Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:10]([C:11]([OH:13])=O)[C:9]=1[C:17]([OH:19])=O.[O:20]=[C:21]1[CH:26]([N:27]2C(=O)C3C(=CC=CC=3NCCOC)C2=O)[CH2:25][CH2:24][C:23](=[O:43])[NH:22]1>>[O:20]=[C:21]1[CH:26]([N:27]2[C:17](=[O:19])[C:9]3[C:10](=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][CH2:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[C:11]2=[O:13])[CH2:25][CH2:24][C:23](=[O:43])[NH:22]1
Reactant: COCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)c1cccc(NCc2cccs2)c1C(=O)O
Product: O=C1CCC(N2C(=O)c3cccc(NCc4cccs4)c3C2=O)C(=O)N1
Yield: 29 %

Procedure:
3-[(Thiophen-2-ylmethyl)-amino]-phthalic acid (2.88 mmol) was treated in the same manner as described above for the synthesis of 2-(2,6-dioxo-piperidin-3-yl)-4-(2-methoxy-ethylamino)-isoindole-1,3-dione. The solid yellow residue was purified by preparative HPLC (Symmetry C18, isocratic, 35% acetonitrile/water) to give 0.31 g (29%) of product as a yellow solid: mp 223–225° C.; 1H NMR (DMSO-d6) δ 11.12 (s, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.39 (d, J=4.8 Hz, 1H), 7.23–6.96 (m, 5H), 5.07 (dd, J=5.3 and 12.4 Hz, 1H), 4.75 (d, J=6.0 Hz, 2H), 2.97–2.83 (m, 1H), 2.63–2.46 (m, 2H), 2.09–1.99 (m, 1H); 13C NMR (DMSO-d6) δ 172.77, 170.03, 168.67, 167.20, 145.60, 142.51, 136.04, 132.15, 126.88, 125.40, 125.00, 117.67, 111.05, 109.80, 48.56, 40.88, 30.96, 22.10; Anal. Calcd. For C18H15N3O4S: C, 58.53; H, 4.09; N, 11.38. Found: C, 58.20; H, 3.96; N, 10.99.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10](/[C:13](/[C:21](=[O:24])[CH:22]=[CH2:23])=[CH:14]\[CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH:30]=[O:31].C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10](/[C:13](=[CH:14]\[CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)/[C:21](=[O:24])[CH2:22][CH2:23][C:30]([C:26]3[S:25][CH:29]=[CH:28][N:27]=3)=[O:31])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: O=Cc1nccs1
Reactant: C=CC(=O)/C(=C/C1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CCC(=O)c1nccs1)/C(=C/C1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Yield: 49 %

Procedure:
To a solution of (1E)-2-[4-(cyclopropylsulfonyl)phenyl]-1-(tetrahydro-2H-pyran-4-yl)penta-1,4-dien-3-one (425 mg) in ethanol (5 mL) were added 1,3-thiazole-2-carbaldehyde (130 μL), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (36.0 mg) and triethylamine (75 μL), and the mixture was stirred with heating under reflux for 4 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (278 mg, yield 49%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 460 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([OH:21])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]#[N:31]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:29][C:30]#[N:31])=[CH:17][N:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(O)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(OCC#N)cn2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
To a stirred solution of 4-(5-hydroxy-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.74 g, 2.5 mmol, 1.0 equiv; intermediate C31/step 2) in DMF (10 mL) was added potassium carbonate (1.05 g, 7.5 mmol, 3.0 equiv), followed by bromoacetonitrile (0.21 mL, 0.37 g, 3.0 mmol, 1.2 equiv). After 90 min, the reaction mixture was poured into ice water and extracted twice with diethylether. The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 0.70 g (84%) of the title compound as a light yellow solid. MS (ISP): 334.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.O[CH2:14][CH:15]([CH2:17]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.OS(O)(=O)=O.O>>[F:9][C:8]1[C:2]([F:1])=[CH:3][C:4]([N+:10]([O-:12])=[O:11])=[C:5]2[C:7]=1[CH:14]=[CH:15][CH:17]=[N:6]2
Reactant: OCC(O)CO
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(F)c(F)c2cccnc12
Yield: 82.8 %

