Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[I:9]N1C(=O)CCC1=O.O>CS(C)=O>[I:9][C:7]1[C:2]([NH2:1])=[N:3][C:4]([NH2:8])=[CH:5][CH:6]=1
Reactant: Nc1cccc(N)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(I)c(N)n1
Temperature: 25 °C
Yield: 22.8 %

Procedure:
2,6-Diaminopyridine (100 g, 916 mmol) was dissolved in dimethyl sulfoxide (400 mL), and N-iodosuccinimide (100 g, 445 mmol) was added in one portion while stirring at room temperature. The reaction solution was stirring for 10 minutes at room temperature. Water (3.5 L) was added to the reaction solution, and the precipitated solids were filtered out. The resulting aqueous layer was extracted with ethyl acetate (1.3 L) 3 times. The ethyl acetate layers were combined and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel chromatography (heptane:ethyl acetate=2:3) to obtain the title compound (23.8 g, 22.8%).
Reaction SMILES: [CH:1]([N:14]1[N:18]=[N:17][C:16]([C:19]2[CH:24]=[C:23](Br)[CH:22]=[C:21](Br)[CH:20]=2)=[N:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](B(O)O)=[CH:30][CH:29]=1.O1[CH2:46][CH2:45]OCC1.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[CH:1]([N:14]1[N:18]=[N:17][C:16]([C:19]2[CH:24]=[C:23]([C:31]3[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:28]([CH3:27])=[CH:29][CH:30]=3)[CH:22]=[C:21]([C:1]3[C:2]4[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:45]([CH3:46])=[CH:9][CH:8]=3)[CH:20]=2)=[N:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cc(Br)cc(-c2nnn(C(c3ccccc3)c3ccccc3)n2)c1
Reactant: C1COCCO1
Reactant: Cc1ccc(B(O)O)c2ccccc12
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
Product: Cc1ccc(-c2cc(-c3nnn(C(c4ccccc4)c4ccccc4)n3)cc(-c3ccc(C)c4ccccc34)c2)c2ccccc12
Temperature: 90 °C
Yield: 90 %

Procedure:
A round-bottomed flask was charged with 2-benzhydryl-5-(3,5-dibromophenyl)-2H-tetrazole (282 mg, 0.60 mmol), 4-methylnaphthalen-1-ylboronic acid (251 mg, 1.32 mmol) and Pd(PPh3)4 (35 mg, 0.03 mmol). After degassed, dioxane (5 mL) and aqueous sodium carbonate (3 mL, 2M, 6.0 mmol) was added. The reaction mixture was heated to 90° C. until the reaction was complete. 30 mL of water was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulphate and then concentrated. The residue was purified by flash chromatography (hexane:CH2Cl2=2:1) to afford 0.32 g (90%) of product as a white solid.
Reaction SMILES: [C:1](#[N:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:11][OH:12]>CCO>[OH:12][N:11]=[C:1]([NH2:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NO
Reactant: N#CC=Cc1ccccc1
Solvent: CCO
Product: NC(C=Cc1ccccc1)=NO
Yield: 70.1 %

Procedure:
Cinnamonitrile (1 g, 7.74 mmol) and hydroxylamine (0.71 cm3, 11.6 mmol, 1.5 eq) were reacted in EtOH (7 cm3) as described for AO6 (two chromatographic separations were needed in purification) to give N′-hydroxycinnamimidamide (0.88 g, 70%) as a light orange solid, mp 85-87° C. (lit 93° C.).
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH2:7][NH2:8])=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:18]=1[CH:19]=O>>[C:1]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[CH:19]([C:18]3[C:17]([O:16][CH3:15])=[CH:24][CH:23]=[CH:22][C:21]=3[O:25][CH3:26])[CH2:22][CH2:21][CH2:18][C:17]2=[O:16])=[CH:5][CH:6]=1
Reactant: COc1cccc(OC)c1C=O
Reactant: NCc1ccc(-c2ccccc2)cc1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(-c2ccccc2)cc1

