Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1)[C:3]([OH:5])=[O:4].C(O)(=[O:17])C.N([O-])=O.[Na+]>O>[OH:17][CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1)[C:3]([OH:5])=[O:4]
Reactant: NC(C(=O)O)c1ccc2c(c1)CCO2
Reactant: CC(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(O)c1ccc2c(c1)CCO2
Temperature: 65 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
α-Amino(2,3-dihydro-5-benzofuranyl)acetic acid (200 mg, 1.04 mmole) is dissolved in 250 mg (4.14 mmole) of glacial acetic acid and 145 mg (2.08 mmole) of sodium nitrite in about 5 ml of water is added dropwise. An additional 1 ml of glacial acetic acid is added and the mixture is heated to 65° C. and held at 65° C. for 4 hours. After cooling the reaction mixture is diluted with water and extracted with ethyl acetate for several hours. The ethyl acetate is dried over magnesium sulfate, filtered and evaporated to give about 65% of the title compound.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([O:23][C:24](=[O:47])[N:25]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([C:38](C)(C)[O:39][SiH2]C(C)(C)C)[CH:32]=1)[CH2:26][CH:27]([F:29])[F:28])([CH3:22])([CH3:21])[CH3:20]>C1COCC1.CCOC(C)=O>[C:19]([O:23][C:24](=[O:47])[N:25]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][OH:39])[CH:32]=1)[CH2:26][CH:27]([F:29])[F:28])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1)CC(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(CO)c1)CC(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.8 %

Procedure:
TBAF (1M in THF, 9.57 mL, 9.57 mmol) was added dropwise to a sol. of [3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzyl]-(2,2-difluoro-ethyl)-carbamic acid tert-butyl ester (2.15 g, 4.78 mmol) in THF (48 mL) at 0° C. The mixture was was stirred for 1 h while warming up to rt. The mixture was diluted with EtOAc, and the resulting mixture was washed with aq. sat. NH4Cl (2×) and brine (1×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 30:70) yielded the title compound (591 mg, 37%). LC-MS: tR=0.97 min; ES+: 336.09.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([NH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#N)[CH:12]=[CH2:13].C[OH:24]>C1(C)C=CC=CC=1>[CH2:11]([NH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:24])[CH:12]=[CH2:13]
Reactant: C=CCNc1cccc(C#N)c1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: C=CCNc1cccc(C=O)c1
Temperature: 0 °C

Procedure:
Di-isobutylaluminum hydride (54 ml., 25% solution in toluene) is added with stirring to a solution of 12.1 g. of 3-(allylamino)benzonitrile under a nitrogen atmosphere. After addition is completed, the solution is stirred for one hour. A solution of methanol in toluene (50 ml., 1:1) is added over 30 minutes and the mixture is poured into 500 ml. vigorously stirred ice-cold 50% aqueous sulfuric acid. The mixture is filtered and the organic layer separated. The aqueous solution is extracted twice with toluene (100 ml.) and the combined organic layers are washed with aqueous sodium bicarbonate, dried over magnesium sulfate, decolorized with charcoal, filtered and evaporated in vacuo to give a light yellow crystalline solid. The product is recrystallized from dichloromethane/hexane giving colorless needles.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][S:21][CH2:22][C:16]=3[NH:15][C:14]2=[O:23])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:24]N(C)C=O>>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][S:21][CH2:22][C:16]=3[N:15]([CH3:24])[C:14]2=[O:23])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CSC3)ccc1Cl
Reactant: CN(C)C=O
Product: CCOC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CSC3)ccc1Cl

Procedure:
using ethyl 2-chloro-5-{1,2,5,7-tetrahydro-2,4-dioxo-thieno[3,4-d]pyrimidin-3(4H)-yl}-benzoate in dimethylformamide there is obtained ethyl 2-chloro-5-{1,2,5,7-tetrahydro-1-methyl-2,4-dioxo-thieno[3,4-d]pyrimidin-3(4H)-yl}-benzoate, m.p. 203°-206° C.,
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[N:10]1>>[Br:1][C:11]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:17]2[NH:9][N:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1cnc2cn[nH]c2c1
Product: Brc1n[nH]c2cccnc12
Yield: 68.6 %