Procedure:
In a similar fashion using route 10 general procedure 20, 4,5-difluoro-2-nitroaniline (200 mg, 1.15 mmol), glycerol (330 mg, 3.56 mmol), 3-nitrobenzenesulfonic acid sodium salt (336 mg, 1.49 mmol) and H2SO4/H2O (1.2 ml, 7:5) gave the title compound (200 mg, 83%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:23]2C(=O)C3C(=CC=CC=3)C2=O)[C:10]2([F:22])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[F:8].C1COCC1.O.NN>CO>[NH2:23][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)[C:10]1([F:22])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(C(c2ccc(F)c(Cl)c2)N2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(F)(C(N)c2ccc(F)c(Cl)c2)C1
Temperature: 60 °C
Yield: 92.3 %

Procedure:
To a stirred solution of 79 (238.5 mg, 0.500 mmol) and THF:MeOH (5.0 mL 1:1) was added hydrazine monohydrate (242.6 μL, 5.001 mmol) and the solution was heated to 60° C. for 16 h. The reaction was then cooled to RT and concentrated in vacuo. The residue was diluted with EtOAc and washed sequentially with water (1×), NaHCO3 (1×), and brine (1×), dried (Na2SO4), filtered and concentrated in vacuo to afford 160.1 mg (92.3%) of tert-butyl 3-(amino(3-chloro-4-fluorophenyl)methyl)-3-fluoropyrrolidine-1-carboxylate (78).
Reaction SMILES: [B].[O:2]=[O:3].[OH2:4]>B(O)(O)O>[O:2]=[O+:3][O-:4].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2]
Reactant: O=O
Agent: OB(O)O
Agent: [B]
Solvent: O
Product: O=[O+][O-]

Procedure:
Kemp, The Chemistry of Borates, Part I, page 70 (1956), reported that an aqueous solution of boric acid kept at 40° C. for 3 weeks deposits a mixture of CaO·3B2O3 ·4H2O and 2CaO·3B2O3 ·9H2O. Kemp also reported that CaO·3B2O3 ·8H2O decomposes to form CaO·3B2O3 ·4H2O. According to Supplement to Mellor's Comprehensive Treatise on Inorganic and Theoretical Chemistry, Volume V, Part A: Boron-Oxygen Compounds, pages 550-551 (1980), CaO·3B2O3 ·4H2O occurs as a solid phase in the systems Na2O--CaO--B2O3 --H2O and CaO--NaCl--B2O3 --H2O at 25° C. and pH 5.5-6.5. Hydrothermal treatment of meyerhofferite in boric acid solution at 85-250° C. produced crystals of both the tetrahydrate and pentahydrate together with ginerite (2CaO·7B2 O3·8H2O).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[CH2:8]([O:15][C:16]1[CH:23]=[C:22](F)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[CH2:8]([O:15][C:16]1[CH:23]=[C:22]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: c1cn[nH]c1
Reactant: N#Cc1ccc(F)cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2cccn2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 74.7 %

Procedure:
To 0.180 g pyrazole in 5 mL DMF is added 0.105 g NaH. After stirring 50 minutes at room temperature, 0.200 g of the material from Step A, above, is added all at once with 5 mL DMF. After 2 hours at room temperature, the reaction is quenched with water and Concentrated in vacuo. The residue is redissolved in ethyl acetate and washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography eluting with toluene provides 0.181 g (74.8%) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[C:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[C:5](=[CH:6][C:7]([O:31][CH3:32])=[C:8]([O:29][CH3:30])[CH:9]=2)[N:4]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:31][CH3:32])=[C:8]([O:29][CH3:30])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:12]=2[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: C1COCCN1
Reactant: CCCCC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Product: CCCCC(=O)c1c(CN2CCOCC2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
According to the same manner as that described in Example 5, 2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-3-valerylquinoline was reacted with morpholine to give 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-morpholinomethyl-3-valerylquinoline. This compound was recrystallized from ethyl acetate-hexane to give colorless prisms. mp. 137°-138° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[S:8][C:9]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[O:13])=[CH:10][N:11]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[S:26](Cl)(=[O:28])=[O:27].CCN(CC)CC>CO.C(Cl)Cl>[CH3:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12]([C:9]1[S:8][C:7]([NH:6][CH2:5][CH2:4][CH2:3][NH:2][S:26]([C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)(=[O:28])=[O:27])=[N:11][CH:10]=1)=[O:13]
Reactant: Cc1ccccc1C(=O)c1cnc(NCCCN)s1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)c1cnc(NCCCNS(=O)(=O)c2cccs2)s1
Yield: 27 %

