Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[C:6]1([CH3:23])[CH:11]=[CH:10][C:9]([O:12][C:13]2[S:17][C:16]([CH2:18][C:19](Cl)=[N:20][OH:21])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[C:24]([C:26]1[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[C:6]1([CH3:23])[CH:11]=[CH:10][C:9]([O:12][C:13]2[S:17][C:16]([CH2:18][C:19]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=4)[O:21][N:20]=3)=[CH:15][CH:14]=2)=[CH:8][CH:7]=1
Reactant: Cc1ccc(Oc2ccc(CC(Cl)=NO)s2)cc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)s2)cc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 14 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (5-p-tolyloxy-thiophen-2-yl)acetohydroximoyl chloride (130 mg, 0.461 mmol) described in Manufacturing Example 48-1-5 and 3-ethynyl-pyridin-2,6-diamine (30.0 mg, 0.226 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (126 μL, 0.903 mmol), which was stirred for 7 hours at 60° C. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (12.0 mg, 14.0%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[NH:27][C:28]([CH:30]1[CH2:32][CH2:31]1)=[NH:29]>>[CH:30]1([C:28]2[N:29]=[C:23]([CH:11]3[CH2:10][CH:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=4)[CH2:14][N:13]([C:15]([N:17]4[CH2:22][CH2:21][S:20][CH2:19][CH2:18]4)=[O:16])[CH2:12]3)[O:24][N:27]=2)[CH2:32][CH2:31]1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1
Reactant: N=C(NO)C1CC1
Product: CCc1ccc(C2CC(c3nc(C4CC4)no3)CN(C(=O)N3CCSCC3)C2)cc1

Procedure:
According to General Method 6A, 300 mg (0.828 mmol) of the compound from Example 7A and 91 mg (0.91 mmol) of N-hydroxycyclopropanecarboximidamide were reacted Yield: 141 mg (40% of theory)
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl-].[Cl-].[Cl-].[Al+3].[C:17](Cl)(=[O:19])[CH3:18].Cl.[OH-].[Na+]>O>[F:1][C:2]1[CH:11]=[C:10]([C:17](=[O:19])[CH3:18])[C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)Cl
Reactant: Oc1ccc(F)c2cccnc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(=O)c1cc(F)c2cccnc2c1O
Temperature: 0 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
A mixture of 5-fluoroquinolin-8-ol (15.0 g, 91.9 mmol, from TCI), aluminum trichloride (50.00 g, 375.0 mmol), and acetyl chloride (30.2 mL, 425 mmol) was stirred at 0° C. for 4 hours, then heated at 130° C. for 12 hours, cooled, and decomposed with water (98 mL) (with external ice-cooling when necessary) and conc. hydrogen chloride in water (33 mL). The precipitate was filtered, and dried under reduced pressure. The solid obtained was then dissolved in 100 mL of water. The mixture was cooled with an ice bath and its pH was adjusted to 4 with slow addition of 20% NaOH. The suspension was filtered, washed with water and air dried to give the desired product (18.9 g, 100%). LCMS calculated for C11H9FNO2 (M+H)+: m/z =206.1; Found: 206.0.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:11][C@H:12]([CH:28]([CH3:30])[CH3:29])[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=[O:14].O1CCOCC1>CO>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:18]2[CH2:17][CH2:16][N:15]([C:13](=[O:14])[C@H:12]([NH:11][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[CH:28]([CH3:30])[CH3:29])[CH2:20][CH2:19]2)=[CH:22][CH:23]=1
Reactant: CC(C)[C@@H](N)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)[C@@H](NC(=O)Nc1ccccc1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction tube was charged with phenyl isocyanate (12 mg), (R)-2-amino-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methylbutan-1-one hydrochloride (17 mg) and 1,4-dioxane (0.75 mL). The reaction mixture was shaken overnight at rt. After this time, the resulting solution was diluted with MeOH and purified by preparative LC-MS to provide Example 201. MS found: (M+H)+=429.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:43])[N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])[CH2:28][CH2:27]1>>[Cl:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[Cl:18])[N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:9](=[O:11])[CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:28][CH2:27]1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCC1CCN(C(c2ccccc2Cl)c2ccccc2Cl)CC1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCC1CCN(C(c2ccccc2Cl)c2ccccc2Cl)CC1

