Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.[Br:17][C:18]1[C:26]([CH3:27])=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][C:19]=1[CH3:28]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:22](=[O:23])[C:21]1[CH:25]=[C:26]([CH3:27])[C:18]([Br:17])=[C:19]([CH3:28])[CH:20]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: Cc1cc(C(=O)O)cc(C)c1Br
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C(=O)OC(C)(C)C)cc(C)c1Br
Temperature: 25 °C
Reaction time: 25 h
Yield: 69.5 %

Procedure:
Dehydrated tert-butanol (0.19 ml, 2.0 mmol), 4-dimethylaminopyridine (81 mg, 0.67 mmol) and EDCI (255 mg, 1.33 mmol) were added to a solution of 4-bromo-3,5-dimethyl-benzoic acid (123 mg, 0.535 mmol) in dichloromethane (1.0 ml) at 0° C., and the mixture was stirred at room temperature for 25 hours. The reaction mixture was diluted with dichloromethane, and the organic layer was washed with water, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/1→50/1) to give 4-bromo-3,5-dimethyl-benzoic acid tert-butyl ester (106 mg, 70%).
Reaction SMILES: [CH3:1][N:2]([CH3:16])/[CH:3]=[N:4]/[C:5]1[NH:6][C:7](=[O:15])[C:8]([N+:12]([O-:14])=[O:13])=[C:9]([CH3:11])[N:10]=1.C1CCN2C(=NCCC2)CC1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>CN(C=O)C>[CH2:28]([N:6]1[C:7](=[O:15])[C:8]([N+:12]([O-:14])=[O:13])=[C:9]([CH3:11])[N:10]=[C:5]1/[N:4]=[CH:3]/[N:2]([CH3:1])[CH3:16])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1nc(/N=C/N(C)C)[nH]c(=O)c1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nc(/N=C/N(C)C)n(Cc2ccccc2)c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 85493.2 %

Procedure:
To a suspension of (E)-N,N-Dimethyl-N′-(4-methyl-5-nitro-6-oxo-1,6-dihydropyrimidin-2-yl)formimidamide (53.4 g, 0.24 mmol) in DMF (690 mL) was added DBU (44.6 mL, 0.30 mol) and benzyl bromide (44.4 mL, 0.29 mol) and stirred at room temperature for 1 h. The excess of DBU was neutralized with HCl, and the mixture was concentrated in vacuo. The residue was dissolved in methylene chloride and extracted twice with 2M HCl and water, then dried over Na2SO4 and concentrated. Trituration with ethanol afforded the crystalline product which was washed with ethanol to give the product (64.7 g, 86% yield) and used in the next step without further purification.
Reaction SMILES: C([O:5][C:6](=[O:48])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([NH:15][CH:16]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=2)[CH2:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])=[O:29])=[CH:23][CH:22]=2)=[O:19])=[O:14])=[CH:9][CH:8]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:47][O:46][C:40]1[CH:39]=[C:38]([CH:16]([NH:15][C:13]([C:10]2[CH:9]=[CH:8][C:7]([C:6]([OH:48])=[O:5])=[CH:12][CH:11]=2)=[O:14])[CH2:17][C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])=[O:29])=[CH:25][CH:26]=2)=[O:19])[CH:43]=[CH:42][C:41]=1[O:44][CH3:45]
Reactant: COc1ccc(C(CC(=O)Nc2ccc(NC(=O)Nc3ccccc3C)cc2)NC(=O)c2ccc(C(=O)OC(C)(C)C)cc2)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(CC(=O)Nc2ccc(NC(=O)Nc3ccccc3C)cc2)NC(=O)c2ccc(C(=O)O)cc2)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-Butyl-4-{[(1-(3,4-dimethoxyphenyl)-3-{[4-({[(2-methylphenyl)amino]carbonyl}amino) phenyl]amino}-3-oxopropyl)amino]carbonyl}benzoate (30 mg, 0.05 mmol) was dissolved in DCM (10 mL) and TFA (0.18 mL, 2.30 mmol) was added at 0° C. and the reaction mixture was stirred at r.t. for 24 h. The solvent was removed in vacuum and the product was isolated (25 mg, 91%). M.p. 166° C. ESI-MS: 598[M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[CH:5][CH:4]=1)#[N:2].Cl.C(=O)([O-])[O-].[NH4+:34].[NH4+]>C(Cl)Cl.C(O)C>[ClH:28].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[CH:5][CH:4]=1)(=[NH:34])[NH2:2]
Reactant: Cc1cc(OCc2ccc(C#N)cc2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(OCc2ccc(C(=N)N)cc2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 147.6 %