Procedure:
A mixture of 31.1 mg (0.1 mmol) [2-(3-Amino-propylamino)-thiazol-5-yl]-o-tolyl-methanone hydrochloride in 1 ml methanol, 18.2 mg (0.1 mmol) Thiophene-2-sulfonyl chloride in 1 ml DCM and 0.15 ml NEt3 was stirred for 16 h at 50° C. After evaporation to dryness the residue was taken up in 1.5 ml MeOH/formic acid 1/1 and subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient. Evaporation of product fractions yielded 11.4 mg (27%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:17]([N:20]([CH:25]([CH3:27])[CH3:26])[C:21](=[O:24])[CH2:22]Br)([CH3:19])[CH3:18]>>[CH:17]([N:20]([CH:25]([CH3:27])[CH3:26])[C:21](=[O:24])[CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)([CH3:19])[CH3:18]
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Reactant: CC(C)N(C(=O)CBr)C(C)C
Product: CC(C)N(C(=O)COc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)C(C)C
Yield: 84.5 %

Procedure:
The product was prepared as in Example 2, Stage A starting with 900 mg of 4'-hydroxy-(4-nitro biphenyl) (Aldrich) and 958 mg of N,N-bis-(isopropyl)-2-bromo-acetamide (Preparation 8) to obtain 1.26 g of the expected product.
Reaction SMILES: [ClH:1].C(OC([NH:9][C@@H:10]([CH3:45])[C:11]([O:13][CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[C:28]([NH2:33])[N:27]=[C:26]2[C:34]([N:36]1[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37]1)=[O:35])=[O:12])=O)(C)(C)C>O1CCOCC1.ClCCl>[ClH:1].[ClH:1].[NH2:9][C@@H:10]([CH3:45])[C:11]([O:13][CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[C:28]([NH2:33])[N:27]=[C:26]2[C:34]([N:36]1[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37]1)=[O:35])=[O:12]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H](N)C(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
911 μl of 4N HCl in dioxane are added to 220 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-4,5-difluorobenzyl (S)-2-tert-butoxycarbonylaminopropionate in 4 ml of dichloromethane with ice-cooling. The mixture is subsequently stirred at 25° C. for a further 1 h, the precipitate is filtered off with suction and washed with 4 ml of dichloromethane. The residue is recrystallised from ethanol.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH3:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.O1C=C[CH:13]=[C:12]1P(C1OC=CC=1)C1OC=CC=1.C(C([Sn])=C(CCCC)CCCC)CCC.[F-].[K+]>CN(C=O)C.C(OCC)C>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH3:10])[C:2]([CH:12]=[CH2:13])=[CH:7][N:6]=1
Reactant: CNc1nc(Cl)ncc1Br
Reactant: c1coc(P(c2ccco2)c2ccco2)c1
Agent: CCCCC([Sn])=C(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=Cc1cnc(Cl)nc1NC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 469.9 %

Procedure:
A mixture of (5-bromo-2-chloro-pyrimidin-4-yl)-methylamine (3.75 g, 16.9 mmol), tris(dibenzylidineacetone)dipalladium(0) (388 mg, 0.4 mmol), and tri-2-furylphosphine (777 mg, 3.3 mmol) in DMF is stirred for 20 minutes at room temperature and then tributylvinyltin (5.93 mL, 20.3 mmol) is added. After stirring for 16 hours at about 65° C., the reaction mixture is cooled to room temperature and stirred with a 10% aqueous solution of potassium fluoride (800 mL) and diethyl ether (600 mL) for 1 hour before filtering through a pad of Celite. The pad of Celite is rinsed with a further portion of diethyl ether (200 mL). The aqueous layer is separated and extracted with CHCl3. The combined organic extract is dried over MgSO4 and concentrated under reduced pressure to give crude oil which is purified by flash column chromatography (SiO2, EtOAc/Hx=1/4) to afford (2-chloro-5-vinyl-pyrimidin-4-yl)-methylamine (2.63 g, 92%) as a white solid.
Reaction SMILES: [OH:1][C:2]1([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)[CH2:5][O:4][CH2:3]1.[H-].[Na+].[CH3:16]I>CN(C=O)C.O>[CH3:16][O:1][C:2]1([C:6]2[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[CH:12][CH:13]=2)[CH2:3][O:4][CH2:5]1
Reactant: N#Cc1ccc(C2(O)COC2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1(c2ccc(C#N)cc2)COC1