Procedure:
Batch size: 1.6 g (10.7 mmol) 3-(3-pyridyl)-acrylic acid, 1.9 g (15.0 mmol) oxalyl chloride and 3.9 g (10.0 mmol) 4-{1-[bis-(2-chlorophenyl)-methyl]-piperidine-4-yl}-butylamine. In the purification, chromatographic purification is done twice over silica gel with CHCl3/CH3OH (97/3 and 97/3 to 95/5) and crystallization is from 25 ml acetic acid after drawing off the solvent. Colorless crystals with a MP of 129-131° C. were recovered; yield: 0.6g (11%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@@H:4]([CH:5]=[C:6]2[CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:10](Cl)=[O:11].C1C=CC=CC=1.[CH3:20][OH:21].N1C=CC=CC=1>O>[CH3:1][C:2]1([CH3:13])[C@@H:4]([CH:5]=[C:6]2[CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:10]([O:21][CH3:20])=[O:11]
Reactant: CO
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C1CCC1
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)[C@@H]1[C@H](C=C2CCC2)C1(C)C
Temperature: 20 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
A mixture of 30 g of (1R,cis) 2,2-dimethyl-3-cyclobutylidenemethyl-cyclopropane-1-carboxylic acid chloride and 50 ml of benzene was added to a solution of 15 g of methanol, 15 g of pyridine and 200 ml of benzene and the mixture was stirred at 20° C. for 8 hours and was then poured into iced water. The decanted organic phase was washed with water, with a sodium bicarbonate solution, with water, with dilute hydrochloric acid and finally with water. The organic phase was dried and evaporated to dryness under reduced pressure at 45° C. The residue was chromatographed over silica gel and was eluted with an 8-2 petroleum ether (b.p.=60°-80° C.)-isopropyl ether mixture to recover the fraction with an Rf=0.5. The solvent was distilled off under reduced pressure at 45° C. and the residue was rectified under reduced pressure to obtain 23 g of methyl (1R,cis) 2,2-dimethyl-3-cyclobutylidenemethyl-cyclopropane-1-carboxylate with a boiling point of 63°-64° C. at 0.1 mm Hg and a specific rotation of [α]D20 =+119° (c=1.5% in chloroform).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([OH:14])[CH2:12][OH:13])=[CH:7][CH:6]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.N1C=CC=CC=1.O>ClCCl>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:13][CH2:12][CH:11]([OH:14])[C:8]2[CH:9]=[N:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:15])[F:16])=[CH:6][CH:7]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC(O)c1ccc(OCC(F)(F)F)nc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(O)c2ccc(OCC(F)(F)F)nc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.8 %

Procedure:
A mixture of 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethane-1,2-diol (1.01 g, 4.24 mmol, Step-3, single enantiomer), p-toluenesulfonyl chloride (0.97 g, 5.09 mmol) and pyridine (3.43 mL, 42.4 mmol) in dichloromethane (21 mL) is stirred at room temperature for 20 hours. Then p-toluenesulfonyl chloride (0.97 g, 5.09 mmol) is added to the reaction mixture and stirred for 24 hours. The reaction mixture is poured into water and extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (2:1 to 1:1) to give 1.64 g (99% yield) of the title compound as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14](=O)[CH2:15]Br)=[CH:12][CH:11]=[C:10]([O:18][CH3:19])[C:8]=2[N:9]=1.[C:21]([O:25][C:26]([NH:28][C:29]([NH2:31])=[NH:30])=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(#N)C>[CH3:1][O:2][C:3](=[O:20])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14]3[N:31]=[C:29]([NH:28][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[NH:30][CH:15]=3)=[CH:12][CH:11]=[C:10]([O:18][CH3:19])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(C(=O)CBr)c2s1
Reactant: CC(C)(C)OC(=O)NC(=N)N
Solvent: CC#N
Product: COC(=O)Nc1nc2c(OC)ccc(-c3c[nH]c(NC(=O)OC(C)(C)C)n3)c2s1
Yield: 17 %

