Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.O=[C:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]1.[OH-].[K+]>CO>[NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:13][CH:12]=2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: c1cc2cc[nH]c2cn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CC=C(c2c[nH]c3cnccc23)CC1
Temperature: 0 °C
Yield: 77.7 %

Procedure:
A suspension of 1H-pyrrolo[2,3-c]pyridine (0.95 g, 8.05 mmol), tert-butyl (4-oxocyclohexyl)carbamate (1.82 g, 8.54 mmol) and KOH (0.95 g, 17.0 mmol) in MeOH (10 mL) was heated at reflux overnight. The solution was added to ice-water (50 mL) and then MeOH (50 mL) was added. The resulting solution was concentrated to circa 50 mL and extracted three times with DCM/MeOH (9:1, 50 mL) and the organic layers were combined and concentrated. The residue was purified by flash chromatography (9:1 DCM/MeOH) to give the title compound as a white solid (1.96 g, 78%). MS (ESI+) m/z=314 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[CH2:5][CH:6]([OH:9])[CH2:7][CH:8]=1)[CH:2]=[CH2:3].[CH3:10][C:11]1([CH3:19])[C:13]([CH3:15])([CH3:14])[CH:12]1[C:16](O)=[O:17].Cl.C(N=C=NCCCN(C)C)C.N>CN(C)C1C=CN=CC=1.ClCCl.C(N(CC)CC)C>[CH3:10][C:11]1([CH3:19])[C:13]([CH3:15])([CH3:14])[CH:12]1[C:16]([O:9][CH:6]1[CH2:7][CH:8]=[C:4]([CH2:1][CH:2]=[CH2:3])[CH2:5]1)=[O:17]
Reactant: CC1(C)C(C(=O)O)C1(C)C
Reactant: C=CCC1=CCC(O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC1=CCC(OC(=O)C2C(C)(C)C2(C)C)C1
Reaction time: 2 h
Yield: 7.5 %

Procedure:
To a mixture of (RS)-3-allyl-3-cyclopenten-1-ol (300 mg), 2,2,3,3-tetramethylcyclopropanecarboxylic acid (343 mg), 4-dimethylaminopyridine (5 mg), triethylamine (733 mg) and dichloromethane (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) was added under ice-cooling. The resulting reaction mixture was further allowed to react for 8 hours at room temperature. Then aqueous ammonia (10 ml) was added to the reaction mixture and the reaction mixture was stirred vigorously for 2 hours. The reaction solution was extracted twice with diethyl ether. After the combined ether layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to afford 45 mg of (RS)-3-allyl-3-cyclopenten-1-yl 2,2,3,3-tetramethylcyclopropanecarboxylate (Compound No. 117). Yield 8%
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:24][C:9]2=[N:10][CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:13]=[C:8]2[CH:7]=1)=[O:5])C.[ClH:25]>O1CCOCC1>[ClH:25].[N:18]1([CH2:17][CH2:16][CH2:15][O:14][C:12]2[CH:13]=[C:8]3[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[NH:24][C:9]3=[N:10][CH:11]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)c1cc2cc(OCCCN3CCCCC3)cnc2[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cc2cc(OCCCN3CCCCC3)cnc2[nH]1
Yield: 98.1 %

Procedure:
To the solution of 0.18 g (0.54 mmol) 5-(3-piperidin-1-yl-propoxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester in 1.2 ml dioxan, 0.54 ml (0.64 g) concentrated hydrochloric acid were added. The reaction mixture was heated under reflux for 18 h, evaporated and dried under high vacuum over phosphorus pentoxide to give 0.18 g (100%) of the compound as a light brown solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C(O[C:14](=O)[CH:15]([CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1.C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1.ClCCl.C(O)C.C(O)(=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25]1)[CH2:14][NH:33][CH2:32][C:31]1[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=1)[CH3:20]
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)C(C(=O)OCC)C1CCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH3-]C#N
Agent: [H-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CNCc1ccc(F)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 49.8 %

Procedure:
Diisobutylaluminum hydride (41.9 mL of a 1.0 M solution in toluene, 41.9 mmol) was added over 5 min to a solution of 2-cyclopentyl-malonic acid diethyl ester (4.78 g, 20.9 mmol) in dichloromethane (45 mL) at −78° C. The reaction mixture was stirred at that temperature for 3.5 h, and then was quenched with saturated aqueous ammonium chloride (33 mL). The cold bath was removed, 1.0 M aqueous hydrochloric acid solution (90 mL) and DL-tartaric acid (4.25 g) were added sequentially, and the mixture was allowed to warm to 25° C. over 1.5 h with vigorous stirring. The biphasic mixture was then partitioned between 1.0 M aqueous hydrochloric acid solution (350 mL) and dichloromethane (350 mL). The organic layer was dried over sodium sulfate and was concentrated in vacuo to afford crude product (1.67 g, 9.07 mmol, 43%). This material was dissolved in ethanol (30 mL) at 25° C. and 4-fluorobenzylamine (1.04 mL, 9.10 mmol), glacial acetic acid (1.5 mL), and sodium cyanoborohydride (1.14 g, 18.1.mmol) were added sequentially. The mixture was stirred at 25° C. for 17 h, then was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 10-80% ethyl acetate in hexanes) to afford rac-2-cyclopentyl-3-(4-fluoro-benzylamino)-propionic acid ethyl ester (1.33 g, 4.53 mmol, 50%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 1.10-1.22 (2H, m), 1.26 (3H, t, J=6.9 Hz), 1.47-1.79 (5H, m), 1.95-2.03 (1H, m), 2.40-2.46 (1H, m), 2.75 (1H, dd, J1=3.8 Hz, J2=11.5 Hz), 2.88 (1H, dd, J1=10.2 Hz, J2=11.7 Hz), 3.72 (1H, d, J=13.3 Hz), 3.80 (1H, d, J=14.0 Hz), 4.13-4.21 (2H, m), 6.96-7.00 (2H, m), 7.25-7.28 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[I:11]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: II
Reactant: Clc1ccc2cn[nH]c2c1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Clc1ccc2c(I)n[nH]c2c1
Reaction time: 2 h

Procedure:
A solution of 6-chloroindazole (1-3, 5.24 g, 34.3 mmol) in ethanol (500 mL) was reacted at the ambient temperature with iodine (8.72 g, 34.3 mmol) in the presence of silver sulfate (10.7 g, 34.3 mmol). After 2 h stirring at the same temperature, all the precipitates were removed by filtration and the filtrate solution was concentrated in vacuo. Trituation with dichloromethane and hexanes gave the desired product as an orange solid (1-4); 1H NMR (400 MHz, DMSO-d6) δ 13.62 (bs, 1H), 7.66 (d, 1H, J=1.6 Hz), 7.46 (d, 1H, J=8.5 Hz), 7.21 (dd, 1H, J=8.6, 1.6 Hz).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:12][CH:11]=1.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[O:22]=[C:20]1[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[S:17][C:16]([C:14]2[N:15]=[C:10]([CH2:9][NH:8][S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH:11]=[CH:12][CH:13]=2)=[N:21]1
Reactant: CCS(=O)(=O)Cl
Reactant: NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: CCS(=O)(=O)NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.5 %

Procedure:
2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (500 mg, 1.3 mmol) and ethanesulfonyl chloride (270 mg, 2.1 mmol) were dissolved in ethyl acetate (10 ml) and water (5 ml), and sodium hydrogen carbonate (270 mg, 3.2 mmol) was added thereto. The mixture was stirred at room temperature for 3 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (2:1, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (101 mg, 21%) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]#[C:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.CO.[OH-].[Na+].Cl>O.CCCCCCC.C1COCC1>[CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH:14]=[C:15]=[CH:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#CCc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C=C=Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
6.02 g (16 mmol) of ethyl 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate, 5 ml of methanol, 5 ml of THF and 50 ml of heptane are introduced into a round-bottomed flask. 850 mg of sodium hydroxide are added and the mixture is refluxed for one hour. The reaction medium is poured into water, adjusted to pH 1 with hydrochloric acid and extracted with ethyl acetate, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is triturated from ethyl alcohol, filtered and dried. 1.37 g (24.5%) of 4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)propa-1,2-dienyl]benzoic acid are collected, with a melting point of 227-8° C.
Reaction SMILES: Br[CH:2]([CH2:15][CH3:16])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)=[O:4].[CH3:17][NH:18][CH3:19].CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl.CO>[CH3:17][N:18]([CH3:19])[CH:2]([CH2:15][CH3:16])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)=[O:4]
Reactant: CNC
Reactant: CCC(Br)C(=O)c1ccc(NC(C)=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCC(C(=O)c1ccc(NC(C)=O)cc1)N(C)C
Reaction time: 48 h

Procedure:
Step-3: A solution of N-(4-(2-bromobutanoyl)phenyl)acetamide (4.80 g, 16.9 mmol) in 30 mL CHCl3 and 30 mL MeOH was treated with 16.9 mL dimethylamine in MeOH (2M, 33.8 mmol) and DIPEA (2.90 mL, 16.9 mmol). After stirring at it for 48 hr, the mixture was concentrated in vacuo and the residue partitioned between DCM and saturated NaHCO3. The aqueous phase was extracted with DCM three times. The combined organic extracts were dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluting with 6% MeOH (2N NH3)/DCM to provide N-(4-(2-(dimethylamino)butanoyl)phenyl)acetamide as a light brown oil. MS ESI: m/z 249.19 [M+1+].
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14]/[CH:15]=[CH:16]/[C:17](OCC)=[O:18])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:22]=[CH:23][CH:24]=[N:25][C:5]1=2.[H-]>ClCCl.C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][CH:15]=[CH:16][CH2:17][OH:18])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:22]=[CH:23][CH:24]=[N:25][C:5]1=2
Reactant: CCOC(=O)/C=C/Cc1ccc2c(c1)N(COC)c1nccnc1S2
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COCN1c2cc(CC=CCO)ccc2Sc2nccnc21
Yield: 54.7 %

Procedure:
2.9 g of ethyl(E)-3-[10-(methoxymethyl)-10H-pyrazino-[2,3-b][1,4]benzothiazin-8-ylmethyl]propenoate was dissolved in 20 ml of dry dichloromethane in a nitrogen atmosphere and ice-cooled. The reaction mixture was stirred and 5.8 ml of a 1.5 M solution of isobutylalminum hydride in toluene was dropped thereinto. After stirring for 2 hours, the reaction mixture was poured into ice-ethyl acetate and stirred for 30 minutes. The insoluble matters were removed by filtering the reaction mixture thorough celite. Then the organic layer was extracted, washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane) to thereby give 1.4 g of 3-[10-(methoxymethyl)-10H-pyrazino-[2,3-b][1,4]benzothiazin-8-ylmethyl]-2-propen-1-ol as a pale yellow oily substance. The obtained compound was dissolved in 10 ml of hexachloroacetone and 1.34 g of triphenylphosphine was added in several portions thereto under ice-cooling. After stirring at room temperature for 30 minutes, the reaction mixture was distributed into an aqueous solution of sodium bicarbonate and diethyl ether and extracted with ether. After drying over anhydrous sodium sulfate and distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane) to thereby give 230 mg of the title compound as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[CH:8]=O.Cl.[NH2:27][C@@H:28]([C:30]([NH2:32])=[O:31])[CH3:29]>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[CH2:8][NH:27][C@H:28]([CH3:29])[C:30]([NH2:32])=[O:31]
Reactant: O=Cc1ccc(OCc2ccccc2F)c(Cc2ccccc2F)c1
Reactant: C[C@@H](N)C(N)=O
Agent: Cl
Product: C[C@@H](NCc1ccc(OCc2ccccc2F)c(Cc2ccccc2F)c1)C(N)=O

Procedure:
The compound of the title is prepared by reacting 3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)benzaldehyde (VIb) prepared as in Example 9a) with D-alaninamide hydrochloride according to the procedure of the Example 8b).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31]O)=[C:26]([N+:33]([O-:35])=[O:34])[CH:25]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:20][CH2:31][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][C:26]=1[N+:33]([O-:35])=[O:34]
Reactant: COc1ccc(CCO)c([N+](=O)[O-])c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CCBr)c([N+](=O)[O-])c1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
A suspension of triphenylphosphine (26 g, 1 mol) in DCM (100 mL) under nitrogen atmosphere at 25-26° C. is cooled down to 0-5° C. A solution of bromine (15.9 g, 0.1 mol) in DCM (150 mL) is added over 30 min at the same temperature. The reaction mixture is stirred for 15 min at 0-5° C. A solution of 2-(4-methoxy-2-nitrophenyl)ethanol (14 g, 0.07 mol) and pyridine (7.8 g, 0.1 mol) in DCM (100 mL) is added to the above reaction mixture over 30 min at 0-5° C. The resulting reaction mixture is warmed up to 25-26° C. and stirred for 3 h. The reaction is quenched by addition of cold water (250 mL). The crude product is extracted with DCM (2×200 mL). The organic layer is washed with water and brine (200 mL each), dried over Na2SO4 and concentrated to dryness. The crude residue obtained is purified by column chromatography (60-120 mesh silica gel, eluent: 5% EtOAc in petrol ether) to give 14.7 g (79%) of the title compound as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 7.51-7.49 (m, 2H), 7.30-7.27 (m, 1H), 3.83 (s, 3H), 3.82-3.68 (m, 2H), 3.32-3.27 (m, 2H).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]2[O:27][CH2:26][CH2:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:23]2)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:54]([N:57]1[CH2:62][CH2:61][CH:60](O)[CH2:59][CH2:58]1)(=[O:56])[CH3:55]>O1CCCC1>[C:54]([N:57]1[CH2:62][CH2:61][CH:60]([O:15][C:16]2[CH:17]=[CH:18][C:19]([C@@H:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:23]3)=[CH:20][CH:21]=2)[CH2:59][CH2:58]1)(=[O:56])[CH3:55]
Reactant: CC(=O)N1CCC(O)CC1
Reactant: Oc1ccc([C@H]2CN(Cc3ccccc3)CCO2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N1CCC(Oc2ccc([C@H]3CN(Cc4ccccc4)CCO3)cc2)CC1
Reaction time: 10 h
Yield: 57.3 %

Procedure:
Diisopropylazodicarboxylate (40% in toluene, 5.7 g, 11.3 mmol) was added to a solution of (2S)-2-(4-hydroxyphenyl)-4-benzylmorpholine (2.0 g, 7.43 mmol), triphenylphosphine (3.0 g, 11.4 mmol) and 1-acetyl-4-hydroxypiperidin (1.6 g, 11.2 mmol) in tetrahydrofuran (40 ml) at room temperature and the mixture stirred for 10 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography eluting 10-50% ethyl acetate in hexane to furnish (2S)-2-(4-(1-acetylpiperidin-4-yloxy)phenyl)-4-benzylmorpholine (1.68 g, 57%) as colorless oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C@H:19]1[C@@H:24](OS(C)(=O)=O)[CH2:23][CH2:22][N:21]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:20]1.C(Cl)Cl>CN(C=O)C.CCOC(C)=O>[F:18][C@H:19]1[C@H:24]([O:11][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)[CH2:23][CH2:22][N:21]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)[C@H](F)C1
Reactant: Oc1cccc2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cccc3cccnc23)[C@H](F)C1
Temperature: 100 °C
Reaction time: 20 h
Yield: 8.4 %

Procedure:
To a solution of quinolin-8-ol (3.50 g, 24.1 mmol) in 60 mL DMF was added cesium carbonate (23.6 g, 72.3 mmol), followed by (cis)-tert-butyl 3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylate (8.24 g, 27.7 mmol). The reaction mixture was heated in a 100° C. sand bath and stirred 20 hours. The reaction mixture was cooled to ambient temperature, filtered through GF/F paper topped with compressed Celite, rinsed with DMF, and concentrated. The crude was purified on silica gel (Biotage 40M, 9:1 DCM:EtOAc until the product eluted, then 2:1 DCM:EtOAc) to give (trans)-tert-butyl 3-fluoro-4-(quinolin-8-yloxy)piperidine-1-carboxylate (0.701 g, 2.02 mmol, 42% yield). LC/MS ESI (+) m/z 347 (M+1) detected.
Reaction SMILES: C([N:4]([S:26]([CH3:29])(=[O:28])=[O:27])[N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([C:21]([F:24])([F:23])[F:22])=[C:11]([CH2:16][NH:17]C(=O)C)[CH:12]=2)[NH:7][C:6]1=[O:25])(=O)C>Cl>[NH2:17][CH2:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[C:21]([F:23])([F:24])[F:22])[NH:7][C:6](=[O:25])[N:5]([NH:4][S:26]([CH3:29])(=[O:27])=[O:28])[C:14]2=[O:15]
Reactant: CC(=O)NCc1cc2c(=O)n(N(C(C)=O)S(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Agent: Cl
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(CN)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A solution of N-[3-(acetyl-methanesulfonyl-amino)-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-ylmethyl]-acetamide (1.8 g, 4.13 mmol) in 2M aq HCl (5.2 mL) was stirred at 80° C. for 2 d. 2M hydrochloric acid (1 mL) was added every half day. Subsequently the solvent was evaporated and the light yellow residue was purified by ion-exchange resin (DOWEX 50*2-100, MeOH): the crude product was dissolved in MeOH, and mixed with a suspension of DOWEX in MeOH and the mixture was stirred at r.t. for 2 h. The resin was then filtered and washed with MeOH (this MeOH fraction was discarded). The resin was suspended in a solution of ammonia in MeOH (7M, 300 mL), stirred for 2 h, filtered and the filtrate was collected. The resin was treated two more times with a solution of ammonia in MeOH as described above and the filtrates were collected. The combined solvent fractions were evaporated to give N-(6-aminomethyl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (1.12 g, 3.18 mmol, 77%) as a yellow solid, 1H-NMR (DMSO-d6, 400 MHz) 3.14 ppm (s, 3H, SO2—CH3); LC-MS rt=0.523 mn; MS: m/z 352.9 [M+H]+ Column: SunFireC18, 4.6*50 mn, 3.5 um; Positive MS Water/Acetonitrile 95:5 to 5:95 in 5 min, Flow: 1.5 mL/min
Reaction SMILES: [CH3:1][N:2]([CH3:14])[N:3]=[CH:4][CH2:5][C:6]1[C:11](Cl)=[CH:10][CH:9]=[CH:8][C:7]=1Cl.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1>>[N:15]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[CH:5]=[CH:4][N:3]3[N:2]([CH3:14])[CH3:1])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CN(C)N=CCc1c(Cl)cccc1Cl
Product: CN(C)n1ccc2c(-n3ccc4ccccc43)cccc21
Yield: 40 %

Procedure:
4-(1-indolyl)-1-(dimethylamino)indole was prepared in the same manner as in Example 16 except that 2,6-dichlorophenylacetaldehyde N,N-dimethylhydrazone was used in place of 2,4-dichlorophenylacetaldehyde N,N-dimethylhydrazone, and indole (212 mg, 1.81 mmol) was used in place of pyrrole. (Yield: 40%).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:18]1[C:14]2=[N:15][C:16]([CH3:17])=[C:11]([CH:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[C:7]([OH:9])=[O:8])[C:12]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[O:27][CH2:26][CH2:25][CH2:24]4)=[C:13]2[CH:20]=[CH:19]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1nc2c(ccn2Cc2ccccc2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and benzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.51-7.43 (m, 1 H), 7.39-7.28 (m, 5 H), 7.24-7.17 (m, 1 H), 7.06 (t, J=3.3 Hz, 1 H), 6.94 (dd, J=6.0, 8.2 Hz, 1 H), 6.29 (dd, J=3.4, 11.6 Hz, 1 H), 5.66-5.48 (m, 3 H), 4.32-4.23 (m, 2 H), 2.97-2.81 (m, 2 H), 2.79 (s, 3 H), 2.15-2.06 (m, 2 H), 0.97 (s, 9 H); LC/MS (m/z) ES+=485.37 (M+1).
Reaction SMILES: C([SiH](CC)CC)C.C([O:15][C:16]1[C:17]2[N:18]([N:23]=[CH:24][C:25]=2[CH2:26]O)[CH:19]=[C:20]([Cl:22])[N:21]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:22][C:20]1[N:21]=[C:16]([OH:15])[C:17]2[N:18]([N:23]=[CH:24][C:25]=2[CH3:26])[CH:19]=1
Reactant: OCc1cnn2cc(Cl)nc(OCc3ccccc3)c12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnn2cc(Cl)nc(O)c12
Temperature: 25 °C
Reaction time: 19 h
Yield: 100 %

Procedure:
Triethylsilane (0.2 ml, 1.25 mmol) was added slowly to a solution of (4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyrazin-3-yl)methanol 5.51 (142 mg, 0.49 mmol) in TFA (3 mL). After 19 hours, an additional 0.4 mL of triethylsilane was added and mixture was heated to 60 degrees for 4.5 hours. Mixture was cooled to rt and concentrated under reduced pressure. Resulting residue was taken up in DCM and washed with sat. NaHCO3 (aq). Aqueous layer was extracted with DCM. Combined organics were dried, filtered, and concentrated under reduced pressure to yield 6-chloro-3-methylpyrazolo[1,5-a]pyrazin-4-ol 5.52 (90 mg), which was used in the next step without further purification.