Procedure:
To a solution of 2-chlorobenzenesulfonic acid 3-[(4-cyanophenyl)methoxy]-5-methylphenyl ester (414 mg, 1.0 mmol), as prepared in the preceding step, in methylene chloride (10 mL) was added 37% HCl in ethanol (20 mL) at 0° C. The mixture was stirred at room temperature for 2 days. The solvent was evaporated and the residue was co-evaporated with methylene chloride several times. The residue was then dissolved in ethanol (20 mL) and ammonium carbonate (385 mg, 4.0 mmol) was added at 0° C. The mixture was stirred at room temperature overnight. The reaction mixture was partitioned between methylene chloride and 10% K2CO3 (50 mL). The organic phase was washed with 50 mL of 10% K2CO3 and dried over K2CO3. The solvent was removed in vacuo. The residue was diluted with CH2Cl2, treated with HCl in methanol (30 mL), and concentrated. The residue was then purified by crystallization (methanol and ethyl acetate) to give the title compound as a white solid (345 mg, 74%). 1H-NMR (300 MHz, DMSO-d6) δ 2.21 (s, 3H), 5.16 (s, 2H), 6.53 (t, 2H, J=9.3 Hz)), 6.86 (s, 1H), 7.55-7.62 (m, 3H), 7.82-7.89 (m, 4 H), 7.93 (d, 1H, J=4.0 Hz), 9.24 (br s, 2H) and 9.44 (br s, 2H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C21H19N2ClO4S: 431.1 (M+H). Found: 43 1.1.
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C([Sn](CCCC)(CCCC)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1)CCC>COCCOC.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>[C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5]
Reactant: Cc1cc2nc(OS(=O)(=O)C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: Cc1cc2nc(-c3ccccn3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 110 °C
Yield: 106.4 %

Procedure:
To a solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26; 50 mg, 0.08 mmol) in 1,2 dimethoxyethane (1 mL) was added 2-(tributylstannyl)pyridine (0.040 mL, 0.125 mmol) and Pd(PPh3)4 and the reaction mixture was degassed with argon for 5 minutes. The reaction was heated to 110° C. in a microwave reactor for 20 minutes. The crude reaction mixture was absorbed onto silica gel and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a clear oil (45.2 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H36ClN2O3: 531.23. found: 531.68.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][NH2:8])[CH3:2].C(=O)([O-])O.[Na+].[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[CH2:10]([O:9][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][CH2:7][NH:8][C:17](=[O:19])[CH3:18])[CH3:11]
Reactant: CCOC(CCCN)OCC
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(CCCNC(C)=O)OCC
Temperature: 0 °C
Reaction time: 6 h

Procedure:
35.8 g (0.2 mol) of 4-aminobutyraldehyde-diethylacetal (90%) are dissolved in 600 ml of dichloromethane, 300 ml of saturated sodium hydrogen carbonate solution are added, and the mixture is cooled to 0° C. 17 ml (0.24 mol) of acetyl chloride are added dropwise at 0°-5° C., and the mixture is stirred for a further 6 hours at 0°-5° C. The organic phase is separated off and the aqueous phase is extracted twice more with dichloromethane. The organic phases are combined, dried over MgSO4, filtered and concentrated by evaporation in a rotary evaporator. The residue is purified by chromatography on silica gel with ethyl acetate. 4-(N-acetylamino)butyraldehyde-diethylacetal is obtained in the form of a yellowish oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(CC)CC.[C:14]1([C:20](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[C:14]1([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C1CNCCN1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: c1ccc(C(c2ccccc2)(c2ccccc2)N2CCNCC2)cc1
Reaction time: 3 h