Procedure:
750 mg of N-bromosuccinimide was reacted on 0.5 g of 1H-pyrazolo[4,3-b]pyridine in the similar method as described in Production example 87, to afford 570 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([C:27]#[N:28])=[N:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:16]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12.C[Sn]([N:33]=[N+:34]=[N-:35])(C)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([C:27]5[NH:35][N:34]=[N:33][N:28]=5)=[N:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:16]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2cccnc2C#N)cc1
Solvent: Cc1ccccc1
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2cccnc2-c2nnn[nH]2)cc1
Temperature: 25 °C

Procedure:
A solution of 7-methyl-2-propyl-3-[[4-(2-cyanopyridin-3-yl)phenyl]methyl]imidazo[4,5-b]pyridine (300 mg, 0.817 mmol) and trimethylstannylazide (504mg, 2.45 mmol) in toluene (3 mL) was heated to reflux for 36 h. The mixture was cooled to rt, concentrated, then purified by flash chromatography on SiO2 (80/20/1 CH2Cl2 /MeOH/NH4OH) to give 7-methyl-2-propyl-3-[[4-[2-(1H-tetrazol-5-yl)-3-pyridinyl]phenyl]methyl]imidazo [4,5-b]pyridine as a white solid.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][C:23]=1[CH3:32]>CO>[NH2:31][S:28]([C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:14]([C:10]2[CH:9]=[C:8]([N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:17][CH:18]3[CH2:20][CH2:19]3)[N:13]=[CH:12][N:11]=2)=[O:16])=[C:23]([CH3:32])[CH:24]=1)(=[O:29])=[O:30]
Reactant: Cc1cc(S(N)(=O)=O)ccc1N
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Solvent: CO
Product: Cc1cc(S(N)(=O)=O)ccc1NC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidine-4-carboxylic acid (Intermediate 13) and 4-amino-3-methyl-benzenesulfonamide (Biofine), the title compound was obtained as an off-white solid after trituration in methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].Cl[CH:17]([C:23]([CH3:25])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][CH:17]([C:23](=[O:24])[CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Oc1ccc(Cl)c(Cl)c1)C(C)=O
Yield: 67.8 %

Procedure:
13.0 g (80 mmol) of 3,4-dichlorophenol and 12.2 g (88 mmol) of potassium carbonate were refluxed for 30 minutes in 400 ml of acetone. 15.8 g (96 mmol) of ethyl 2-chloroacetoacetate were subsequently added dropwise, the mixture was refluxed for 8 hours and evaporated in vacuo, and water was added to the residue. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were dried over magnesium sulfate and evaporated. Column chromatography of the residue gave 15.8 g (68% of theory) of ethyl 2-(3,4-dichlorophenoxy)-3-ketobutanate as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:14][O:15][C:16](=[O:29])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:14][O:15][C:16](=[O:29])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](=[O:26])(=[O:27])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C=Cc1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C=Cc1ccccc1S(=O)(=O)Nc1ccccc1
Yield: 60.5 %