Procedure:
0.25 g of (7-bromoacetyl-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester (0.0007 Mol) and 0.33 g of tert-butoxycarbonylguanidine (0.0021 Mol) were heated to reflux in acetonitril (3 ml) for 3 hrs. After evaporation of the solvent the residue was triturated with water (10 ml) and filtered. The filtrate was evaporated and the residue subjected to column chromatography (silicagel, ethyl-acetate/hexanes 1:1) to yield the title compound as a white solid (17%); F.p.: 255-265° C.
Reaction SMILES: [C:1]([CH:3]([C:11]#[N:12])[C:4]([CH3:10])([CH3:9])[C:5](OC)=[O:6])#[N:2].CC(C)([O-])C.[K+].[CH:19]1([CH2:24][N:25]2[C:29]3=[N:30][CH:31]=[C:32]([F:34])[CH:33]=[C:28]3[C:27]([C:35](=[NH:37])[NH2:36])=[N:26]2)[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)(C)(C)C>[NH2:2][C:1]1[C:3]2[C:4]([CH3:10])([CH3:9])[C:5](=[O:6])[NH:12][C:11]=2[N:37]=[C:35]([C:27]2[C:28]3[C:29](=[N:30][CH:31]=[C:32]([F:34])[CH:33]=3)[N:25]([CH2:24][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[N:26]=2)[N:36]=1
Reactant: N=C(N)c1nn(CC2CCCC2)c2ncc(F)cc12
Reactant: COC(=O)C(C)(C)C(C#N)C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC1(C)C(=O)Nc2nc(-c3nn(CC4CCCC4)c4ncc(F)cc34)nc(N)c21

Procedure:
30 ml of tert-butanol, 1.068 g (6.429 mmol) of methyl 3,3-dicyano-2,2-dimethylpropanoate dissolved in 15 ml of tert-butanol and 901 mg (8.037 mmol) of potassium tert-butoxide were added to 1.400 g (5.358 mmol) of 1-(cyclopentylmethyl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide, and the mixture was heated under reflux for 24 h. The reaction mixture was concentrated on a rotary evaporator, triturated with 60 ml of water/ethanol (v/v=5:1), filtered off with suction and dried under high vacuum. This gave 1.296 g (57% of theory) of the target compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:23][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:24])([CH3:25])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(Cl)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(F)c(Cl)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.9 %

Procedure:
To a stirred mixture solution of 2-(3-chloro-4-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.0, 2.8 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL) was added 50% sodium hydroxide in water (1.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-(3-chloro-4-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (840 mg, 90%) as a white foam: LC/MS m/e calcd for C18H17ClFNO2 (M+H)+: 334.79, observed: 334.1.
Reaction SMILES: Cl.[F:2][C:3]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:4]=1[O:5][C@H:6]1[C@@H:10]([OH:11])[CH2:9][N:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:7]1=[O:18].[Cl:27][C:28]1[CH:33]=[N:32][C:31](Cl)=[CH:30][N:29]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:27][C:28]1[N:29]=[CH:30][C:31]([N:15]2[CH2:14][CH2:13][CH:12]([N:8]3[CH2:9][C@H:10]([OH:11])[C@H:6]([O:5][C:4]4[CH:19]=[CH:20][C:21]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:22][C:3]=4[F:2])[C:7]3=[O:18])[CH2:17][CH2:16]2)=[N:32][CH:33]=1
Reactant: CS(=O)(=O)c1ccc(O[C@@H]2C(=O)N(C3CCNCC3)C[C@@H]2O)c(F)c1
Reactant: Clc1cnc(Cl)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(O[C@@H]2C(=O)N(C3CCN(c4cnc(Cl)cn4)CC3)C[C@@H]2O)c(F)c1
Temperature: 100 °C
Yield: 7.7 %

