Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.CCOCC>[OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([O:5][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4]
Reactant: O=C(O)[C@@H](O)CC1CCCC1
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(OCc1ccccc1)[C@@H](O)CC1CCCC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 287 mg (1.81 mmol) of 2-(S)-hydroxy-3-(cyclopentyl)propanoic acid (from Step F) in 8 mL of DMF was treated with 0.38 mL (2.72 mmol) of TEA and 0.33 mL (2.77 mmol) of benzyl bromide and stirred at rt for 22 h. The reaction was diluted with 200 ml of ether and washed with 200 mL of H2O, 200 mL of 2.0 N HCl, 200 mL of 1.0 N NaHCO3, 200 mL of H2O and 200 mL of sat'd NaCl. The organic layer was dried over MgSO4 and concentrated. Flash chromatography on silica gel using 17:3 v/v hexanes/EtOAc afforded 102 mg (22%, 95.5% ee) of the title compound: RF: 0.40 (4:1 v/v hexanes/EtOAc); 1H NMR (300 MHz): δ 1.04-1.17 (m, 2H), 1.46-1.87 (m, 8H), 1.99 (m, 1H), 2.65 (m, 1H), 4.22 (dd, J=7.8, 4.8, 11H), 5.23 (ABq, J=12.3, 2H), 7.32-7.41 (m, 5H). HPLC: Chirapak AS 4.6×250 mm column, 17:3 v/v hexanes/iPrOH, 0.5 mL/min, 220 nm. Retention times: (S)-Enantiomer, 12.2 min; (R)-enantiomer, 15.3 min.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[Br:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CC#N
Product: Clc1ncc(Br)c(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 11.8 g (52.0 mmol) of 5-Bromo-2,4-dichloropyrimidine in 10 ml of acetonitrile at 0° C. is mixed with 4.73 ml (52.0 mmol) of aniline. The batch is stirred for 3 days at room temperature and finally concentrated by evaporation. The remaining residue is purified by chromatography (hexane/ethyl acetate: 3:1 plus 1% triethylamine). 4.94 g (17.4 mmol, corresponding to 33% of theory) of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.C[Si]([N-:15][Si](C)(C)C)(C)C.[Na+].O>C1COCC1>[NH2:15][CH2:10][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:9]
Reactant: Clc1cccc([C@@H]2CO2)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NC[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-2-(3-chlorophenyl)oxirane (13 g, 84 mmol) in THF (84 mL) was added NaHMDS (1 M in THF) (252 mL, 252 mmol) slowly at 0° C. The reaction mixture was warmed up to room temperature and stirred for overnight. To the reaction mixture, water (33 mL, 2.5 mL/g) added. After stirring for 5 h at room temperature, solvent was removed in vacuo to about ¼ and partitioned by DCM. The bottom layer is a little cloudy and the top layer was a brown solution. Both layers were concentrated, which contained the desired (R)-2-amino-1-(3-chlorophenyl)ethanol (14 g, 97%). The combined products were used in next step without further purification. LCMS (m/z): 172.1 (MH+), 0.37 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:17][CH2:16][C@@H:15]3[C@H:10]([O:11][CH2:12][CH2:13][NH:14]3)[CH2:9]2)=[CH:6][C:5]([C:18]#[N:19])=[CH:4][C:3]=1[NH:20][C:21]1[N:26]=[C:25]([NH:27][CH2:28][CH3:29])[C:24]2=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:23]2[N:22]=1.CCN(C(C)C)C(C)C.[C:44](Cl)(=[O:47])[O:45][CH3:46]>CO>[Cl:1][C:2]1[C:3]([NH:20][C:21]2[N:26]=[C:25]([NH:27][CH2:28][CH3:29])[C:24]3=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:23]3[N:22]=2)=[CH:4][C:5]([C:18]#[N:19])=[CH:6][C:7]=1[N:8]1[CH2:17][CH2:16][C@@H:15]2[C@H:10]([O:11][CH2:12][CH2:13][N:14]2[C:44]([O:45][CH3:46])=[O:47])[CH2:9]1
Reactant: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@H]4NCCO[C@@H]4C3)c2Cl)nn2c(C#N)cnc12
Reactant: COC(=O)Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H]4[C@@H](C3)OCCN4C(=O)OC)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(+/−)-2-((2-chloro-5-cyano-3-((4aR,8aR)-hexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 371)(10 mg, 0.021 mmol, was taken up in MeOH (1 mL) and DIPEA 20 μL was added. The reaction was stirred at 5° C. (ice bath) and methyl carbonochloridate (1.617 μl, 0.021 mmol) was added; the reaction stirred at 25° C. 1 hr. The solvents removed and the crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium acetate; Gradient: 40-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (+/−)-(4aR,8aR)-methyl 6-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (7.8 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[C:30]3[CH:29]=[C:28]4[C:31]5([CH2:37][O:38][C:27]4=[CH:26][C:25]=3[CH2:24][CH2:23]2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[O:21])=[CH:16][CH:15]=1.Br[CH2:40][CH2:41][CH2:42][CH3:43]>>[CH2:40]([N:34]1[CH2:35][CH2:36][C:31]2([C:28]3[C:27](=[CH:26][C:25]4[CH2:24][CH2:23][N:22]([C:20]([C:17]5[CH:18]=[CH:19][C:14]([C:3]6[CH:4]=[CH:5][C:6]([N:8]7[CH2:12][CH2:11][CH2:10][C:9]7=[O:13])=[CH:7][C:2]=6[CH3:1])=[CH:15][CH:16]=5)=[O:21])[C:30]=4[CH:29]=3)[O:38][CH2:37]2)[CH2:32][CH2:33]1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCBr
Reactant: Cc1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCNCC2)CO4)cc1
Product: CCCCN1CCC2(CC1)COc1cc3c(cc12)N(C(=O)c1ccc(-c2ccc(N4CCCC4=O)cc2C)cc1)CC3

Procedure:
The title compound was prepared from 5-[2'-methyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E18) and 1-bromobutane using a similar procedure to Example 19, as a yellow oil (55%). This was converted to its hydrochloride salt and crystallised from acetone as a white solid.
Reaction SMILES: N[C:2](=[C:9]([C:14](=[O:24])[CH2:15][CH:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]([NH:12][CH3:13])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.CCOCC>C(O)C>[C:3]1([C:2]2[O:23][CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][C:14](=[O:24])[C:9]=2[C:10]([NH:12][CH3:13])=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNC(=O)C(C(=O)CC(O)c1ccccc1)=C(N)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CNC(=O)C1=C(c2ccccc2)OC(c2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 21.4 grams (0.066 mole) of 2-(α-aminobenzylidene)-5-hydroxy-N-methyl-3-oxo-5-phenylvaleramide in 220 milliliters of ethanol is treated by dropwise addition with 10 milliliters of concentrated hydrochloric acid. The resulting suspension is stirred for 1.5 hours at room temperature. Ether is then added, and the mixture is filtered. The resulting solid is triturated thoroughly with hot methanol to give 5,6-dihydro-2,6-diphenyl-N-methyl-4-oxo-4H-pyran-3-carboxamide, m.p. 212° C. - 214° C.
Reaction SMILES: [CH:1]([C@:4]1([C:16]([O:18][CH3:19])=[O:17])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:5]1)([CH3:3])[CH3:2].C=O.[C:22](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:1]([C@:4]1([C:16]([O:18][CH3:19])=[O:17])[CH2:8][CH2:7][C@@H:6]([N:9]([CH3:22])[CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@]1(C(C)C)CC[C@@H](NC2CCOCC2)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@]1(C(C)C)CC[C@@H](N(C)C2CCOCC2)C1
Reaction time: 0.58 h
Yield: 95.4 %

Procedure:
Methyl (1S,3R)-1-isopropyl-3-(tetrahydro-2H-pyran-4-ylamino)cyclopentanecarboxylate (1.0 g, 3.7 mmol) was combined with 37% aqueous formaldehyde solution (3.0 mL, 37 mmol) in 50 mL of DCM. After stirring for 35 min, 4 Å powdered molecular sieves, and sodium triacetoxyborohydride (3.9 g, 19 mmol) were added and the reaction mixture was stirred overnight under a nitrogen atmosphere. The reaction mixture was diluted with DCM, filtered through celite, and the filtrate was washed with saturated NaHCO3 solution, and brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated to afford 1.0 g of methyl (1S,3R)-1-isopropyl-3-[methyl(tetrahydro-2H-pyran-4-yl)amino]cyclopentanecarboxylate.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[C:14]([C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([O:26][CH3:27])[C:19]=1[NH:28]C(=O)OC(C)(C)C)([O:16][CH3:17])=[O:15].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[NH2:28][C:19]1[C:20]([O:26][CH3:27])=[N:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1cc(OC)nc(OC)c1NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(OC)nc(OC)c1N
Temperature: 25 °C
Yield: 97 %

Procedure:
p-Toluene sulfonic acid hydrate (0.282 g, 1.48 mmol) was dissolved in toluene (11 mL) and heated to reflux overnight with azeotropic removal of H2O (Dean-Stark trap). The next day, the reaction was cooled to room temperature and the product of Example 28, dissolved in toluene (4 mL), was added. The reaction was heated back to reflux for 0.5 hours. The reaction was cooled to room temperature and poured into NaHCO3 (sat) and extracted 3 times with ether. The organics were combined, washed with brine, dried over MgSO4, concentrated in vacuo. The residue was purified by column chromatography using hexane/ethyl acetate as eluant (gradient 100% to 9/1) to provide 0.278 g (97%) of methyl 3-amino-2,6-dimethoxyisonicotinate as a yellow solid. Electrospray Mass Spec: 212.8 (M+H)+
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][O:22][CH3:23])=[CH:16][CH:15]=2)=[CH:6]1.C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C.O>C1(C)C=CC=CC=1>[CH3:23][O:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2[C:8]3[N:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:5]3[C:6]=2[CH2:2][CH2:3][CH2:4]3)=[CH:15][CH:16]=1
Reactant: COCOc1ccc(-c2cn(CCCBr)c3cccnc23)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: COCOc1ccc(-c2c3n(c4cccnc24)CCC3)cc1
Temperature: 110 °C
Yield: 23.1 %

Procedure:
A solution of 1-(3-bromopropyl)-3-[4-(methoxymethoxy)phenyl]-1H-pyrrolo[3,2-b]pyridine (486 mg), tri-n-butyltin hydride (0.697 mL), and AIBN (21.27 mg) in toluene (25 mL) was heated at 110° C. overnight. To the mixture was added AIBN (21.27 mg), and the mixture was heated at 110° C. for 2 h. The mixture was added to water and extracted with AcOEt. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (88 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:19][CH3:20]>CN(C=O)C>[CH2:19]([O:10][C:9]([C:3]1[C:2]([Br:1])=[CH:6][S:5][C:4]=1[CH:7]=[O:8])=[O:11])[CH3:20]
Reactant: O=Cc1scc(Br)c1C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Br)csc1C=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 63.5 %

Procedure:
4-Bromo-2-formyl-thiophene-3-carboxylic acid (0.16 g, 0.68 mmol), K2CO3 (0.188 g, 1.36 mmol), and 4 mL of anhydrous DMF were stirred at room temperature for 10 min, then iodoethane was added (0.128 g, 0.8 mmol) dropwise. The reaction solution was stirred at 50° C. for 3 h. The reaction mixture was cooled, extracted with EA (3×50 mL), concentrated and the residue was purified by TLC (PE/EA=8/1) to give 0.4 g of the title compound (yield: 63.5%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[C:8]([CH3:15])=[CH:9][CH:10]=[C:11]([N+:12]([O-])=O)[C:4]=2[O:3]1.[H][H]>[Ni].C1COCC1>[NH2:12][C:11]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:7][CH2:6][C:5]=2[C:8]([CH3:15])=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: Cc1ccc([N+](=O)[O-])c2c1CCC(C)O2
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1ccc(N)c2c1CCC(C)O2

Procedure:
A mixture of 27 g of 1D, 200 ml of THF and 2 g of activated Raney nickel catalyst was treated with hydrogen (40 psig) in a Parr shaker for 3 hours. The resulting mixture was dried (MgSO4), filtered and concentrated to dryness, to give 8-amino-3,4-dihydro-2,5-dimethyl-2H-1-benzopyran (1E), as an amber syrup.
Reaction SMILES: B(Cl)(Cl)Cl.C[O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:19][CH:18]=3)=[O:16])=[C:13]([C:32]3[CH:37]=[CH:36][C:35]([O:38]C)=[CH:34][CH:33]=3)[S:12][C:11]=2[CH:40]=1.CO>ClCCCl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15](=[O:16])[C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]4)=[CH:21][CH:22]=3)=[C:13]([C:32]3[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=3)[S:12][C:11]=2[CH:40]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCCl
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 35 °C
Reaction time: 16 h
Yield: 85.5 %

Procedure:
Boron trichloride gas is condensed into a cold graduated cylinder (2.8 ml), and added to a solution of [6-methoxy-2-(4-methoxyphenyl)-benzo-[b]-thien-3-yl] [4-[2-(1-piperidinyl)ethoxy]phenyl] methanone (6.37 g, 12.7 mmol) in 52 ml of 1,2-dichloroethane. The resulting solution is heated to 35° C. After about 16 hours the reaction is complete. Methanol (30 ml) is added to the reaction mixture over a 20 minute period, causing the methanol to reflux. The resulting slurry was stirred at 25° C. After 1 hour, the crystalline product is filtered, washed with cold methanol (8 ml), and dried at 40 ° C. in vacuo to give 5.14 g of the title compound. mp 225° C.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]1[CH:14]=[C:15]([C:21](=[O:23])[CH3:22])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>C1COCC1>[F:12][C:13]1[CH:14]=[C:15]([C:21]2([CH3:8])[CH2:22][O:23]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: C[S+](C)C
Reactant: COc1ccc(C(C)=O)cc1F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2(C)CO2)cc1F
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(3-fluoro-4-methoxyphenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS, the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([CH3:24])([S:20]([CH3:23])(=[O:22])=[O:21])[C:17](O)=[O:18])=[CH:10][CH:9]=1.CN(C=O)C.[Si]([O:34][NH2:35])(C)(C)C>C(Cl)Cl>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([CH3:24])([S:20]([CH3:23])(=[O:22])=[O:21])[C:17]([NH:35][OH:34])=[O:18])=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)ON
Reactant: CC(CCc1ccc(Br)cc1)(C(=O)O)S(C)(=O)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(CCc1ccc(Br)cc1)(C(=O)NO)S(C)(=O)=O
Yield: 96.8 %

Procedure:
Oxalyl chloride (4.50 mL, 50 mmol) was added to a solution of 4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoic acid (II) (14.69 g, 43.82 mmol) in DCM (300 mL) under nitrogen at ambient temperature, followed by DMF (340 ul). The reaction was stirred until effervescence ceased and then was allowed to stir for 1 hour. O-TMS-hydroxylamine (16.0 mL, 130 mmol) was added via syringe and the suspension was stirred for 1 hour. The reaction was quenched with methanol (60 mL), stirred for 1 hour and concentrated in vacuo to afford a yellow-white solid. The solid was triturated in DCM (200 mL) overnight. The solid was collected by filtration, washed with 1:1 DCM:heptane (2×100 mL), and dried under vacuum to afford the title compound as a white solid (14.85 g, 96.76%). LC-MS m/z 350.0 (M+1). 1H NMR (500 MHz, METHANOL-d4) δ ppm 1.64 (s, 3H) 2.00-2.10 (m, 1H) 2.44-2.58 (m, 2H) 2.61-2.77 (m, 1H) 3.04 (s, 3H) 7.18 (d, J=8.29 Hz, 2H) 7.44 (d, J=8.29 Hz, 2H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Br:10]N1C(=O)CCC1=O>O1CCCC1>[Br:10][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Brc1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridine (15.6 g, 132 mmol) in 400 mL tetrahydrofuran at −40° C. was added a suspension of N-bromosuccinimide in 120 mL tetrahydrofuran. Reaction mixture was warmed to room temperature and allowed to stir for 4 hours. Solid was filtered off. The reaction mixture was quenched with a sodium metabisulfite solution, and extracted with ethyl acetate. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was triturated with 1:1 hexane/ethyl acetate and filtered. The filtrate was concentrated and the trituration step was repeated three more times to afford a total of 25 g of the title compound, which was used without further purification. MS (DCI+) m/z 196.9 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]2[CH:15]=[N:14][C:13]3[C:8]2=[N:9][C:10]([O:17][CH2:18][CH2:19][CH3:20])=[N:11][C:12]=3[NH2:16])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1>C(O)C.[Pd]>[CH:1]1([N:7]2[CH:15]=[N:14][C:13]3[C:8]2=[N:9][C:10]([O:17][CH2:18][CH2:19][CH3:20])=[N:11][C:12]=3[NH2:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCOc1nc(N)c2ncn(C3C=CCCC3)c2n1
Agent: [Pd]
Solvent: CCO
Product: CCCOc1nc(N)c2ncn(C3CCCCC3)c2n1

Procedure:
A solution of 2.21 g (7.8 mmoles) of 9-(2-cyclohexenyl)-2-propoxy-9H-adenine in 30 mL of 90% ethanol was hydrogenated overnight with 250 mg of 10% palladium on carbon and then filtered. The filtrate was evaporated in vacuo, giving a residue which was crystallized from ethyl acetate--n-hexane. Yield 1.85 g (76%); melting point 148°-150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[N:9]=[CH:8][N:7]=[C:6]2[O:21]C1C=CC=CC=1.N>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=1)[N:9]=[CH:8][NH:7][C:6]2=[O:21]
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1OCc1ccncc1
Agent: Cl
Agent: N
Product: COc1cc2c(=O)[nH]cnc2cc1OCc1ccncc1
Yield: 56.7 %

Procedure:
A solution of 6-methoxy-4-phenoxy-7-(4-pyridylmethoxy)quinazoline (200 mg, 0.56 mmol) in 2M hydrochloric acid (15 ml) was heated at reflux for 90 minutes. The reaction mixture was allowed to cool and neutralised to pH6-7 with aqueous ammonia. The precipitated product was extracted with methanol/methylene chloride (1:9) and the extract solution dried (MgSO4). Removal of the solvent by evaporation gave 6-methoxy-7-(4-pyridylmethoxy)-3,4-dihydroquinazolin-4-one (90 mg, 57%) as a grey solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14](=O)[CH3:15])[C:10]([O:12]C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([NH:21][NH:22][CH3:23])[CH2:20][CH2:19][CH2:18]1.C([O-])(=O)C.[Na+]>CCOC(C)=O.O>[CH:17]1([N:21]2[C:10](=[O:12])[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:14]([CH3:15])[N:22]2[CH3:23])[CH2:20][CH2:19][CH2:18]1
Reactant: CNNC1CCC1
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(NC(=O)OC(C)(C)C)c(=O)n(C2CCC2)n1C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-oxobutanoate (400 mg, 1.730 mmol) in EtOAc (6.407 mL) was treated with 1-cyclobutyl-2-methylhydrazine (284 mg, 2.076 mmol) followed by sodium acetate (213 mg, 2.59 mmol). The suspension was stirred at room temperature for 30 minutes and at 80° C. for 4 hours. The resulting mixture was diluted with water (10 mL) and EtOAc was added. The layers were separated and aqueous extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue was dissolved in EtOAc and iso-hexane was added. The resulting suspension was filtered and the solid rinsed with iso-hexane. The filtrate was concentrated under reduced pressure. The crude material was then adsorbed onto silica and purification by chromatography eluting with 50-100% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8]C(=O)[O:10][C:11](=O)[C:6]=2[CH:5]=[C:4]([I:14])[CH:3]=1.[CH3:15][NH:16][CH3:17]>O1CCCC1>[NH2:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([I:14])=[CH:5][C:6]=1[C:11]([N:16]([CH3:17])[CH3:15])=[O:10]
Reactant: CNC
Reactant: O=c1[nH]c2c(F)cc(I)cc2c(=O)o1
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(I)cc(F)c1N
Temperature: 60 °C
Yield: 67 %

Procedure:
550 mg (1.79 mmol) of 8-fluoro-6-iodo-1H-benzo[d][1,3]oxazine-2,4-dione was combined with 4 mL tetrahydrofuran in a 15 mL-sized sealed tube. To the solution was added 1.79 mL (3.58 mmol) of a 2.0 M dimethylamine solution in tetrahydrofuran. The sealed tube was capped and heated in an oil bath at 60° C. for 48 hours. The solution was concentrated down and then purified by flash chromatography on silica gel. A gradient of ethyl acetate and hexanes was used to afford 368 mg (1.19 mmol, 67% yield) of 2-amino-3-fluoro-5-iodo-N,N-dimethyl-benzamide as a golden oil. 1H NMR (500 MHz, CDCl3) δ 7.29 (dd, 1H), 7.19 (s, 1H), 4.50 (s, br., 2H), 3.03 (s, br., 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:7]2[C:12]([C:13](=[O:25])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=1)=[CH:11][CH:10]=[C:9]([Cl:26])[CH:8]=2)=[O:4].[NH2:33][C:34]([CH3:42])([CH3:41])[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:7]2[C:12]([C:13](=[O:25])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:23])[NH:33][C:34]([CH3:42])([CH3:41])[CH2:35][C:36](=[O:37])[N:38]([CH3:40])[CH3:39])=[CH:18][CH:17]=1)=[CH:11][CH:10]=[C:9]([Cl:26])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1c(Cc2ccc(C(=O)O)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: CN(C)C(=O)CC(C)(C)N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(Cc2ccc(C(=O)NC(C)(C)CC(=O)N(C)C)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
A mixture of 3-(4-carboxy-benzyl)-7-chloro-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxylic acid methyl ester (75 mg, 0.17 mmol), 3-amino-3,N,N-trimethyl-butyramide (24 mg, 0.17 mmol), BOP (150 mg, 0.34 mmol) and DIPEA (1 mL) in THF (15 mL) was stirred at RT overnight. The reaction mixture was partitioned between water and EtOAc, the organic layer separated, washed with water, dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude residue was purified by preparative TLC (EtOAc/hexane, 75:25) to yield 7-chloro-3-[4-(2-dimethylcarbamoyl-1,1-dimethyl-ethylcarbamoyl)-benzyl]-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (71 mg) as a light brown foam. MS=574 [M+H]+; MP=84.1-95.5° C.