Procedure:
To a mixture of aniline (0.33 g, 3.53 mmol) and pyridine (1 ml) a solution of 3-(2-chlorosulfonylphenyl)acrylic acid methyl ester (33) (0.45 g, 1.72 mmol) in dichloromethane (3 ml) was added and the resultant solution was stirred at 50° C. for 1 hour. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 10% HCl. The organic layer was washed successively with water, saturated NaCl and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with ethyl acetate-chloroform (1:7, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.33 g, 60%). 1H NMR (CDCl3, HMDSO), δ: 3.86 (3H, s); 6.27 (1H, d, J=16.0 Hz); 6.69 (1H, br s); 6.87–7.67 (8H, m); 7.94–8.13 (1H, m); 8.49 (1H, d, J=16.0 Hz).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:5]([CH2:6][O:7][C:8](=[O:10])[NH2:9])[N:4]([S:11]([OH:14])(=[O:13])=[O:12])[C:3]1=[O:15].[NH2:16][C:17]1[S:18][CH:19]=[C:20](/[C:22](=[N:26]/[O:27][CH2:28][CH2:29][S:30]([CH3:33])(=[O:32])=[O:31])/[C:23](O)=[O:24])[N:21]=1>>[NH2:16][C:17]1[S:18][CH:19]=[C:20](/[C:22](=[N:26]/[O:27][CH2:28][CH2:29][S:30]([CH3:33])(=[O:31])=[O:32])/[C:23]([NH:1][C@H:2]2[C@@H:5]([CH2:6][O:7][C:8](=[O:10])[NH2:9])[N:4]([S:11]([OH:14])(=[O:12])=[O:13])[C:3]2=[O:15])=[O:24])[N:21]=1
Reactant: NC(=O)OC[C@@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Reactant: CS(=O)(=O)CCO/N=C(\C(=O)O)c1csc(N)n1
Product: CS(=O)(=O)CCO/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1COC(N)=O)c1csc(N)n1

Procedure:
In the same manner as described in Example 9, from 12 g of (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid and 2-(2-amino-4-thiazolyl)-2-[(Z)-[2-(methylsulphonyl)ethoxy]imino]-acetic acid there are obtained 1.15 g of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[2-(methylsulphonyl)ethoxy]imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:18][NH:17][C:16](=[O:19])[C:15]=2[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:23])=[N-]>CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:18][N:17]=[C:16]([O:19][CH3:23])[C:15]=2[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=[N+]=[N-]
Reactant: Cc1c(C2CCN(C(=O)OC(C)(C)C)CC2)[nH][nH]c1=O
Solvent: CCOCC
Product: COc1n[nH]c(C2CCN(C(=O)OC(C)(C)C)CC2)c1C

Procedure:
A suspension of 1-tert-butoxycarbonyl-4-(4-methyl-(1H)-pyrazol-3-one-5-yl)piperidine (from Step C) in 12.5 mL (9.9 mmol) of 0.8 M diazomethane in Et2O was allowed to stand (occasional swirling) until all solids were in solution. Excess diazomethane was quenched with HOAc. The reaction was partitioned between 1 N NaHCO3 and Et2O. After separating phases, the organic layer was dried over MgSO4 and concentrated. The residue was purified by flash chromatography using 19:1 v/v hexanes/acetone, 9:1 v/v hexanes/acetone and 4:1 v/v hexanes/acetone as the gradient to afford the title compound as a yellow oil: RF: 0.18 (4:1 v/v hexanes/acetone); 1H-NMR (500 MHz) δ 1.48 (s, 9H), 1.57–1.65 (m, 2H), 1.82–1.85 (m, 2H), 1.89 (s, 3H), 2.70–2.79 (m, 3H), 3.91 (s, 3H), 4.24 (m, 2H)-; 13C-NMR (125 MHz) δ 55.7 (O—CH3).
Reaction SMILES: S(Cl)(Cl)(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]CC1C=CC=CC=1)=[CH:11][C:10]2=[O:31].N12CCN(CC1)CC2>>[Cl:6][C:7]1[CH:16]=[CH:15][C:14]2[N:13]3[S:23][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[C:12]3=[CH:11][C:10](=[O:31])[C:9]=2[CH:8]=1
Reactant: O=c1cc(-c2ccccc2SCc2ccccc2)[nH]c2ccc(Cl)cc12
Agent: C1CN2CCN1CC2
Solvent: O=S(=O)(Cl)Cl
Product: O=c1cc2c3ccccc3sn2c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
Sulfuryl chloride (0. 305 ml, 3.78 mmole, 1.0 equiv.) was added dropwise over 3 min to a suspension of 6-chloro-2-[2-[(phenylmethyl)thio]phenyl]-4(1H)-quinolinone (1.43 g, 3.78 mmole, 1 equiv.) in dry, EtOH-free CHCl3 (190 ml) at -15° C. The mixture was stirred for 0.5 hr, then was heated to reflux After 20 min, the reaction was cooled to 25° C., and 1,4-diazabicyclo[2.2.21octane (636 mg, 5.67 mmole, 1.5 equiv.) was added. The nearly homogeneous solution was stirred at 25° C. for an additional 5 min, then was washed with H2O (3×50 ml). The combined aqueous layers, which contained suspended product, were back-extracted with CHCl3, and the combined organic layers were diluted with CHCl3 (200 ml) and MeOH (50 ml) to dissolve suspended solids. Drying (MgSO4), concentration, and silica gel chromatography (CHCl3, then 10% MeOH in 50% EtOAc/CHCl3, then 10% MeOH/CHCl3) gave 3-chloro-5H-[1,2]benzisothiazolo [2,3-a]quinoline-5-one (0.28 g, 26%) as a yellow solid. Two recrystallizations from CHCl3 /EtOAc gave yellow, very fine needles: mp>350° C.; TLC (5% MeOH in 50% EtOAc/CHCl3) Rf 0.32; 1H NMR (CDCl3) δ8.52 (d, J=2.2 Hz, 1H), 8.00 (app d, 1H), 7.62-7.74 (m, 3H), 7.50-7.60 (m, 1H), 7.44 (d, J=8.8 Hz, 1H), 7.08 (s, 1H); IR (KBr) 1613, 1587, 1567, 1554, 1539, 1461, 1450 cm-1 ; MS (NH3), m/e (%) 288 (41, (37Cl M+H)+), 286 (100, (35Cl M+H)+). Anal. Calcd for C15H8ClNOS: C, 63.05; H, 2.82; N, 4.90. Found: C, 62.83; H, 2.51; N, 4.75.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7]=[N:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C[Si]([C:23]#[N:24])(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)[C:23]#[N:24])=[CH:17][CH:18]=1
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc(C=Nc2ccc(SC)cc2)cc1
Product: COc1ccc(C(C#N)Nc2ccc(SC)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(4-methoxybenzylidene)-4-methylthioaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a pale brown powder (yield 92%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]([CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][NH2:8])=[O:4].[Cl:32][CH2:33][CH2:34][CH2:35][S:36](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:38])=[O:37]>>[Cl:32][CH2:33][CH2:34][CH2:35][S:36]([NH:8][CH2:7][CH:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:38])=[O:37]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)NC(=O)OC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)NC(=O)OC

Procedure:
2-Methoxycarbonylamino-3-octadecylcarbamoyloxypropylamine IVe1 is allowed to react and worked up by the same procedure as described in (4). m.p. 99°-101° C. The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[NH:7]1[CH2:10][CH2:9][CH2:8]1>C(Cl)Cl>[N:7]1([CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH2:10][CH2:9][CH2:8]1
Reactant: C=CC(=O)OC
Reactant: C1CNC1
Solvent: ClCCl
Product: COC(=O)CCN1CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.5 %

Procedure:
Methyl acrylate (2.082 mL, 23.12 mmol) was added to a solution of azetidine (1.2 g, 21.02 mmol) in DCM and the resulting solution stirred at ambient temperature, under an inert atmosphere for 16 h. The reaction mixture was evaporated and the crude product purified by FCC, eluted with 25% EtOAc in DCM, to afford the desired material (2.0 g, 66.5%) as a colourless oil. NMR Spectrum: 1H NMR (400 MHz, CDCl3) δ 1.97-2.1 (2H, m), 2.33 (2H, d), 2.67 (2H, d), 3.18 (4H, t), 3.67 (3H, s).
Reaction SMILES: C1([C@H]([N:9]2[CH:13]3[CH2:14][N:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH:12]3[CH2:11][CH2:10]2)C)C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH:9]1[CH2:10][CH2:11][CH:12]2[CH2:16][N:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][CH:13]12
Reactant: CCOC(=O)N1CC2CCN([C@H](C)c3ccccc3)C2C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)N1CC2CCNC2C1
Temperature: 50 °C

Procedure:
5% Palladium hydroxide on activated carbon (13.9 g, 50% w/w in water) was added to a pressure reactor. The product of Example A3 (as 506.8 g of a 25.9 wt % solution of ethyl 1-((R)-1-phenylethyl)hexahydropyrrolo[2,3-c]pyrrole-5(1H)-carboxylate (131.3 g) in MeOH) was added, followed by a methanol rinse (37 g). The mixture was heated to 50° C. under an atmosphere of hydrogen (40 psi) for 4 hours. The mixture was filtered through Hyflo® Filter Aid and rinsed with 200 mL of MeOH to provide a solution containing 78.9 g of the title compound.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[O:19][CH3:20]>>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:16][C:15]1[CH:17]=[CH:18][C:12]([Cl:11])=[C:13]([O:19][CH3:20])[CH:14]=1
Reactant: COc1cc(N)ccc1Cl
Reactant: Clc1nc2ccccc2s1
Product: COc1cc(Nc2nc3ccccc3s2)ccc1Cl

Procedure:
The title compound was synthesised from 2-chloro-benzothiazole (commercially available) and 4-chloro-3-methoxyaniline (commercially available) according to the procedure described for Example 1a) above. MS (m/z): 291.3 (MH+, 100%).
Reaction SMILES: C(Cl)(=O)C.[N+:5]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)([O-:7])=[O:6].NC1C=C2C(=CC=1)CN(C(N[C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:39])NCCC)=[CH:30][CH:29]=1)=O)C2>>[CH:30]1([CH2:31][C:34]([NH:12][C:11]2[CH:13]=[CH:14][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=2)=[O:39])[CH2:29][CH2:28][CH2:33][CH2:32]1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)Cl
Product: O=C(CC1CCCC1)Nc1ccc([N+](=O)[O-])cc1

Procedure:
The title compound was prepared as described in Example 278, substituting 2-cyclopentylacetyl chloride for acetyl chloride and 4-nitroaniline for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCOc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(OCCCC(=O)O)cc2)CC(C)(C)C1
Yield: 94.7 %

Procedure:
The hydrolysis conditions described for 191 was followed. A solution of ethyl 4-({4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)butanoate (222) (0.760 g, 1.7 mmol) in THF/EtOH (1:1, 40 mL) was treated with 1 N NaOH (20 ml, excess) at 70° C. for 1 h. The reaction mixture was poured into 20% aqueous HCl (200 mL). The precipitated product was filtered and dried under reduced pressure to afford 0.68 g (95%) of compound 223 as an off-white solid. mp 203-204° C. 1H NMR (300 MHz, CD3OD): δ 7.05 (d, J=8.7 Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.7 Hz, 2H), 6.70 (d, J=8.4 Hz, 2H), 4.00 (t, J=6.3 Hz, 2H), 2.50 (t, J=7.2 Hz, 2H), 2.06 (quintet, J1=13.5, J2=6.9 Hz, 2H), 2.00 (d, J=4.2 Hz, 4H), 1.31 (s, 2H), 0.94 (s, 12H). LCMS (ESI): m/z 421 (M−H)−. Anal. Calcd for C27H34O4, C, 76.75; H, 8.11. Found: C, 75.63; H, 8.03.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1.[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O>C1COCC1>[C:16]([O:15][C:13]([NH:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:6]=1)=[O:12])([CH3:19])([CH3:18])[CH3:17]
Reactant: COCOc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: COCOc1cccc(NC(=O)OC(C)(C)C)c1
Temperature: 65 °C
Yield: 99.9 %

