Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[CH:20]1([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28](O)=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=C(O)c1ccccc1C1CCCCC1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1ccccc1C1CCCCC1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-Cyclohexyl-benzoic acid. LC-MS (basic): tR=1.42 min; [M+H]+=463.2.
Reaction SMILES: C([O:5][C:6](=[O:42])[CH2:7][C:8]1([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:41])[CH2:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[CH3:38])=[O:30])=[C:24]([O:39][CH3:40])[CH:23]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)(C)(C)C.ClCCl.O.CO>FC(F)(F)C(O)=O>[CH3:40][O:39][C:24]1[CH:23]=[C:22]([CH2:21][C:20]([NH:19][C:16]2[CH:15]=[CH:14][C:13]([C:8]3([CH2:7][C:6]([OH:42])=[O:5])[CH2:12][CH2:11][CH2:10][CH2:9]3)=[CH:18][CH:17]=2)=[O:41])[CH:27]=[CH:26][C:25]=1[NH:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38])=[O:30]
Reactant: COc1cc(CC(=O)Nc2ccc(C3(CC(=O)OC(C)(C)C)CCCC3)cc2)ccc1NC(=O)Nc1ccccc1C
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(CC(=O)Nc2ccc(C3(CC(=O)O)CCCC3)cc2)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 19.1 %

Procedure:
A solution of [1-{4-[2-[3-methoxy-4-[3-o-tolyl-ureido]-phenyl]-acetylamino]-phenyl}-cyclopentyl]-acetic acid tert-butyl ester (0.29 g, Reference Example 8) in a mixture of trifluoroacetic acid (7.5 mL), dichloromethane (1.5 mL) and water (1 mL) was stirred at room temperature for 1.5 hours and then evaporated. The residue was chased with toluene to yield a green glass, which was subjected to preparative HPLC [HyperPrep HS C-18 silica column using methanol with 0.05% trifluoroacetic acid and water with 0.05% trifluoroacetic acid as the mobile phase] to give the title compound (0.05 g) as a white solid, m.p. 223–226° C. LC-MS: RT=3.51 minutes, MS(ES+): 538(M+Na+), 516(M+H)+, 554(M+K)+; MS(ES−): 514(M−H)−.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][C:22]1[S:26][C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][N:34]=2)[CH:30]=O)=[N:24][CH:23]=1>>[CH2:19]([O:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][N:34]=[C:27]([C:25]3[S:26][C:22]([CH3:21])=[CH:23][N:24]=3)[CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1)[CH3:20]
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Reactant: Cc1cnc(-c2cc(C=O)ccn2)s1
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccnc(-c2ncc(C)s2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with 2-(5-methylthiazol-2-yl)isonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.86 min.; [M+H]+: 425.99 g/mol.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH:12]1(Br)[CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.O.O>[CH:12]1([O:9][C:8]2[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=2[O:6][CH3:7])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COc1cc(C=O)ccc1O
Reactant: BrC1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C=O)ccc1OC1CCCC1
Reaction time: 55 h
Yield: 96.7 %

Procedure:
A mixture of vanillin (10 g, 65.7 mmoles), cyclopentyl bromide (21.09 g, 196.7 mmoles), tetrabutylammonium bromide (211.8 mg, 0.675 mmoles) and K2CO3 (27.16 g, 199.48 mmoles) in tetrahydrofuran/water 8:2 (200 ml) was refluxed under nitrogen and vigorous stirring for 55 hours, then diluted with water, extracted with ethyl acetate, and the extract was washed with water, anhydrified over Na2SO4 and dried to give an oil which was purified by silica gel flash chromatography (eluent: petrolatum/ethyl acetate 9:1) and gave 14 g of the title product (yield: 97%).
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([F:14])[F:13])[N:7]=1)(C)(C)C>ClCCl>[F:13][CH:12]([F:14])[C:8]1[NH:7][C:6](=[O:5])[CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)Oc1cccc(C(F)F)n1
Solvent: ClCCl
Product: O=c1cccc(C(F)F)[nH]1
Reaction time: 16 h
Yield: 103.2 %

Procedure:
To a solution of 2-tert-butoxy-6-difluoromethylpyridine (4.3 g) in dichloromethane (25 ml) trifluoroacetic acid (2 ml) was added. The reaction was stirred for 16 hours and then concentrated. The residue was diluted with water and neutralised with sodium bicarbonate. The solid formed was extracted into ethyl acetate, dried and concentrated to give 6-difluoromethylpyrid-2-one (3.2 g, 72% yield) as a white solid; 1H NMR (270 MHz): δ 6.31, 6.53, 6.75 (1H,t), 6.56(1H,m), 6.75(1H,m), 7.52(1H,m), 12.5(1H,brs) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=1>N1C=CC=CC=1>[CH3:24][C:19]1[CH:20]=[C:21]([CH3:23])[N:22]=[C:17]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[N:18]=1
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: c1ccncc1
Product: Cc1cc(C)nc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)n1
Yield: 24.1 %

Procedure:
1-(4-Nitrophenyl)-piperazine (2.18 g, 10.6 mmol) was added to 2-chloro-4,6-dimethyl-pyrimidine (1.5 g, 10.6 mmol) in pyridine (10 mL) and the mixture was heated at reflux for 7 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated to afford 4,6-dimethyl-2-[4-(4-nitro-phenyl)-piperazin-1-yl]-pyrimidine (0.8 g, 24%) as a solid.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.C1(N)C=[CH:49][C:48]([NH2:51])=[CH:47][CH:46]=1.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[CH:49][C:48]([NH2:51])=[CH:47][CH:46]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH3:34])[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: Nc1ccc(N)cc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: Cn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(N)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 1,4-phenylenediamine as the aniline component. (25%, MS=471.2 (M+H))
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][C:11]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:13])=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2]
Reactant: Nc1ccccc1
Reactant: CC(C)CN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Product: CC(C)CN(CC(=O)Nc1ccccc1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-isobutylglycine and aniline: MS (APCI) m/z 376 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl.[CH3:30][O:31][NH:32][CH3:33]>S(Cl)(Cl)=O>[CH3:30][O:31][N:32]([CH3:33])[C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:21][CH:20]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 3 h

Procedure:
To a solution of 4-(Quinolin-2-ylmethoxy)-benzoic acid (25.98 g, 93 mmole) was added 250 ml of thionyl chloride under N2. The reaction mixture stirred 3 h and the excess thionyl chloride was removed under vacuum. The acid chloride was dissolved in tetrahydrofuran (450 ml) and triethylamine (50 ml, 4 eq.) was slowly added. O,N-dimethyl hydroxyl amine hydrochloride (27 g, 3 eq.) was added and the reaction stirred 18 h. The reaction mixture was placed on a rotovap to remove the solvent, partitioned between 1N NaOH and methylene chloride, separated, dried magnesium sulfate, filtered and concentrated. The crude product was filtered through silica gel eluting with 30-70% ethyl acetate/hexane to proved the title compound as a brown oil (26.26 g, 87%); 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J=8.7 Hz, 1 H), 8.06 (d, J=8.3 Hz, 1 H), 7.81 (d, J=8.3 Hz, 1H), 7.67 (m, 3 H), 7.63 (d, J=8.3 Hz, 1 H), 7.52 (m, 1 H), 7.01 (M, 2 H), 5.39 (s, 2 H), 3.52 (s, 3 H) 3.31 (s, 2H); MS: (M+H m/z=323.2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[C:19]([CH3:22])[CH:18]=[C:17]([O:23][CH2:24][C:25]([O:27]C)=[O:26])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:29](=[O:31])[NH2:30])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[C:19]([CH3:22])[CH:18]=[C:17]([O:23][CH2:24][C:25]([OH:27])=[O:26])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:29](=[O:31])[NH2:30])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)COc1cc(C)cc2c1c1c(C(N)=O)cccc1n2Cc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCC(=O)O)c2c3c(C(N)=O)cccc3n(Cc3cccc(F)c3)c2c1
Yield: 16.7 %

Procedure:
A solution of {9-[(3-fluorophenyl)methyl]-2-methyl-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (68.3 mg, 0.162 mM) and 0.81 mL (1.6 mM) of 2 N NaOH in 8.1 mL of ethanol was stirred for 30 minutes at 25° C. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH, then dried in vacuo to afford 11 mg (16%) of {9-[(3-fluorophenyl)methyl]-2-methyl-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. The filtrate was acidified with 1N HCl to pH=2. After cooling to 5° C., the resultant white precipitate was collected by filtration, washed with water, then dried in vacuo to afford 31 mg (47%) {9-[(3-fluorophenyl)methyl]-2-methyl-5-carbamoylcarbazol-4-yl}oxyacetic acid. 1H NMR (DMSO-d6) δ7.75 (bs, 1H), .7.6 (d, 1H, J=8 Hz), 7.45 (bs, 1H), 7.4-7.25 (m, 2H), 7.05 (m, 3H), 6.95 (d, J=8 Hz, 1H), 6.9 (d, J=8 Hz, 1H), 6.45 (s, 1H), 5.65 (s, 2H), 4.8 (s, 2H), 2.4 (s, 3H). MS (ES) m/e 390, 407. Recrystallization from acetone/hexane provided an analytical sample:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:21]([O-])=O)=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:6]#[N:7].O>C(O)(=O)C.[Fe]>[NH2:21][C:4]1[C:3]([O:2][CH3:1])=[C:10]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: COc1c(OCCCN2CCOCC2)ccc(C#N)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COc1c(OCCCN2CCOCC2)ccc(C#N)c1N
Temperature: 0 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
3-Methoxy-4-(3-morpholin-4-ylpropoxy)-2-nitrobenzonitrile (Step 2, 7.7 g, 24.1 mmol) was suspended in acetic acid (170 mL) and cooled to 0° C. Water (0.4 mL) was added, followed by iron powder (6.7 g, 120 mmol) and the resulting mixture was stirred at room temperature for 4 h at which time the reaction mixture was filtered through a pad of Celite and washed with acetic acid (400 mL). The filtrate was concentrated under reduced pressure to 100 mL and diluted with EtOAc (200 mL) at which time potassium carbonate was added slowly. The resulting slurry was filtered through a pad of Celite washing with EtOAc and water. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution. The organic layer was separated and passed through a pad of silica gel. The resultant solution was concentrated under reduced pressure to provide the title compound (6.5 g, 92%): 1H NMR (DMSO-d6) δ: 7.13 (1H, d), 6.38 (1H, d), 5.63 (2H, br s), 4.04 (2H, t), 3.65 (3H, s), 3.55 (4H, m), 2.41 (2H, t), 2.38 (4H, m), 1.88 (2H, m).
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:9]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:25][CH2:24]2)[C:8]1=[O:36])=[O:4]>CO.[OH-].[Na+]>[C:3]([CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:9]([CH:23]2[CH2:24][CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:27][CH2:28]2)[C:8]1=[O:36])([OH:4])=[O:2]
Reactant: COC(=O)CCN1C(=O)N(C2CCN(Cc3ccccc3)CC2)C(c2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCN1C(=O)N(C2CCN(Cc3ccccc3)CC2)C(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 78 mg (0.16 mmol) of 1-(2methoxycarbonylethyl)-3-(1-benzylpiperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone in 1 ml of methanol, 0.5 ml of 1N aqueous sodium hydroxide solution was added and stirred at room temperature for 2.5 hours. After neutralization with 1N hydrochloric acid, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Ether was added to the residue and precipitated crystals were collected to give the title compound as colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH:19]=O)[CH:6]=1.[NH2:22][C@@H:23]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:24][OH:25].C([BH3-])#N.[Na+]>C(O)(=O)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][NH:22][C@@H:23]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][OH:25])[CH:6]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN[C@H](CO)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[3-(4-Bromo-2-formyl-phenoxy)-phenyl]-acetic acid methyl ester (0.166 g, 0.49 mmol), (S)-(−)-2-amino-3-phenyl-1-propanol (0.091 g, 0.6 mmol), sodium cyanoborohydride (0.062 g, 1.0 mmol), and acetic acid (1 drop) were combined in CH2Cl2 (10 mL) and stirred overnight at room temperature. After aqueous work-up, the crude material was used directly in the next step.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([Cl:20])[CH:13]=1>CN(C)C=O>[CH2:3]([O:10][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([Cl:20])[CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: O=Cc1ccc(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)cc1Cl
Temperature: 0 °C
Yield: 72.3 %

Procedure:
Sodium hydride (404.8 mg, 10.12 mmol, 60% dispersed oil) was slowly added to benzylalcohol (1 g, 9.2 mmol) dissolved in dried dimethylformamide (30 ml) under nitrogen at room temperature while stirring. Then, the mixture was further stirred at room temperature for 30 minutes. Thereto, 4-fluoro-2-chlorobenzaldehyde (1.46 g, 9.2 mmol) dissolved in dried dimethylformamide was added over 10 minutes and stirred at room temperature for 18 hours until the initial reaction product disappeared. Subsequently, ice water was added thereto, and the reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water several times, dried with anhydrous magnesium sulfate, filtered and solvent-evaporated. The residual oil was chromatographed on a silica gel column (hexane:ethyl acetate=20:1) to afford the intermediate, 4-(benzyloxy)-2-chlorobenzaldehyde (1.64 g, yield: 71.9%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH:7]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH2:6][N:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:4]1.Cl[C:25]1[C:34]2[C:29](=[N:30][CH:31]=[CH:32][N:33]=2)[CH:28]=[C:27]([Cl:35])[N:26]=1.CCN(C(C)C)C(C)C>C1COCC1>[Si:10]([O:9][CH:7]1[CH2:8][CH:3]([CH2:2][NH:1][C:25]2[C:34]3[C:29](=[N:30][CH:31]=[CH:32][N:33]=3)[CH:28]=[C:27]([Cl:35])[N:26]=2)[CH2:4][N:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:6]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC(CN)CC(O[Si](C)(C)C(C)(C)C)C1
Reactant: Clc1cc2nccnc2c(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(CNc2nc(Cl)cc3nccnc23)CC(O[Si](C)(C)C(C)(C)C)C1