Procedure:
(3S,4S)-3-(2-fluoro-4-(methylsulfonyl)phenoxy)-4-hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride (0.03 g, 0.073 mmol) was dissolved in DMF (2 mL) and 2,5-dichloropyrazine (0.012 g, 0.081 mmol) and Hunig's base (0.040 mL, 0.22 mmol) were added. The reaction was heated at 100° C. for 4 hours. The reaction was cooled and concentrated. The residue was purified by reverse phase chromatography (5 to 95% ACN in water) to afford (3S,4S)-1-(1-(5-chloropyrazin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenoxy)-4-hydroxypyrrolidin-2-one (0.0027 g, 0.0056 mmol, 7.6% yield). Mass spectrum (apci) m/z=485.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:19][CH3:20])=[CH:5][C:6]2[O:12][CH2:11][CH2:10][CH:9]([C:13]([O:15]C)=[O:14])[C:8](=O)[C:7]=2[CH:18]=1.[BH4-].[Na+].Cl>C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[C:4]([O:19][CH3:20])=[CH:5][C:6]2[O:12][CH2:11][CH2:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][C:7]=2[CH:18]=1
Reactant: COC(=O)C1CCOc2cc(OC)c(OC)cc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(cc1OC)OCCC(C(=O)O)=C2

Procedure:
In a mixture of methylene chloride (60 ml) and methanol (80 ml) is dissolved methyl 7,8-dimethoxy-5-oxo-2,3,4,5-terahydro-1-benzoxepin-4-carboxylate obtained in Reference Example 11 (1.9 g). To the solution is added, while stirring, sodium borohydride (0.6 g) in limited amounts taking one hour. The reaction mixture is treated with dilute hydrochloric acid, followed by extraction with methylene chloride. The organic layer is washed with a small volume of a saturated aqueous saline solution, dried, and concentrated under reduced pressure. The residue is dissolved in methanol (5 ml), and to the solution is added a 2N aqueous solution of sodium hydroxide (20 ml). The mixture is stirred at room temperature for two hours. After addition of water (50 ml), the reaction mixture is washed with ether. The aqueous layer is acidified with dilute hydrochloric acid, and extracted with methylene chloride. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue is dissolved in dioxane (10 ml), to the solution is added concentrated hydrochloric acid (3 ml), and then the mixture is stirred for one hour at 90° C. After cooling, the reaction mixture is extracted with ethyl acetate. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate to afford 7,8-dimethoxy-2,3-dihydro-1-benzoxepin-4carboxylic acid as colorless needles (1.2 g), m. p. 209°-210° C.
Reaction SMILES: [Br:1]Br.[NH:3]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:14])[C:8]=2[CH2:7][CH2:6][C:4]1=[O:5]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:6]1[CH2:7][C:8]2[C:9](=[O:14])[CH2:10][CH2:11][CH2:12][C:13]=2[NH:3][C:4]1=[O:5]
Reactant: O=C1CCC2=C(CCCC2=O)N1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1CCCC2=C1CC(Br)C(=O)N2
Reaction time: 0.02 h