Procedure:
A solution of crude 12 (4.13 g, 27 mmol) in 135 mL anhydrous THF was treated with BOC2O (12.14 g, 54 mmol) and the reaction mixture was warmed at reflux (65° C.) for 18 h. The solvents were removed under reduced pressure, and flash chromatography (SiO2, 4×15 cm, 20% EtOAc/hexane) provided pure 13 (6.83 g, 100%) as a yellow oil: 1H NM (CDCl3, 250 MHz) δ 7.15 (m, 2H), 6.94 (m, 1H), 6.68 (m, 1H), 6.58 (br s, 1H), 5.13 (s, 2H), 3.44 (s, 3H), 1.50 (s, 9H); 13C NMR (CDCl3, 62.5 MHz) δ 157.7, 152.5, 139.5, 129.6, 111.9, 110.7, 106.6, 94.2, 80.5, 55.9, 28.2; IR (film) νmax 3337, 2977, 1728, 1605, 1537, 1236, 1153, 1015 cm−1; FABHRMS (NBA/NaI) m/z 276.1203 (C13H19NO4+Na+ requires 276.1212)
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.C([O:14][C:15](=O)[CH:16]([CH3:19])[CH:17]=O)C>C(O)C>[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[NH:9][C:15](=[O:14])[C:16]([CH3:19])=[CH:17][N:8]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)C=O
Reactant: N=C(N)c1ccc(Cl)cc1
Agent: [Na]
Solvent: CCO
Product: Cc1cnc(-c2ccc(Cl)cc2)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
Sodium metal (276 mg, 12 mmol) was added portion wise to ethanol (15 ml) under a nitrogen atmosphere and the mixture allowed to stir at room temperature for 30 minutes until the reaction became homogeneous. 4-Chloro-benzamidine (hydroiodide salt) (1.41 g, 5 mmol) was then added in one portion and the reaction stirred at room temperature for a further 60 minutes. 2-Methyl-3-oxo-propionic acid ethyl ester (716 mg, 5.5 mmol) was finally added drop wise. The reaction was left to stir at room temperature overnight before quenching the reaction slowly with 2M Hydrochloric acid until reaction pH measured pH 1. The resulting precipitate was filtered and air dried, to give 2-(4-Chloro-phenyl)-5-methyl-3H-pyrimidin-4-one as a white solid (570 mg, 2.58 mmol, 52% yield).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([Cl:11])=[N:8]2)=[C:4]([Cl:12])[N:3]=1.Br[CH2:14][CH2:15][CH:16]1[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([Cl:11])[N:8]2[CH2:14][CH2:15][CH:16]2[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]2)=[C:4]([Cl:12])[N:3]=1
Reactant: CC1(C)OCC(CCBr)CO1
Reactant: Nc1nc(Cl)c2[nH]c(Cl)nc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(CCn2c(Cl)nc3c(Cl)nc(N)nc32)CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.6 %

Procedure:
A mixture of 2-amino-6,8-dichloropurine (0.82 g), 5-bromoethyl-2,2-dimethyl-1,3-dioxan (0.9 g) and anhydrous potassium carbonate (0.83 g) in N,N-dimethylformamide (20 ml) was stirred at room temperature for 18 hours under dry nitrogen. The mixture was then filtered and the filtrate evaporated. The residue was purified by column chromatography on silica (100 g) [eluent 2% methanol-dichloromethane] to give 2-amino-6,8-dichloro-9-(2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl)purine (t.l.c. r.f. 0.50, 5% methanol-dichloromethane) as a pale solid (0.62 g, 45%). Recrystallisation from diethyl ether gave an off-white solid m.p. 149°-150° C.