Procedure:
Piperazine (5.0 g, 58.04 mmol) was dissolved in CHCl3 (100 ml) and Et3N (9 ml, 64.6 mmol) was added. This solution was heated to reflux and a solution of triphenylmethyl chloride (16.36 g, 58.68 mmol) in CHCl3 (100 ml) was added dropwise, via the reflux condenser, over a period of 4 hours. The reflux was then continued for 3 hours more and then was cooled and allowed to stand at room temperature overnight. A solid precipitated and was filtered off. The filtrate was evaporated to dryness to an oil which was partitioned between 10% aqueous Na2CO3 (150 ml) and CHCl3 (150 ml). The aqueous layer was washed with two additional portions of CHCl3 (2×150 ml) and the pooled organic layers were dried (MgSO4), filtered and evaporated to dryness to give a straw-colored syrup. This was purified on a silica gel 60 column (800 g) wet packed in CHCl3 and then developed with CHCl3 :MeOH (9:1) and then CHCl3 :MeOH (4:1). Fractions containing the required product were pooled and evaporated to dryness to give the title compound. Mass spec showed M+ at m/e 328. NMR (CDCl3, δ from TMS): 3.04 (br) piperazine methylenes; 7.06-7.58 (m) aromatics.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[C:34]([CH3:41])[CH:33]=1>COCCOC>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])=[C:34]([CH3:41])[CH:33]=1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cc(F)ccc1-c1ccccc1CCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 9.2 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 4-fluoro-2-methyl-phenylboronic acid (30 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 72 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient and then by RP HPLC to afford the product as a solid (5 mg, 9%). LC-MS m/e 419.28 (M+H+)
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:18](O)=[O:19])[C:15]([O:16][CH3:17])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[CH3:24][NH:25][OH:26]>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:18]([N:25]([OH:26])[CH3:24])=[O:19])[C:15]([O:16][CH3:17])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: COc1c(C(=O)O)ncc2c1ccn2Cc1ccc(F)cc1
Reactant: CNO
Agent: Cl
Product: COc1c(C(=O)N(C)O)ncc2c1ccn2Cc1ccc(F)cc1

Procedure:
The title compound was prepared by coupling of 1-(4-fluorobenzyl)-4-methoxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid with N-methyl hydroxylamine hydrochloride in a manner similar to step 8 of example 1. 1H NMR (DMSO-d6) 6; 9.70 (s, 1H), 8.50 (s, 1H), 7.76 (s, 1H), 7.33 (m, 2H), 7.16 (d, 2H, J=8.9 Hz), 6.76 (s, 1H), 5.51 (s, 2H), 4.00 (s, 3H), 2.96 (s, 3H). LCMS (APCI, M+H+): 330.1. HRMS calcd for C17H17FN3O3 (M+H) 330.1249, found 330.1250. HPLC: 98% purity.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][NH:16][CH2:15][C:14]=2[C:13]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=2[F:28])=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.Br[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>C(#N)C>[CH3:1][C:2]([CH3:30])([CH3:29])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:15][C:14]=2[C:13]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=2[F:28])=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CCOC(=O)CBr
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCNC2)C(C)(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN1CCc2c(c(-c3cc(F)c(F)cc3F)nn2C(=O)N[C@H](C(=O)NC)C(C)(C)C)C1
Temperature: 60 °C
Yield: 57 %

Procedure:
A mixture of intermediate 84 (0.39 g), DIEA (0.35 mL) and ethyl bromoacetate (0.22 mL) in acetonitrile was heated at 60° C. for 1.5 h. After evaporation of MeCN, the residue was extracted between EtOAc and saturated sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography with 70% to 90% EtOAc/Hex to give compound 83 (0.27 g, 57%). LCMS (+ESI) m/z=510.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]3[CH:21]=[CH:20][N:19]=[N:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:34][C:33](=[O:35])[NH:32][N:31]=2)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[NH:31][N:32]=[C:33]([O:35][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]5[CH:21]=[CH:20][N:19]=[N:18]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH:34]=2)=[CH:28][CH:29]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCn1ccnn1
Reactant: COc1ccc(C2=NNC(=O)C2)cc1
Product: COc1ccc(-c2cc(Oc3ncnc4cc(OCCn5ccnn5)c(OC)cc34)n[nH]2)cc1
Yield: 0 %

Procedure:
Using a procedure analogous to that described in Example 23, 4-chloro-6-methoxy-7-(2-(1,2,3-triazol-1-yl)ethoxy)quinazoline (160 mg, 0.52 mol) was reacted with 3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-5-one (120 mg, 0.63 mol), (prepared as described for the starting material in Example 10), to give 4-(5-(4-methoxyphenyl)pyrazol-3-yloxy)-6-methoxy-7-(2-(1,2,3-triazol-1-yl)ethoxy)quinazoline (105 mg, 44%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[CH:18]=[CH:19][C:20]([OH:37])=[C:21]([CH:36]=1)[CH2:22][N:23]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][N:27]=1)[CH2:24][CH3:25]>CN(C=O)C.O>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([O:37][CH2:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)=[C:21]([CH:36]=1)[CH2:22][N:23]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][N:27]=1)[CH2:24][CH3:25]
Reactant: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)OC)cn1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(Cc1cc(Br)ccc1OCc1ccncc1)c1ccc(C(=O)OC)cn1
Reaction time: 24 h
Yield: 64.5 %

