1.03 (d, J=6.82 Hz, 3 H) 1.21 (s, 9 H) 2.07 (m, 1 H) 3.68 (dd, J=9.85, 4.55 Hz, 1 H) 5.15 (d, J=9.85 Hz, 1 H) 7.37 (m, 3 H) 7.53 (t, J=7.83 Hz, 1 H) 7.66 (m, 5 H) 7.77 (m, 2 H) 7.92 (d, J=8.34 Hz, 2 H).
Reaction SMILES: [OH:1]/[N:2]=[C:3]1\[CH2:4][C:5]2([O:18][C:19]3[C:24]\1=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>N1C=CC=CC=1>[S:32]([O:1]/[N:2]=[C:3]1\[CH2:4][C:5]2([O:18][C:19]3[C:24]\1=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)([C:29]1[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=1)(=[O:34])=[O:33]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C/C(=N\O)c1ccccc1O2
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O/N=C2\CC3(CCN(C(=O)OC(C)(C)C)CC3)Oc3ccccc32)cc1
Yield: 81.6 %

Procedure:
A mixture of tert-butyl (4E)-4-hydroxyiminospiro[chromane-2,4′-piperidine]-1′-carboxylate (448 mg, 1.34 mmol) and 4-methylbenzenesulfonyl chloride (514 mg, 2.70 mmol) were stirred in pyridine (2.1 mL) at 0° C. for 6 hours. The reaction mixture was poured over ice and the mixture was extracted with ethyl acetate. The organics were dried over sodium sulfate and evaporated to give (E)-tert-butyl 4-(tosyloxyimino)spiro[chroman-2,4′-piperidine]-1′-carboxylate (532 mg, 81%). ESI-MS m/z calc. 486.2. found 487.5 (M+1)+; Retention time: 2.20 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH:10][C:12](=[O:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NNc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CC(=O)NNc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
N′-(3,4-Dichlorophenyl)hydrazine was liberated from its hydrochloride (10.0 g, 46.8 mmol) by partitioning the solid between diluted Na2CO3 solution (10 ml saturated solution and 40 ml water) and AcOEt. The aqueous layer was extracted two more times with AcOEt, the organic extracts were dried (Na2SO4), the solvent was removed in vacuo, and the residue was taken up in dry toluene (100 ml). To this solution acetic anhydride (4.78 g, 46.8 mmol) was slowly added, and the reaction mixture was stirred at room temperature for 15 min. Light petroleum (50 ml) was added, the mixture was cooled in the refrigerator (−20° C.), and the resulting crystals were collected on a sintered glass funnel and washed with cold petrol ether. Recrystallization from MeOH yielded (V) (8.30 g, 81%) as shiny white crystals, mp 179-182° C. (lit. 168-171° C.). TLC CHCl3/MeOH 9:1.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Cl:10][C:11]1[CH:19]=[C:18]([Cl:20])[C:17]([F:21])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[Cl:10][C:11]1[C:19]([N+:1]([O-:4])=[O:2])=[C:18]([Cl:20])[C:17]([F:21])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(F)c(Cl)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Temperature: 25 °C

Procedure:
40 ml of concentrated nitric acid are added dropwise, with ice cooling and stirring, to 34 ml of concentrated sulphuric acid. 20.9 g of 2,4-dichloro-5-fluorobenzoic acid are added in portions to this nitration mixture, the temperature increasing to 45°-50° C. The mixture is then heated for a further 3 hours at 90°-100° C. and, after cooling to room temperature, poured into 350 ml of ice water, and the precipitate is filtered off under suction and washed with water. The moist crude product is dissolved in 30 ml of hot methanol, and 150 ml of H2O are added to the solution. The precipitate is filtered off under suction when cold, washed with CH3OH/H2O and dried at 80° C. in vacuo. 21.2 g of crude 2,4-dichloro-5-fluoro-3-nitro-benzoic acid are obtained. It is sufficiently pure for the further reactions. Melting point: 192° C. (from toluene/petroleum ether).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([CH2:22][OH:23])[CH2:17]2)[CH:11]=1)[CH3:9])(C)(C)C.Cl>>[NH2:7][CH:8]([C:10]1[CH:11]=[C:12]([N:16]2[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][OH:23])[CH2:17]2)[CH:13]=[CH:14][CH:15]=1)[CH3:9]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(N2CCOC(CO)C2)c1
Agent: Cl
Product: CC(N)c1cccc(N2CCO[C@H](CO)C2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of (S)-{1-[3-(2-hydroxymethyl-morpholin-4-yl)phenyl]-ethyl}-carbamic acid tert-butyl ester (1.0 g, 3.4 mmol) and hydrochloric acid (1.0M solution in diethyl ether) (10.2 mmol, 3eq) was stirred at room temperature overnight. Concentrated under vacuum and the title compound was obtained as pale red solid (quantitative yield) ready for use for next step without purification.