Procedure:
To a solution of 4-(3-hydroxyoxetan-3-yl)benzonitrile (Step 1 of Intermediate O, 600 mg, 3.43 mmol) in DMF (12.5 mL) was added sodium hydride (60% suspension in mineral oil, 151 mg, 3.77 mmol) at a temperature of ˜5° C. The reaction mixture was allowed to stirr for 1 h at this temperature, before methyl iodide (256 μL, 4.11 mmol) was added. Stirring was continued at rt over night. The mixture was diluted with water and extracted with diethyl ether. The organic extract was dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the crude product was purified by MPLC (silica, cyclohexane/ethyl acetate 20:1→4:1) to afford the title compound in pure form (566 mg, 87%): 1H NMR (500 MHz, DMSO-d6) δ 7.93 (d, 2H), 7.68 (d, 2H), 4.81 (d, 2H), 4.73 (d, 2H), 3.05 (s, 3H); ES-MS m/z 190 (MH)+; HPLC RT (Method E) 1.22 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][C:15]([I:22])=[CH:16][CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].CCN(C(C)C)C(C)C.Cl[CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20]([CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[C:19](=[O:21])[C:18]3[C:13](=[CH:14][C:15]([I:22])=[CH:16][CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(I)ccc3c(=O)[nH]2)c1
Reactant: COCCOCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(-c2nc3cc(I)ccc3c(=O)n2COCCOC)c1
Reaction time: 18 h

Procedure:
To a mixture of 1-(7-iodo-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (1.65 g, 4.02 mmol) and THF (20 mL) was added DIPEA (2.10 mL, 12.1 mmol) followed by 1-chloromethoxy-2-methoxy-ethane (1.01 mL, 8.85 mmol) at 23° C. After stirring for 18 h, the reaction mixture was concentrated under reduced pressure. The residue was used in subsequent reactions without further purification (1.89 g, 94%). MS (ESI): mass calcd. for C18H19IN4O5, 498.0; m/z found, 499.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 8.85 (d, J=0.6 Hz, 1H), 8.30 (d, J=0.6 Hz, 1H), 8.17 (d, J=1.4 Hz, 1H), 8.00 (dd, J=8.3, 1.6 Hz, 1H), 7.95 (d, J=8.3 Hz, 1H), 5.65 (s, 2H), 4.30 (q, J=7.1 Hz, 2H), 3.50-3.48 (m, 2H), 3.26-3.23 (m, 2H), 3.05 (s, 3H), 1.31 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:3]=1>[Pd].CO>[NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])[CH:3]=1
Reactant: Nc1cc(OCC(F)(F)F)c(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(OCC(F)(F)F)c(C(=O)O)cc1N

Procedure:
Prepared analogously to example 655d from the product obtained in (675c) by hydrogenation using palladium on charcoal in methanol.
Reaction SMILES: CS(C)=O.Cl.Cl.[NH2:7][CH:8]1[CH2:11][NH:10][CH2:9]1.[NH2:12][C:13]1[CH:14]=[C:15]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:32])=[C:27](F)[C:28]=3[Cl:30])[C:23](=[O:33])[C:22]([C:34]([OH:36])=[O:35])=[CH:21]2)[CH:16]=[N:17][C:18]=1[Cl:19]>C(N(CC)CC)C>[NH2:7][CH:8]1[CH2:11][N:10]([C:27]2[C:28]([Cl:30])=[C:29]3[C:24]([C:23](=[O:33])[C:22]([C:34]([OH:36])=[O:35])=[CH:21][N:20]3[C:15]3[CH:16]=[N:17][C:18]([Cl:19])=[C:13]([NH2:12])[CH:14]=3)=[CH:25][C:26]=2[F:32])[CH2:9]1
Reactant: NC1CNC1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)cnc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)cnc1Cl
Yield: 49.6 %

Procedure:
To dimethylsulfoxide solution 1 ml of 53 mg of 3-aminoazetidine dihydrochloride and 146 mg of triethylamine at 80° C. was added 80 mg of 1-(5-amino-6-chloropyridine-3-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid with stirring, and the mixture was stirred at 80° C. for 1 hour. The reaction solution was allowed to cool and decanted with diethylether. Ethanol was added to the residue to disperse the solid content, aisd the solid content was collected by filtration, washed with ethanol, and dried to obtain 45 mg of the title compound as a pale yellow powder.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([C:14](=[O:16])[CH3:15])[CH:8]=1)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C.O>[C:14]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[OH:13])[CH2:6][CH2:5][OH:4])(=[O:16])[CH3:15]
Reactant: CC(=O)OCCc1ccc(O)c(C(C)=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)c1cc(CCO)ccc1O
Yield: 108.1 %