Procedure:
Prepared according to the described general procedure 6 (GP6) with commercially available [1,1′-biphenyl]-4-ylmethanamine and commercially available 2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.84 min.; [M+H]+: 401.85 g/mol.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7](=[P:27]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:8]1[C@H:11]([CH2:12][C:13]([OH:15])=[O:14])[C@@H:10]([C@H:16]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH3:17])[C:9]1=[O:26])=[O:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[C:53](Cl)(=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55]>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]([C:7](=[P:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[N:8]1[C@H:11]([CH2:12][C:13]([O:15][C:53](=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])=[O:14])[C@@H:10]([C@H:16]([O:18][Si:19]([C:22]([CH3:24])([CH3:23])[CH3:25])([CH3:21])[CH3:20])[CH3:17])[C:9]1=[O:26])=[O:6])[CH:2]=[CH2:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C=CCOC(=O)C(N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1CC(=O)O)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CCOC(=O)C(N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1CC(=O)OC(=O)C(C)(C)C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 0.65 g of (3S,4R)-1-[(allyloxycarbonyl)(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-(carboxymethyl)azetidine-2-one in 4 ml of toluene were added under ice-cooling 0.14 ml of triethylamine and 0.12 ml of pivaloyl chloride, and the mixture was stirred at room temperature. The resulting precipitate was collected by filtration, and the filtrate was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give 0.60 g of (3S,4R)-1-[(allyloxycarbonyl)(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(pivaloyloxycarbonyl)methyl]azetidine-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Clc1ccncc1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: Cl
Product: O=C(O)c1cc(Cl)ccc1Nc1ccncc1
Yield: 40.8 %

Procedure:
5-Chloro-2-(4-pyridinylamino)benzoic acid was prepared from 25 g of 5-chloroanthranilic acid and 21 g of 4-chloropyridine hydrochloride according to the procedure of Example 1, part (a). There was obtained 14.2 g of 5-chloro-2-(4-pyridinylamino)benzoic acid, m.p. 306°-308° C. (decompn.).
Reaction SMILES: C(O)(=O)[C:2](O)=[O:3].[CH2:7]([O:9][C:10]([CH:12]1[CH2:14][CH2:13]1)=[O:11])[CH3:8]>O>[CH2:7]([O:9][C:10]([C:12]1([CH:2]=[O:3])[CH2:14][CH2:13]1)=[O:11])[CH3:8]
Reactant: CCOC(=O)C1CC1
Reactant: O=C(O)C(=O)O
Solvent: O
Product: CCOC(=O)C1(C=O)CC1
Yield: 51.1 %

Procedure:
Oxalic acid (11.2 g, 0.124 mol) was dissolved in water (40 mL) and 144,4,6-trimethyl-[1,3]oxazinan-2-yl)-cyclopropanecarboxylic acid ethyl ester (15 g, 0.062 mol) was added. Steam distillation of this mixture was carried out until 500 mL of distillate had been collected. The distillate was saturated with NaCl and extracted with EtOAc (2×100 mL). The organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give 1-formyl-cyclopropanecarboxylic acid ethyl ester (4.5 g, 51%). 1H NMR (CDCl3 400 MHz): δ10.39 (s, 1H), 4.26 (q, J=7.2 Hz, 2H), 1.67-1.64 (m, 2H), 1.61-1.58 (m, 2H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C1COCC1.N1CCCCC1>C(N(CC)CC)C>[CH3:16][C:4]1[C:5]([C:8]2[S:12][C:11]([C:13]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:15])=[CH:10][CH:9]=2)=[N:6][O:7][C:3]=1[C:2]([F:1])([F:18])[F:17]
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: C1CCNCC1
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccc(C(=O)N3CCOCC3)s2)noc1C(F)(F)F
Yield: 95 %