Procedure:
A solution of 3.6 g of bromine in 50 ml of carbon tetrachloride was added, while stirring under ice-cooling, to a solution of 4.0 g of 3,4,5,6,7,8-hexahydrocarbostyril-5-one in 50 ml of carbon tetrachloride. After allowing the mixture to stand for one minute, the precipitate formed was removed by decantation. The carbon tetrachloride layer was distilled at room temperature to remove the solvent (CCl4), and the resulting crystals were combined with the above precipitate followed by being washed with acetone to give quantitatively 8-(or 6-) bromo-3,4,5,6,7,8-hexahydrocarbostyril-5-one having a melting point of 126°-127° C. as yellow crystals. The thus obtained crystals were dissolved in 80 ml of carbon tetrachloride, and 3.0 g of 3-chloro-1,2-propanediol and 1.5 g of 2,4,6-tribromophenol were added to the solution. The mixture was heated at reflux for 2 hours and thereafter worked up in the same manner as described in Example 6 to give 2.1 g of 5-(2-hydroxy- 3-chloro)propoxy-3,4-dihydrocarbostyril having a melting point of 157°-158° C. as colorless amorphous crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=[C:13]2[O:24][CH3:25].CC([O-])=O.[K+].[Br:31]Br>CC(O)=O.O>[Br:31][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][C:2]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([F:22])([F:21])[F:23])[CH:14]=[C:13]2[O:24][CH3:25]
Reactant: COc1cc(C(F)(F)F)nc2ccc(-c3cc4ccccc4o3)cc12
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(F)(F)F)nc2ccc(-c3oc4ccccc4c3Br)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.6 %

Procedure:
To a stirred solution of 6-(1-benzofuran-2-yl)-4-methoxy-2-(trifluoromethyl)quinoline (0.930 g, 2.71 mmol) in HOAc (30 mL) at 0° C. was added KOAc (0.319 g, 3.25 mmol). The reaction was stirred at this temperature for 10 minutes, and then a solution of Br2 (0.154 mL, 2.98 mmol) in HOAc (5 mL) was added dropwise to it over a period of ˜10 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 2.5 hours. The reaction mixture was then diluted with H2O (10 mL). The solid that formed was filtered off and washed with excess H2O and hexane. This solid was then recrystallized from EtOAc:hexane to afford the product (0.750 g, 66%) as a solid. Mass spectrum (+ESI, [M+H]+) m/z 422/424. 1H NMR (500 MHz, DMSO-d6): δ 8.95 (s, 1H), 8.65 (d, 1H, J=8.9 Hz), 8.29 (d, 1H, J=8.9 Hz), 7.80 (d, 1H, J=8.1 Hz), 7.66 (d, 1H, J=8.1 Hz), 7.36-7.58 (m, 3H), and 4.26 ppm (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:5]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[F:20])=[CH:4][C:3]=1[NH:21][C:22](=O)[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([F:30])[CH:24]=1>C(O)(=O)C>[F:30][C:25]1[CH:24]=[C:23]([C:22]2[NH:1][C:2]3=[N:7][C:6]([C:8]4[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=4)=[C:5]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[F:20])[CH:4]=[C:3]3[N:21]=2)[CH:28]=[CH:27][C:26]=1[CH3:29]
Reactant: Cc1ccc(C(=O)Nc2cc(-c3ccncc3F)c(-c3cccnc3)nc2N)cc1F
Solvent: CC(=O)O
Product: Cc1ccc(-c2nc3cc(-c4ccncc4F)c(-c4cccnc4)nc3[nH]2)cc1F
Yield: 26.1 %

Procedure:
A solution of N-(6′-amino-3″-fluoro-3,2′:3′,4″-terpyridin-5′-yl)-3-fluoro-4-methylbenzamide (0.12 g, 0.288 mmol) in acetic acid (2 mL) was heated in a sealed tube at 118° C. for 16 h. The solvent was evaporated and 4% sodium bicarbonate aqueous solution was added and extracted with ethyl acetate. The organic layer was dried and evaporated. The residue was purified by silica gel flash chromatography (95:5 dichloromethane/methanol) to give the title compound (0.03 g, 26% of yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11](O)[CH:12]([CH3:22])[CH2:13][N:14]2[CH2:19][CH:18]([CH3:20])[O:17][CH:16]([CH3:21])[CH2:15]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)[Br:25]>N1C=CC=CC=1>[Br:25][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)[CH:12]([CH3:22])[CH2:13][N:14]1[CH2:19][CH:18]([CH3:20])[O:17][CH:16]([CH3:21])[CH2:15]1
Reactant: BrP(Br)Br
Reactant: CC1CN(CC(C)C(O)c2ccc(C(C)(C)C)cc2)CC(C)O1
Solvent: c1ccncc1
Product: CC1CN(CC(C)C(Br)c2ccc(C(C)(C)C)cc2)CC(C)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 200.5 %