Procedure:
A solution of tert-butyl 3-(aminomethyl)-5-(tert-butyldimethylsilyloxy)piperidine-1-carboxylate (4.74 g, 13.7 mmol), 5,7-dichloropyrido[4,3-b]pyrazine (2.75 g, 13.7 mmol) and DIPEA (2.12 g, 16.4 mmol) in THF (20 mL) was stirred at room temperature for 48 hours. The volatiles were removed under reduced pressure and the residue was treated with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[CH2:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:15]([NH:23][C:24]1[CH:36]=[C:35](Br)[CH:34]=[CH:33][C:25]=1[C:26]([O:28]C(C)(C)C)=[O:27])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:15]([NH:23][C:24]1[CH:36]=[C:35]([CH2:2][CH2:1][CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH:34]=[CH:33][C:25]=1[C:26]([OH:28])=[O:27])(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Reactant: C=CC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(CCC2CCCCC2)ccc1C(=O)O)c1ccccc1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
0.074 mL of vinylcyclohexane, 0.17 g cesium carbonate, 26 mg of tetrabutylammonium bromide and 42 mg of polymer supported di(acetato)dicyclohexylphosphino palladium(II) were added to 2.0 mL of toluene solution containing 0.10 g of tert-butyl 2-(benzamido)-4-bromobenzoate at room temperature and stirred at 110° C. for 48 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated, and the solvent was evaporated under reduced pressure after washed with 10% citric acid aqueous solution. 2.4 mL of tetrahydrofuran, 0.6 mL of water, 0.42 g sodium formate, 0.44 mL of acetic acid and 50 mg of 3.9% palladium-carbon (ethylenediamine complex) were added to the obtained residue and stirred at 50° C. for 12 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated and the solvent was evaporated under reduced pressure. 10 mL of trifluoroacetic acid was added to the obtained residue and stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. The obtained residue was purified with reversed-phase silica gel column chromatography [eluent; 60-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to obtain 4.8 mg of 2-(benzamido)-4-(2-cyclohexylethyl)benzoic acid as white solid.
Reaction SMILES: [CH3:1][C:2]1[N:14]2[C:5]([C:6]3[CH:7]=[CH:8][CH:9]=[N:10][C:11]=3[CH:12]=[CH:13]2)=[N:4][C:3]=1[C:15](OC)=[O:16].[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[N:14]2[C:5]([C:6]3[CH:7]=[CH:8][CH:9]=[N:10][C:11]=3[CH:12]=[CH:13]2)=[N:4][C:3]=1[CH2:15][OH:16]
Reactant: COC(=O)c1nc2c3cccnc3ccn2c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1c(CO)nc2c3cccnc3ccn12
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
A solution of methyl 3-methylimidazo[2,1-f][1,6]naphthyridine-2-carboxylate (100 mg, 0.39 mmol) in DCM (8 mL) was cooled to 0° C. Diisobutylaluminium hydride (1 M in cyclohexane, 1.2 mL, 1.2 mmol) was added dropwise over 10 min. Then the mixture was stirred at 0° C. for 1 h. 2 mL of saturated ammonium chloride aqueous solution was added slowly to quench the reaction. Then 5 mL of saturated sodium bicarbonate aqueous solution was added. The mixture was extracted with DCM (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by column chromatography to give 42 mg of the product as a yellow solid. MS (ESI) m/z 214.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:5][CH:4]([C:6]([N:8]([CH3:10])[CH3:9])=O)[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1([F:11])[CH2:5][CH:4]([CH2:6][N:8]([CH3:10])[CH3:9])[CH2:3]1
Reactant: CN(C)C(=O)C1CC(F)(F)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CC1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.4 %

Procedure:
A solution of 3,3-difluoro-N,N-dimethylcyclobutanecarboxamide (24 g, 147 mmol) prepared in Part A in THF (500 mL) was added to a stirred suspension of lithium aluminum hydride (7.5 g, 198 mmol) in 500 mL THF at 0° C. The mixture was allowed to come to RT. After stirring the reaction mixture at RT for 18 h, it was quenched by slowly adding 10 mL 6 N NaOH and 5 mL water at 5° C. with stirring. The mixture was stirred at RT for 0.5 h, dried over Na2SO4 and filtered. The filtrate was concentrated to ca. 30 mL by a careful distillation of most of the THF using a Vigreux column. The remaining material was distilled under slightly reduced pressure (ca. 100-200 mm Hg); the fraction (20 mL, by 70-90° C.) contained the title compound contaminated with THF. The residual THF was carefully purged with a gentle stream of nitrogen to yield 1-(3,3-difluorocyclobutyl)-N,N-dimethylmethanamine (12 g, 80 mmol, 54.7% yield). 1H NMR (400 MHz, CDCl3) δ ppm 2.46-2.94 (2 H, m), 2.38 (2 H, d, J=6.55 Hz), 2.16-2.28 (9H, m).