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and morpholine by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperidine derivative. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried to afford product as a colorless solid (66 mg, 95%). 1H NMR (CDCl3) 2.34 (d, J=1.3, 3 H), 3.71-3.77 (m, 8 H), 7.32 (d, J=4.0, 1 H), 7.43 (d, J=4.0, 1 H). 13C NMR 7.9, ˜48 (br), 67.0, 114.7, 118.7 (q, J=271), 128.0, 129.5, 131.7, 139.5, 157.9, 162.8. 19F NMR −63.2. LC/MS 5.93 min, [M+1]+ 347.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=C(C(O)=O)[C:12]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[CH:11][C:7]=1[C:8](O)=[O:9].[C:23](Cl)(=O)[C:24]([Cl:26])=[O:25].CN(C=O)C.C(Cl)[Cl:35]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[C:23]([C:24]([Cl:26])=[O:25])[C:12]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[CH:11][C:7]=1[C:8]([Cl:35])=[O:9]
Reactant: ClCCl
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(-c2cccs2)c(C(=O)O)cc1-c1cccs1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(-c2cccs2)c(C(=O)Cl)cc1-c1cccs1
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
To a solution of 2,5-dithien-2-ylterephthalic acid (4.06 g, 12.29 mmol) and oxalyl chloride (3.12 g, 24.58 mmol) in DCM (100 cm3) is added DMF (1 cm3) at 0° C. After 10 minutes, this mixture is allowed to warm to 23° C. and stirred overnight. The solvent is removed under reduced pressure to give the crude product as a yellow oil (4.38 g, 97%). 1H NMR (300 MHz, CDCl3): δ(ppm) 7.90 (s, 2H, Ar—H), 7.51 (dd, J=4.9 and 1.4 Hz, 2H, Ar—H), 7.13-7.20 (m, 4H, Ar—H). This product is used for next step without further purification.
Reaction SMILES: [OH-].[Na+].CO.C[O:6][C:7](=[O:42])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[N:36]([CH3:40])[C:35](=[O:41])[CH:34]=[CH:33]3)[CH2:16][CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:10][CH:9]=1.O>C(O)(=O)C>[CH3:40][N:36]1[C:37]2[C:32](=[CH:31][C:30]([O:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N:15]([CH2:14][C:11]3[CH:12]=[CH:13][C:8]([C:7]([OH:42])=[O:6])=[CH:9][CH:10]=3)[CH2:16][CH2:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:39][CH:38]=2)[CH:33]=[CH:34][C:35]1=[O:41]
Reactant: COC(=O)c1ccc(CN(CCCCCOc2ccc3c(ccc(=O)n3C)c2)CCc2cccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cn1c(=O)ccc2cc(OCCCCCN(CCc3cccnc3)Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
A 1N-sodium hydroxide aqueous solution(0.72 ml) was added to a methanol solution (2 ml) of 4-{[[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-(2-pyridin-3-ylethyl)amino]methyl}benzoic acid methyl ester(153 mg). The mixture was stirred at 50° C. for 3 hours. The reaction mixture was condensed under reduced pressure. Water was added to the residue, and acetic acid was added for neutralization. The mixture was extracted using dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and condensed under reduced pressure. Diisopropyl ether was added to the residue. The generated insoluble matter was separated by filtration and dried to give the title compound(115 mg) as a white powder.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=C\CCCCCCCC.[C:21]([OH:40])(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=C\C/C=C\CCCCC.OO.[OH2:43]>[Co](Cl)Cl>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:39])=[O:43].[C:21]([OH:40])(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: O
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: Cl[Co]Cl
Agent: OO
Product: CCCCCCCCC(=O)O
Product: O=C(O)CCCCCCCC(=O)O
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 70 %
Yield: 69 %

Procedure:
Using the same apparatus as in Example 1, 100 g of crude oleic acid (80% purity) containing 9% linoleic acid and 0.75 g of H2WO4 is added. The stirred mixture is brought to 60°-65° C. and 28 g of 60% w/w H2O2 is added. The H2O2 is gradually added over about 30 mins in order to maintain the temperature between 65°-75° C. Once the addition of H2O2 is completed the mixture is left at that temperature for 1.5 hours. The crude reaction product so obtained is charged into an stirred 500 ml autoclave containing 150 ml of water and 1.0 g of hydrous cobalt chloride. The autoclave is then pressurised with 65 atm of air and the temperature is raised to 70° C. The reaction mixture is treated according to the way described in example 1 obtaining 42 g of azelaic acid (yield=70%) and 30.9 g of pelargonic acid (yield=69%).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]2[C:22]([Cl:23])=[C:21]3[C:16]([CH:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:19][O:20]3)=[CH:15][C:14]=2[Cl:29])=[CH:10][CH:9]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:29][C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([Cl:23])[C:13]=1[O:12][C:11]1[CH:30]=[CH:31][C:8]([C:6]([OH:7])=[O:5])=[CH:9][CH:10]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1)c2Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)O)cc1)c2Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 113.6 %