Procedure:
A solution of 4-chloromethylpyridine hydrochloride (0.12 g, 0.73 mmol) in DMF (3 ml) was treated with potassium carbonate (0.29 g, 2.10 mmol). A solution of methyl 2-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridine-5-carboxylate (0.26 g, 0.71 mmol) in DMF (4 ml) was added. The reaction was stirred for 24 hours and then the reaction was diluted with water and extracted with ethyl acetate (×3). The organic phases were combined and washed with water and brine once, dried (MgSO4) and evaporated. Chromatography eluant: ethyl acetate/hexane gave methyl 2-[N-(5-bromo-2-(4-pyridylmethoxy)benzyl)-N-ethylamino]pyridine-5-carboxylate as a white solid (0.209 g, 65%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:10]=[C:11]2[C:27](=[O:28])[NH:26][N:25]=[CH:24][C:13]3=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[NH:15][C:16]([CH:17]=1)=[C:12]23>CN(C)C=O.CO>[O:28]=[C:27]1[C:11]2[C:12]3[C:13](=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[NH:15][C:16]=3[CH:17]=[C:9]([NH:8][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[CH:10]=2)[CH:24]=[N:25][NH:26]1
Reactant: O=C1CCC(=O)O1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(O)CCC(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Temperature: 22 °C
Reaction time: 24 h
Yield: 77.5 %

Procedure:
Succinic anhydride (3 eq, 0.022 g) was added to a solution of the title compound of Example 7 (0.02 g, 0.072 mmol) in N,N-dimethylformamide (0.7 M, 1 mL) and methanol (2.5 M, 0.3 mL). The reaction mixture was stirred at 22° C. for 24 hours and concentrated under reduced pressure. The yellow solid was triturated with methanol (1.0 mL) and collected by filtration. Following washes with methanol (4 mL) and diethyl ether (5.0 mL), the title compound (21 mg) was obtained in 77% yield.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:34])[NH:7][C@H:8]1[C:11](=[O:12])[N:10](C2C=CC(OC)=CC=2)[C@H:9]1[CH2:21][O:22][N:23]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])[CH3:3].O.[C:36]([OH:40])(=[O:39])[CH:37]=O>C1COCC1>[CH3:3][C:2]([CH3:4])([O:5][C:6]([NH:7][C@H:8]1[C:11](=[O:12])[NH:10][C@H:9]1[CH2:21][O:22][N:23]=[CH:37][C:36]([OH:40])=[O:39])=[O:34])[CH3:1]
Reactant: COc1ccc(N2C(=O)[C@H](NC(=O)OC(C)(C)C)[C@@H]2CON2C(=O)c3ccccc3C2=O)cc1
Reactant: O=CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C(=O)N[C@H]1CON=CC(=O)O
Reaction time: 1 h
Yield: 79.7 %

Procedure:
A solution of the oxyamine produced in Example 1 (637 mg, 2.75 mmol) and glyoxylic acid monohydrate (295 mg, 3.20 mmol) in THF (25 ml) was allowed to stir for 1 hour. The solvent was removed under reduced pressure and the resulting solid triturated with a solution of methanol-methylene chloride (1:20) to afford [[[cis-3-[[(1,1-dimethylethoxy)carbonyl]amino]-4-oxo-2-azetidinyl]methoxy]imino]acetic acid (630 mg, 79%): IR (KBr) 3325, 2960, 1755, 1705, 1685, 1595, 1515, 1330, 1265, and 1155 cm-1 ; NMR (DMSO-d6) δ 1.40 (9H, s), 3.86 (1H, m), 4.25 (2H, m), 4.88 (1H, dd, J=9, 5 Hz), 7.59 (1H, s), 7.65 (1H, d, J=9 Hz, exchangeable), 8.40 (1H, s, exchangeable); FAB HRMS, m/e 288.1194 (M+ calculated for C11H18O6N3 : 288.1195).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([F:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH3:25][O:26][C:27](=[O:32])[CH2:28][C:29](Cl)=[O:30]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[C:29](=[O:30])[CH2:28][C:27]([O:26][CH3:25])=[O:32])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([F:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: COC(=O)CC(=O)Cl
Reactant: CCOC(=O)c1cc2cc(F)ccc2n1NCc1ccc(F)cc1
Product: CCOC(=O)c1cc2cc(F)ccc2n1N(Cc1ccc(F)cc1)C(=O)CC(=O)OC

Procedure:
Prepared according to the acylation condition used in Example 2 step f) from 5-fluoro-1-(4-fluoro-benzylamino)-1H-indole-2-carboxylic acid ethyl ester and chlorocarbonyl-acetic acid methyl ester (1.2 eq.). 1H NMR (CDCl3, δ in ppm): 7.3-6.77 (m, 8H), 4.82 (dd, 2H), 4.17 (m, 2H), 3.54 (s, 3H), 3.26 (s, 2H), 1.31 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:12]([NH2:14])=O)[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.S.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:12](=[S:17])[NH2:14])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2C(N)=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S
Solvent: c1ccncc1
Product: Cc1cnc2c(c1)CCCC2C(N)=S
Temperature: 0 °C
Yield: 180.7 %

Procedure:
A solution of 3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (27.9 g. 0.14 m) in dry pyridine (300 ml.), saturated with H2S gas, was treated with P2S5 (26 g., 0.14 m) and heated at reflux for 45 min. whilst maintaining a slow stream of H2S gas. The reaction mixture was evaporated to dryness in vacuo and cooled to 0° C., made alkaline with 10% sodium hydroxide and the solution extracted with chloroform (3× 100 ml.). The combined extracts were washed with brine, dried and evaporated in vacuo. The residual oil was triturated with benzene and the solid filtered and recrystallised from benzene to give the title compound as pale yellow needles m.p. 149° (21.8 g., 87%). The hydrochloride was prepared as already described in Example 18 and isolated as colourless needles m.p. 219° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Br:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Br:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][C:12](=[O:16])[NH:13]2)=[CH:9][C:8]=1[C:3](=[O:4])[CH2:2][Cl:1]
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C1Cc2cc(C(=O)CCl)c(Br)cc2N1
Temperature: 50 °C
Reaction time: 17 h
Yield: 97.8 %

Procedure:
Chloroacetyl chloride (0.65 mL, 8.2 mmol) was added to a cooled (0° C.) suspension of 6-bromooxindol (0.825 g, 3.9 mmol) and aluminium chloride (1.82 g, 13.6 mmol) in 1,2-dichloroethane (8 mL). The resulting mixture was stirred at 0° C. for 20 min and at 50° C. for 17 h. The mixture was cooled to room temperature and was then poured on ice. The formed solid was filtered off, washed with water, and dried in vacuo to give 1.10 g (99% yield) of the title compound: 1H NMR (DMSO-d6, 400 MHz) δ 7.69 (s, 1H), 7.09 (s, 1H), 4.97 (s, 2H), 3.52 (s, 2H).
Reaction SMILES: C([SiH](CC)CC)C.[F:8][C:9]1[C:10]([NH:44][CH:45]2[CH:51]3[CH2:52][CH2:53][CH:47]([CH2:48][CH2:49][CH2:50]3)[CH:46]2[C:54]([O:56][CH3:57])=[O:55])=[N:11][C:12]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([F:24])[CH:22]=3)[N:17](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:16]=2)=[N:13][CH:14]=1.FC(F)(F)C(O)=O>ClCCl>[F:8][C:9]1[C:10]([NH:44][CH:45]2[CH:51]3[CH2:52][CH2:53][CH:47]([CH2:48][CH2:49][CH2:50]3)[CH:46]2[C:54]([O:56][CH3:57])=[O:55])=[N:11][C:12]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([F:24])[CH:22]=3)[NH:17][N:16]=2)=[N:13][CH:14]=1
Reactant: COC(=O)C1C2CCCC(CC2)C1Nc1nc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(F)cc23)ncc1F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1C2CCCC(CC2)C1Nc1nc(-c2n[nH]c3ncc(F)cc23)ncc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylsilane (0.434 mL, 2.721 mmol) was added to a stirred solution of racemic methyl 7-(5-fluoro-2-(5-fluoro-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-ylamino)bicyclo[3.2.2]nonane-6-carboxylate, 58, (0.365 g, 0.544 mmol) and trifluoroacetic acid (0.419 mL, 5.440 mmol) in dichloromethane (20 mL). The resulting yellow solution was stirred at room temperature for 2 hr and concentrated in vacuo. Water (10 mL) and aqueous saturated NaHCO3 (5 mL) were added and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic phases were dried (MgSO4), filtered and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (10-90% MeOH/CH2Cl2 gradient) to afford 178 mg of the desired product as a white foamy solid: 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.55 (s, 1H), 8.31 (s, 1H), 5.20 (s, 1H), 3.71 (s, 3H), 2.62 (m, 1H), 2.53 (m, 1H), 2.24 (m, 1H), 2.06 (m, 1H), 1.98-1.58 (m, 9H); LC/MS Gradient 10-90%, 0.1% formic 5 min, C18/ACN, RT=2.74 minutes (M+H) 329.86.