Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].C(O)C.[CH2:8]([CH:15](C(C)=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:24]N1C(=O)CCC1=O>>[Br:24][C:14]1[C:9]([CH2:8][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCc1ccccc1Br
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
To a 2 L 4-necked round bottom flask that was equipped with an overhead stirrer, an addition funnel, a condenser and a temperature-probe, was added the solution of sodium ethoxide/ethanol (21% wt. %, 161.8 g) at 20–25° C. under nitrogen. Ethyl 2-benzylacetoacetate (103.1 g, 0.454 mole) was added dropwise. The resulting solution was stirred at 20–25° C. for 30 minutes. The reaction mixture was then cooled to −35° C. with a dry ice/acetone bath. N-Bromosuccinimide (NBS; 97.95 g, 0.545 mole) was added portion-wise over 30 minutes. After the addition was over, the reaction mixture was stirred at −35° C. for 1 hr before warming up to 20–25° C. and it was stirred for an additional 2 hrs. The reaction was then quenched with water (400 mL) and ethyl acetate (600 mL) was added. The layers were separated and the product was extracted from aqueous layer with ethyl acetate (400 mL×3). The combined organic layers was washed with saturated sodium bicarbonate twice (400 mL×2), water twice (400 mL×2) and brine (500 mL). After the removal of solvent, the product (crude, 132 g) was distilled under reduced pressure. Ethyl 2-bromo-3-benzenepropanoate (97.7 g) was obtained at yield 83.7%.
Reaction SMILES: [Li+].[OH-].F[C:4]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O.[SH:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].Cl>CN(C=O)C.O>[OH:8][C:6]1[C:5]2[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:4]=2[S:18][C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: COC(=O)CS
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1sc2cc(C(F)(F)F)ccc2c1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
LiOH (4.5 mmol, 0.11 g) was added to a solution of methyl 2-fluoro-4-trifluoromethylbenzoate 68a (2.25 mmol, 0.50 g) and methyl 2-mercaptoacetate 67d (2.25 mmol, 0.21 mL) in DMF (3 mL) at 0° C. The mixture was stirred at 0° C. for 30 min and then warmed to room temperature and stirred for 1 h. Water was added and the resulting solution was acidified with 1N aqueous HCl. The precipitates were filtered, washed with water, and dried to give compound 68b.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:23]5[CH2:27][CH2:26][CH2:25][C@@H:24]5[CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)=[O:20])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1
Reactant: c1ccc(C[C@H]2CCCN2)nc1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCC[C@@H]1Cc1ccccn1

Procedure:
Following Example 103, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50 mg, 0.20 mmol) in DMF at room temperature was added (R)-2-(pyrrolidin-2-ylmethyl)pyridine (0.24 mmol), followed by the addition of DIPEA (0.056 ml, 0.32 mmol). Finally, HATU (0.067 grams, 0.18 mmol) was added and the reaction mixture was heated as a slurry at 50 C for 4 hours. The reaction mixture was conc. in vacuo and taken into a large volume of EtOAc and the organic phase was washed with dilute aqueous bicarb, water and then saline and dried (Na2SO4), then concentrated to a residue. The crude material was purified by preparative RP-HPLC to give 216 as a lyophilized solid. MS: (ESI+)=458.5
Reaction SMILES: C[O:2][C:3]1[C:12]([C:13]([OH:15])=[O:14])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1>Br>[OH:2][C:3]1[C:12]([C:13]([OH:15])=[O:14])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cccnc2c1C(=O)O
Agent: Br
Product: O=C(O)c1c(O)ccc2cccnc12

Procedure:
The title compound of Step A (2.9 g, 14.1 mmol) in HBr (14 mL) was heated at 90° C. for 1 h. The mixture was then concentrated washed with PhCH3 and used without further purification in subsequent steps.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:13]([C:14](=[O:18])[NH:15][C:16]=2[CH:17]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3)([O-])=O>CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:13]([C:14](=[O:18])[NH:15][C:16]=2[CH:17]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2c2ccccc12
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1)[nH]c(=O)c1ccccc12
Reaction time: 2 h
Yield: 126.8 %

Procedure:
A mixture of 3-nitro-6(5H)-phenanthridinone (structure 55 of Scheme XVI, where R1 =H, R2 =R3 =benzo, Y=NH) (480 mg, 1.5 mmol) and 50 mg of 10% Pd/C in 60 mL of DMF was stirred under an atomsphere of H2 for 2 h. The mixture was filtered through a Celite™ pad and the filtrate was concentrated to give 0.4 g of the crude aniline as a yellow solid. This material was used without further purification.
Reaction SMILES: NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(O)=CC=2)C=1C#N.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][OH:27].[CH2:29]([O:36][C:37]1[CH:38]=[C:39](O)[CH:40]=[CH:41][CH:42]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([O:36][C:37]1[CH:42]=[C:41]([CH:40]=[CH:39][CH:38]=1)[O:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Oc1cccc(OCc2ccccc2)c1
Reactant: CN(C)CCO
Agent: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Product: CN(C)CCOc1cccc(OCc2ccccc2)c1

Procedure:
Compound 113A was prepared in a similar manner to the synthesis of step 1 of Example 35 by substituting compound 34D and compound 31F with 2-(dimethylamino)ethanol and 3-(benzyloxy)phenol, respectively: DCI (+)MS: 272 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:12][N:4]1[CH:5]=[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]([O:1][CH2:14][C:15]2[CH:20]=[N:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)=[N:3]1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Reactant: COC(=O)Cc1cn(C)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cn(C)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)nc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
A mixture of methyl 3-hydroxy-1-methyl-1H-pyrazol-4-ylacetate (298 mg), 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (551 mg), potassium carbonate (484 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 1-methyl-3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-ylacetate (670 mg, yield 85%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]([N:15]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[CH:28][C:27]=4[O:39][CH3:40])[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17][C:16]2=[O:41])[CH:12]=[CH:13][CH:14]=1.CCN(C(C)C)C(C)C.[Cl:51][CH2:52][C:53](Cl)=[O:54]>C(Cl)Cl>[Cl:51][CH2:52][C:53]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[CH:28][C:27]=4[O:39][CH3:40])[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17][C:16]2=[O:41])[CH:10]=1)=[O:54]
Reactant: O=C(Cl)CCl
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(N)c3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(NC(=O)CCl)c3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
8-(3-Aminophenyl)-24(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (1b, 131 mg, 0.29 mmol) in DCM (5 mL) at 0° C. was treated with DIEA (0.13 mL, 0.72 mmol) and cooled in an ice bath at 0° C. The solution was then treated with 2-chloroacetyl chloride (Sigma Aldrich; 0.027 mL, 0.344 mmol) slowly dropwise over 10 min and stirred at 0° C. for 30 min. LC-MS indicated only trace amounts of the desired product. The reaction mixture was sonicated for 10 min to help dissolve the substrate and another 2 drops of 2-chloroacetyl chloride was added. After 30 min, LC-MS indicated 74% conversion to the desired product m/z (ESI, +ve ion) 533.9 (M+H)+ along with unreacted starting material. 2 more drops of 2-chloroacetyl chloride was added and the solution stirred for another 75 min resulting in clean conversion to the desired product. The reaction mixture was concentrated, treated with DMSO (8 mL) and purified on a Gilson preparatory HPLC (Gemini Phenomenex; 30×150 mm, 5μ, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water). The product containing fractions were concentrated under reduced pressure (rotary evaporator) and the resulting aqueous solution treated with a 10% aqueous solution of Na2CO3 and extracted with DCM (4×30 mL), dried over sodium sulfate and dried under vacuum overnight affording 2-chloro-N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acetamide (53.4 mg, 0.100 mmol, 35% yield) as a yellow solid. m/z (ESI, +ve ion) 533.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.50 (1H, s), 8.75 (1H, s), 8.17 (1H, s), 7.91 (1H, d, J=9.4 Hz), 7.75 (1H, d, J=8.2 Hz), 7.49-7.57 (2H, m), 7.25 (1H, d, J=9.0 Hz), 7.04 (1H, d, J=7.8 Hz), 6.53 (1H, d, J=2.2 Hz), 6.44 (1H, d, J=9.4 Hz), 6.04 (1H, br. s.), 4.25 (2H, s), 3.78 (3H, s), 3.06 (4H, br. s.), 2.40-2.48 (4H, m), 2.23 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2([C:15]([OH:17])=O)[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[N:29]1([C:34]2[CH:39]=[C:38]([CH2:40][NH2:41])[CH:37]=[C:36]([C:42]3[CH:47]=[CH:46][C:45]([O:48][C:49]([F:52])([F:51])[F:50])=[CH:44][CH:43]=3)[N:35]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2([C:15]([NH:41][CH2:40][C:38]3[CH:37]=[C:36]([C:42]4[CH:43]=[CH:44][C:45]([O:48][C:49]([F:52])([F:50])[F:51])=[CH:46][CH:47]=4)[N:35]=[C:34]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:39]=3)=[O:17])[CH2:13][CH2:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: NCc1cc(-c2ccc(OC(F)(F)F)cc2)nc(N2CCCC2)c1
Reactant: O=C(O)C1(NS(=O)(=O)c2ccc(F)cc2)CC1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: O=C(NCc1cc(-c2ccc(OC(F)(F)F)cc2)nc(N2CCCC2)c1)C1(NS(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
Acid 15C (260 mg, 1 mmol) was dissolved in 5 ml of THF and at rt DEPC (1.1 equiv, 0.17 ml) and [2-pyrrolidin-1-yl-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 27C (1.1 equiv., 371 mg) were added to the solution. The mixture was stirred at rt overnight then evaporated. The residue was dissolved in EtOAc (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (3:7 EtOAc:Petroleum ether) afforded 130 mg of a white solid. Yield=22% 1HNMR (DMSO, 200 MHz) δ 0.71 (2H, bm), 1.08 (2H, bm), 1.92 (4H, m), 3.47 (4H, m), 4.29 (2H, d, J=5.6 Hz), 6.41 (1H, s), 7.09 (1H, s), 7.45 (4H, m), 7.82 (2H, m), 8.17 (2H, d, J=9 Hz), 8.38 (1H, t), 8.71 (1H, bs) [M+1] 579.4 (C27H26F4N4O4S requires 578.58).
Reaction SMILES: [NH2:1][C:2]([CH:4]([CH:17]([C:29]([NH2:31])=[O:30])[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=O.N>N1C=CC=CC=1>[C:2]([CH:4]([CH:17]([C:29]([NH2:31])=[O:30])[C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][CH:28]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)#[N:1]
Reactant: CCOC(=O)c1ccc(C(C(N)=O)C(C(N)=O)c2ccccc2N2CCCCC2)cc1
Agent: N
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(C(C(N)=O)C(C#N)c2ccccc2N2CCCCC2)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Two hundred thirty-four milligrams (1.22 m mol) of 4-toluene-sulfochloride were added in two batches to 520 mg (1.22 m mol) of ethyl 4-[(α-aminocarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate in 0.22 ml of pyridine, and the mixture was heated to 50° C. After two hours and then one hour later, the same quantities of pyridine and 4-toluene-sulfochloride were again added, and the resulting mixture was heated for a further hour at 50° C. After the mixture was left to stand for two days at 20° C., 2N ammonia was added, and the mixture was extracted with chloroform. The chloroform solution was extracted twice with water. After drying and filtering, the solution was concentrated by evaporation in vacuo. The evaporation residue was purified by column chromatography on silica gel [chloroform/methanol (10:1)].
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[K+].Br[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Product: Oc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.02 mmol, 2.0 mol %), phenylboronic acid (183 mg, 1.5 mmol), potassium fluoride (174 mg, 3.0 mmol), and 4-bromophenol (173 mg, 1.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) was added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at room temperature until the starting aryl bromide had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL), filtered through celite, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 154 mg (91%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-])=O)[CH:3]=1.Cl.C(=O)([O-])O.[Na+]>C(O)C>[Cl:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([NH2:11])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)c2c(c1)CCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1cc(Cl)c2c(c1)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a mixture of 7-chloro-5-nitro-2,3-dihydro-1-benzofuran (7.40 g) and ethanol (300 mL) were added reduced iron (12.4 g) and concentrated hydrochloric acid (20.0 mL) under ice-cooling, followed by warming to room temperature and stirring overnight. This mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution and sodium hydrogen carbonate under ice-cooling, filtered through celite, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, the insoluble materials were separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20 to 60:40) to obtain 7-chloro-2,3-dihydro-1-benzofuran-5-amine (5.49 g) as a pale yellow solid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[O:19][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:18])[CH:11]=[CH:10]3)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.Cl>O1CCCC1>[NH2:2][CH2:1][CH2:3][CH2:4][CH:5]1[O:19][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:18])[CH:11]=[CH:10]3
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CCC#N)C2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CCCN)C2
Temperature: 30 °C
Reaction time: 2 h
Yield: 111.6 %

Procedure:
2-(2-Cyanoethyl)-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (1.35 g) was dissolved in tetrahydrofuran (100 ml), to which lithium aluminum hydride (1.4 g) was added and stirred at 30° C. for 2 hours. To the reaction liquid, methanol (20 ml) was added and stirred for 10 minutes, then filtered through cerite. The filtrate was condensed under reduced pressure, and the resultant crude product was purified by alumina column chromatography (eluent: first, chloroform:ethyl acetate=1:1; later, chloroform:methanol=3:1). Crude crystals (1.05 g) was obtained. These crude crystals were converted into a hydrochloride, which was then recrystallized from a solvent mixture of chloroform-ethanol-ether to obtain 1.53 g of a hydrochloric acid salt of 2-(3-aminopropyl)-5-methyl -2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one as yellow needles (73.4%).
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:20])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:40][C:41]([O:43][CH3:44])=[O:42]>CN(C)C=O.C(#N)C>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([CH:10]2[C:9]3[C:8](=[O:20])[CH2:7][CH2:6][CH2:5][C:4]=3[N:3]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=3)[C:2](=[O:1])[N:11]2[CH2:40][C:41]([O:43][CH3:44])=[O:42])=[CH:19][CH:18]=1)#[N:17]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Reactant: COC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 0 °C

Procedure:
A solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-benzonitrile (example 1, 3.56 g, 6.12 mmol) in a mixture of N,N-dimethyl-formamide (10 mL) and acetonitrile (30 mL) is cooled at 0° C. in an ice bath. Lithium diisopropylamide (2.0 M in tetrahydrofuran, 6.7 mL, 13.4 mmol) is added while the temperature is kept below 5° C. Methyl bromoacetate is added dropwise while the temperature is kept below 10° C. After 1.5 h the ice bath is removed and stiffing is continued over night. The mixture is concentrated under reduced pressure and the residue is purified by preparative HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 1.87 g; ESI mass spectrum [M+H]+=484; Retention time HPLC: 0.95 min (Z018_S04).
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][OH:4].[Bi](Br)(Br)Br.O[CH:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)[CH3:12]>ClC(Cl)(Cl)Cl>[CH2:3]([O:4][CH:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)[CH3:12])[CH:2]([CH3:5])[CH3:1]
Reactant: COC(=O)c1ccc(C(C)O)cc1
Reactant: CC(C)CO
Agent: Br[Bi](Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C(C)OCC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a solution of 2-methylpropan-1-ol (150 mg, 2 mmol) in perchloromethane (4 mL) was added bismuth(III) bromide (900 mg, 2 mmol). The mixture was stirred at room temperature for 30 minutes then methyl 4-(1-hydroxyethyl)benzoate (180 mg, 1 mmol) was added and the mixture was stirred at room temperature for 12 hours. The suspension was concentrated in vacuum and quenched with aqueous 1N hydrochloric acid (5 mL). The residue was taken up with water (50 mL) and extracted with dichloromethane (50 mL). The combined extract was dried over sodium sulphate, evaporated and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20:1) to give the product methyl 4-(1-isobutoxyethyl)benzoate (0.18 g, 76%) as colorless oil. 1H NMR (300 MHz, CD3OD) δ 8.01 (d, J=8.1 Hz, 2H), 7.36 (d, J=8.1 Hz, 2H), 4.44-4.41 (m, 1H), 3.12-3.00 (m, 2H), 1.87-1.82 (m, 1H), 1.44 (d, J=6.3 Hz, 3H), 0.88 (d, J=6.6 Hz, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.ClCCl.C(N(CC)CC)C.[C]=O.[CH3:37][OH:38]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CN(C=O)C>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([N:10]2[C:37](=[O:38])[C:2]3[N:3]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=[CH:6][C:7]=3[CH2:8][CH2:9]2)[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(NCCc2ccc(Cl)nc2Cl)CC1
Reactant: CO
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C]=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(n1)C(=O)N(C1CCN(C(=O)OC(C)(C)C)CC1)CC2

Procedure:
A mixture of tert-butyl 4-((2-(2,6-dichloropyridin-3-yl)ethyl)amino)piperidine-1-carboxylate (10.5 g), a dichloromethane adduct of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.30 g), triethylamine (11.8 mL), methanol (20 mL), and DMF (60 mL) was stirred at 90° C. for 7 hours in a carbon monooxide (5 atm) atmosphere. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (4.01 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]3)[O:18][N:17]=2)[N:3]=1.[CH3:28][C:29]([O:31][I:32]1([O:46][C:47]([CH3:49])=[O:48])([O:42][C:43]([CH3:45])=[O:44])[O:41][C:39](=[O:40])[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]1=2)=[O:30]>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([N:21]3[CH2:22][CH2:23][C:24](=[O:27])[CH2:25][CH2:26]3)[O:18][N:17]=2)[N:3]=1.[CH3:45][C:43]([O:42][I:32]1([O:46][C:47]([CH3:49])=[O:48])([O:31][C:29]([CH3:28])=[O:30])[O:41][C:39](=[O:40])[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]1=2)=[O:44]
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(N3CCC(O)CC3)n2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(N3CCC(=O)CC3)n2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)piperidin-4-ol (Intermediate 132, 120 mg, 0.325 mmol) in DCM (20 mL) at 0 C was added Dess-Martin Periodinane (138 mg, 0.325 mmol). The resulting reaction mixture was stirred at room temperature for 2 h and then further Dess-Martin Periodinane (138 mg, 0.325 mmol) was added. The reaction mixture was stirred for a further 16 h at room temperature and then quenched with a saturated sodium bicarbonate aq. solution (10 mL). The resulting bi-layer was separated and the organics washed further with a 1M aq. HCl solution (10 mL). Organics were dried over magnesium sulfate, evaporated to dryness and purified by silica chromatography (0 to 3% MeOH in DCM) to afford the title compound as an off-white solid (Dess-Martin Periodinane impurities (17%) also present) (179 mg, 150%). Method C HPLC-MS: MH+ requires m/z=367. Found: m/z=367, Rt=1.14 min (74%).