Procedure:
To a solution of ethyl 7-(4-(tert-butoxycarbonyl)phenoxy)-6,8-dichlorochroman-4-carboxylate (1.85 g, 3.96 mmol) in 20 mL of DCM was added trifluoroacetic acid (10 mL). After stirring at ambient temperature for 1 hour, the mixture was concentrated to a sticky residue. The residue was dissolved in ethyl acetate and washed successively with saturated sodium bicarbonate and brine. The solution was dried over sodium sulfate and filtered. The filtrate was concentrated to give 4-(6,8-dichloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (1.85 g, 90.9% yield) as a powder. 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=8.8 Hz, 2H), 7.35 (s, 1H), 6.90 (d, J=8.8 Hz, 1H), 4.36-4.48 (m, 2H), 4.25 (q, J=7.1 Hz, 2H), 3.80 (t, J=4.7 Hz, 1H), 2.37-2.43 (m, 1H), 2.11-2.20 (m, 1H), 1.32 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[Cl:10].C(N(CC)C(C)C)(C)C.CO.[C:22]([O:25][CH2:26]C)(=[O:24])C>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH3:26][O:25][C:22](=[O:24])[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[Cl:10]
Reactant: Cc1cc(Cl)c(Br)cc1F
Reactant: CCOC(C)=O
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C]([PH+](c2ccccc2)c2ccccc2)[CH]1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(F)c(C)cc1Cl
Temperature: 90 °C
Reaction time: 24 h

Procedure:
To a solution of 1-bromo-2-chloro-5-fluoro-4-methylbenzene (70 g) dissolved in ethyl acetate (400 mL) was added N,N-diisopropylethylamine (161 mL), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (5.15 g) and methanol (120 mL). The resulting mixture was stirred at 90° C. for 24 h under carbon monoxide (4 bar) in a 1.5 L autoclave. Further dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (2.57 g) was added and the reaction heated at 90° C. for a further 3 h. The cooled reaction mixture was evaporated to dryness and the residue purified by silica chromatography, eluting with 50% dichloromethane in iso-hexane to give the subtitle compound (57.7 g).
Reaction SMILES: C([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:14]3[C:34]4[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=4)[C:16]4([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[CH2:15]3)[C:8]=2[C@H:7]([CH3:36])[CH2:6]1)(=O)C.C1COCC1.O[Li].O>O>[Cl:35][C:31]1[CH:30]=[C:29]2[C:16]3([CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]3)[CH2:15][N:14]([C:13]3[C:8]4[C@H:7]([CH3:36])[CH2:6][CH:5]([OH:4])[C:9]=4[N:10]=[CH:11][N:12]=3)[C:34]2=[CH:33][CH:32]=1
Reactant: CC(=O)OC1C[C@@H](C)c2c1ncnc2N1CC2(CCN(C(=O)OC(C)(C)C)CC2)c2cc(Cl)ccc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CC(O)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Cl)ccc43)c21
Reaction time: 4 h
Yield: 41.7 %

Procedure:
A solution of tert-butyl 1-((5R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5-chlorospiro[indoline-3,4′-piperidine]-1′-carboxylate (0.170 g, 0.331 mmol) in 2:1 THF:H2O (1.8 mL) was cooled to about 0° C. LiOH—H2O (0.034 g, 0.83 mmol) was added and the reaction was stirred at about room temperature for 4 hours. The reaction was quenched by the addition of 1N HCl to pH 6. The aqueous phase was extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by column chromatography (30-70% EtOAc/Hexane) to yield tert-butyl 5-chloro-1-((5R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.065 g, 42%). LCMS (APCI+) m/z 471, 473 [M+H]+; Rt=3.82 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([CH3:25])([CH3:24])[O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:26]1[C:27](=[O:41])[N:28]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:29]=[C:30]([NH2:32])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:42][C:43]1[CH:57]=[CH:56][C:46]([CH2:47][N:48]2[CH:52]=[C:51]([C:53](O)=[O:54])[CH:50]=[N:49]2)=[CH:45][CH:44]=1.FC1C=CC(CN2C=C(C(O)=O)C=N2)=CC=1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([CH3:25])([CH3:24])[O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:26]1[C:27](=[O:41])[N:28]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:29]=[C:30]([NH:32][C:53]([C:51]2[CH:50]=[N:49][N:48]([CH2:47][C:46]3[CH:56]=[CH:57][C:43]([CH3:42])=[CH:44][CH:45]=3)[CH:52]=2)=[O:54])[CH:31]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc(Cn2cc(C(=O)O)cn2)cc1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(N)cn(COCC[Si](C)(C)C)c2=O)cc2cc(C(C)(C)O[SiH2]C(C)(C)C)ccc21
Agent: O=C(O)c1cnn(Cc2ccc(F)cc2)c1
Product: Cc1ccc(Cn2cc(C(=O)Nc3cc(-c4cc5cc(C(C)(C)O[SiH2]C(C)(C)C)ccc5n4C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c3)cn2)cc1

Procedure:
The title compound was prepared by the route outlined in Scheme 8 and using the experimental from Example 20, step 4, with intermediate (8d), 2-[5-amino-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(tert-butyl-dimethyl-silanyloxymethyl)-indole-1-carboxylic acid tert-butyl ester (1.0 g, 1.67 mmol) and 1-(4-methyl-benzyl)-1H-pyrazole-4-carboxylic acid (0.43 g, 1.99 mmol) which had been synthesised according to the protocol described for intermediate (6e) in example 21. The resultant crude product was purified by flash chromatography on SiO2 with hexane—50% ethyl acetate/hexane (gradient) to afford the title compound as a pink oil, 0.721 g, 54%.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[CH3:16][N:17](C)C=O.S(Cl)(Cl)=O.CN>ClCCCl.C(O)C>[CH3:16][NH:17][C:13]([C:3]1[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][O:6][C:2]=1[CH3:1])=[O:15]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Reactant: CN(C)C=O
Agent: CN
Solvent: CCO
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: CNC(=O)c1c(-c2ccccc2)noc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 50.0 g (0.25 mol) of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid in 1.2 l of 1,2-dichloroethane (DCE) is added 1.9 ml dimethyl formamide (DMF) and 21.4 ml (0.3 mol, 1.2 eq.) of thionyl chloride. The mixture is stirred for 2 h at reflux until a clear, yellow solution is formed. The solution is cooled to room temperature and then slowly added to a 8M solution of methylamine in ethanol (146 ml) at 5° C. The suspension is poured onto methylene chloride, washed with sat. NaHCO3-solution, dried over Na2SO4 and concentrated. This yields 52.3 g (99%) of the title compound as light brown solid, which is used for further reaction without purification. Mass spectrum: m/z (M+H)+: 217.1
Reaction SMILES: [CH3:1][C:2]12[CH2:8][C:6]([C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=3)([CH2:7]1)[C:5](=[O:18])[NH:4][C:3]2=[O:19].C(O)C>COCCO.[Pd]>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]23[CH2:8][C:2]([CH3:1])([CH2:7]2)[C:3](=[O:19])[NH:4][C:5]3=[O:18])=[CH:14][CH:13]=1
Reactant: CC12CC(c3ccc([N+](=O)[O-])cc3)(C1)C(=O)NC2=O
Agent: [Pd]
Solvent: CCO
Solvent: COCCO
Product: CC12CC(c3ccc(N)cc3)(C1)C(=O)NC2=O

Procedure:
In a manner analogous to that described in Example 12a, 3.7 g of 5-methyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 80 ml of 2-methoxyethanol are hydrogenated in the presence of 0.4 g of 5% palladium-on-carbon and worked up. Melting point 216° (from ethanol).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH:33]2[CH2:36][CH2:35][CH2:34]2)[CH2:29][CH2:28]1)=[O:26].C([O-])([O-])=O.[K+].[K+].O>CC#N.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2([CH2:21][CH2:20][N:19]([CH2:24][C:25]([N:27]3[CH2:32][CH2:31][N:30]([CH:33]4[CH2:36][CH2:35][CH2:34]4)[CH2:29][CH2:28]3)=[O:26])[CH2:18][CH2:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C2(CCNCC2)N1Cc1ccccc1
Reactant: O=C(CCl)N1CCN(C2CCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: O=C(CN1CCC2(CC1)c1ccccc1C(=O)N2Cc1ccccc1)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-benzylspiro[isoindole-1,4′-piperidin]-3(2H)-one (1.84 mmol) and 1-(chloroacetyl)-4-cyclobutylpiperazine (1.84 mmol) in CH3CN (8 ml) is added K2CO3 (761 mg, 5.52 mmol). The resulting suspension is stirred at rt overnight. Water (10 ml) and EtOAc (10 ml) is added and the layers are separated. The aqueous layer is extracted with EtOAc (20 ml) and the combined extracts are washed with brine (20 ml), dried over Na2SO4 and evaporated. The residue is purified by flash column to give 2-benzyl-1′-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]spiro[isoindole-1,4′-piperidin]-3(2H)-one as an off-white solid (LC-MS (M+1): 472.3) and 2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl 2-benzyl-3-oxo-2,3-dihydro-1′H-spiro[isoindole-1,4′-piperidine]-1′-carboxylate as a minor product.