Procedure:
A solution of 2-(3-acetyl-4-hydroxyphenyl)ethyl acetate (35.7g) in ethanol (400 ml), and sodium bicarbonate (42g) in water (200 mls) was refluxed for 81/2 hours. The ethanol was removed on a `Rotavapor` and the residue was extracted with ether (3x). The combined ethereal extracts were washed with water, sodium bicarbonate solution, saturated brine solution, dried over anhydrous magnesium sulphate, and evaporated to yield a red oil (31.3g). The oil was recrystallised from hexane and ether (4:1) to yield the product as a pale yellow crystalline solid (18.3g). The mother liquors were concentrated and an additional batch of product was obtained as a pale yellow crystalline solid (9.3g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:8])[CH:2]=1.[F:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][N:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]2=[O:27])=[CH:18][CH:17]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:15][C:16]1[CH:29]=[CH:28][C:19]([CH:20]([N:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]2=[O:27])[C:7]([OH:8])([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:18][CH:17]=1
Reactant: O=c1ccccn1Cc1ccc(F)cc1
Reactant: O=C(c1cccnc1)c1cccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1ccccn1C(c1ccc(F)cc1)C(O)(c1cccnc1)c1cccnc1
Reaction time: 0.5 h

Procedure:
A solution of dipyridin-3-ylmethanone (1 g, 5.9 mmol) and 1-(4-fluorobenzyl)pyridin-2(1H)-one (1 g, 4.9 mmol) in THF (50 mL) was cooled to −78 C. To the resulting white suspension was added in a dropwise manner, LiHMDS (1M in THF, 6 mL). The resulting cream suspension was stirred for 30 min then allowed to warm up gradually to −30 C over 1 h. The reaction mixture was quenched with saturated NaHCO3 and then it was extracted once with ether and once with ethyl acetate. The combined extracts were dried over Na2SO4 and concentrated. The resulting yellow oil was purified by normal phase Gilson chromatography eluting with 98% DCM, 2% methanol. The product was isolated as a white solid.
Reaction SMILES: [F:1][CH2:2][CH2:3][N+:4]1[CH:12]=[C:11]2[N:6]([C:7](=[O:13])[NH:8][CH2:9][CH2:10]2)[CH:5]=1.CCN(C(C)C)C(C)C.[C:23]([OH:27])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:7](=[O:13])[NH:8][CH2:9][CH2:10][C:11]1[N:6]=[CH:5][N:4]([CH2:3][CH2:2][F:1])[CH:12]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C1NCCc2c[n+](CCF)cn21
Reactant: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCc1cn(CCF)cn1
Yield: 39 %

Procedure:
To a warmed (30° C.) suspension of 2-(2-fluoro-ethyl)-5-oxo-5,6,7,8-tetrahydro-imidazo[1,5-c]pyrimidin-2-ium (1.01 g, 3.82 mmol) in t-butanol (38 ml), was added Hunig's base (1.33 ml, 7.64 mmol) and the mixture heated to reflux under an inert atmosphere for 1.5 h. The mixture was cooled and the solvent evaporated to a yellow semi-solid, which was triterated with dichloromethane. The solid was filtered off and the filtrate purified by silica column chromatography, to yield a colourless solid (0.384 g, 39%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15](OC)=[O:16])[CH2:11][CH2:10]1>C(OC)(C)(C)C>[CH3:7][O:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]1
Reactant: COC(=O)C1CCC(OC)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COC(C)(C)C
Product: COC1CCC(CO)CC1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
13.7 ml (27.5 mmol) of lithium aluminium hydride solution (2M in THF) was diluted with 82 ml of methyl tert-butyl ether, and a solution of 4.30 g (25.0 mmol) of methyl 4-methoxycyclohexanecarboxylate (cis/trans isomer mixture) in 82 ml of methyl tert-butyl ether was then added dropwise. The reaction solution was stirred at 40° C. for another 6 h and the reaction was then terminated by addition of 10 ml of water and 10 ml of aqueous 10% strength potassium hydroxide solution. The organic phase was decanted, dried over sodium sulphate and filtered, and the solvent was removed under reduced pressure. Yield: 3.24 g (90% of theory)