Procedure:
21.6 g (0.07 mole) of 1-(p-tert.-butyl-phenyl)-2-methyl-3-(2,6-dimethylmorpholin-4-yl)-1-propanol (obtained according to Example 2) were dissolved in 250 ml of petroleum ether with 1.9 ml of pyridine and a solution of 2.9 ml (0.03 mole) of phosphorus tribromide in 50 ml of petroleum ether was added dropwise at -5° to -10° C. The mixture was subsequently stirred at room temperature for 3 hours and the precipitate was filtered off, washed with petroleum ether and dissolved in chloroform. The chloroform phase was washed with sodium bicarbonated solution, dried over sodium sulphate and concentrated in vacuo. 23 g (88% of theory) of 1-bromo-1-(p-tert.-butyl-phenyl)-2-methyl-3-(2,6-dimethylmorpholin-4-yl)-propane were obtained as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]2[CH:13]=[C:14]([C:29](O)=[O:30])[CH:15]=[C:16]3[C:21]=2[O:20][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:18][C:17]3=[O:28])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[NH:32]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]2[CH:13]=[C:14]([C:29]([N:32]3[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]3)=[O:30])[CH:15]=[C:16]3[C:21]=2[O:20][C:19]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[CH:18][C:17]3=[O:28])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OC1CCNCC1
Reactant: CC(Nc1ccc(F)c(Cl)c1)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Product: CC(Nc1ccc(F)c(Cl)c1)c1cc(C(=O)N2CCC(O)CC2)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 74.1 %

Procedure:
8-(1-(3-chloro-4-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (125 mg, 0.28 mmol) was reacted with piperidin-4-ol (34.0 mg, 0.34 mmol) using a procedure similar to the one described in Example 2.00 to afford 8-(1-(3-chloro-4-fluorophenylamino)ethyl)-6-(4-hydroxypiperidine-1-carbonyl)-2-morpholino-4H-chromen-4-one (110 mg, 74.2%) as a white solid. Mass Spectrum: M+H+ 530. NMR Spectrum: (DMSOd6) at 323° K: 1.24 (bs, 2H), 1.51 (d, 3H), 2.99 (bs, 2H), 3.30 (bs, 2H), 3.37 (bs, 2H), 3.49-3.63 (m, 4H), 3.63-3.72 (m, 1H), 3.72-3.82 (m, 4H), 4.62 (d, 1H), 4.92-5.02 (m, 1H), 5.56 (s, 1H), 6.36-6.46 (m, 2H), 6.59 (dd, 1H), 7.01 (dd, 1H), 7.51 (d, 1H), 7.76 (d, 1H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([C:21]2[N:22]([S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[CH:23]=[C:24]([CH2:26][C:27]([CH3:31])([CH3:30])[CH2:28][CH3:29])[N:25]=2)=[O:20])=[CH:14][CH:13]=1>C(Cl)Cl>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([C:21]2[N:22]([S:32]([N:35]([CH3:37])[CH3:36])(=[O:33])=[O:34])[CH:23]=[C:24]([CH2:26][C:27]([CH3:31])([CH3:30])[CH2:28][CH3:29])[N:25]=2)[OH:20])=[CH:14][CH:13]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(=O)Cc2ccc(Br)cc2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(O)Cc2ccc(Br)cc2)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Diisobutylaluminum hydride (1 M in methylene chloride) (31 mL, 31 mmol) was added to a −78° C. solution of 2-[(4-bromophenyl)acetyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (intermediate 8) (7.03 g, 15.5 mmol) in methylene chloride (100 mL). After stirring at −78° C. for 1 h, the reaction mixture was quenched with saturated aqueous sodium potassium tartrate and stirred vigorously at ambient temperature until layers separated. The aqueous phase was extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% ethyl acetate/hexane afforded 2-[2-(4-bromophenyl)-1-hydroxyethyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide.