Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC=O)(=[O:3])C.[OH:7][C@@H:8]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][C@H:9]1[CH2:21][N:22]1[CH2:38][CH2:37][C:25]2([N:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:28][NH:27][C:26]2=[O:36])[CH2:24][CH2:23]1>>[CH:1]([O:7][C@@H:8]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][C@H:9]1[CH2:21][N:22]1[CH2:23][CH2:24][C:25]2([N:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:28][NH:27][C:26]2=[O:36])[CH2:37][CH2:38]1)=[O:3]
Reactant: COc1cc2c(cc1OC)[C@@H](O)[C@H](CN1CCC3(CC1)C(=O)NCN3c1ccccc1)C2
Reactant: CC(=O)OC=O
Product: COc1cc2c(cc1OC)[C@@H](OC=O)[C@H](CN1CCC3(CC1)C(=O)NCN3c1ccccc1)C2
Reaction time: 288 h

Procedure:
To 0.11 mole of a stirred formic acid-acetic anhydride mixture (prepared as described in Rec. Trav. Chem., 83, 1287 (1964) is added 0.10 mole of trans-8-[(2,3-dihydro-1-hydroxy-5,6-dimethoxy-1H-inden-2-yl)methyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one. The temperature of the reaction mixture is maintained below 20° C and stirring is continued for 12 days under argon. The reaction mixture is then poured, with stirring, into excess ice-cold aqueous sodium bicarbonate, extracted with ether and the ether extracts dried with anhydrous sodium sulfate. The ether is evaporated and the residue is crystallized from cyclohexane to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1>C(=O)(O)[O-].[Na+]>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Reactant: Brc1ccccn1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(Nc1cn2cc(Oc3cccc(Nc4ccccn4)c3)ccc2n1)C1CC1
Temperature: 120 °C
Reaction time: 15 h
Yield: 40.1 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (19.7 mg, 0.064 mmol), 2-bromopyridine (15.4 mg, 0.098 mmol), tris(dibenzylideneacetone)2 palladium(0) (6.1 mg, 0.007 mmol), 5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.9 mg, 0.007 mmol), potassium t-butoxide (18.1 mg, 0.161 mmol) and toluene (4.0 mL) was stirred at 120° C. for 15 hr. The reaction mixture was diluted with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by preparative HPLC to give the title compound (9.9 mg, 40%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCCCc1ccccc1
Reaction time: 0.5 h

Procedure:
4-Phenylbutanol (700 mg, 4.66 mmol) was added to a solution of the Dess-Martin reagent (2.40 g, 5.66 mol) in dichloromethane (35 mL). After 30 min at RT, the solution was quenched with 10% aq. Na2S2O3, washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), and concentrated. Purification by chromatography (SiO2, 9:1 hexane/ethyl acetate) yielded the title compound. MS 149 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]#[N:19])[C:9]2=[O:20])=[CH:4][CH:3]=1.[OH2:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]([NH2:19])=[O:21])[C:9]2=[O:20])=[CH:4][CH:3]=1
Reactant: N#Cc1nc2ccccc2n(-c2ccc(Cl)cc2)c1=O
Reactant: O
Product: NC(=O)c1nc2ccccc2n(-c2ccc(Cl)cc2)c1=O

Procedure:
1-(4-Chlorophenyl)-3-cyano-1,2-dihydroquinoxalin-2-one (6.6 g) was heated at 110° C. for 1 hour with polyphosphoric acid (25 g). The mixture was diluted with water and extracted with chloroform. Evaporation of the solvent and recrystallisation of the residue from ethanol gave the title compound (3.8 g) mp 293°-297° (decomp).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:6]
Reactant: NCCN1CCCCC1
Reactant: O=C(O)c1ccc(OCCCN2CCCCC2)cc1F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCN1CCCCC1)c1ccc(OCCCN2CCCCC2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-Fluoro-4-(3-piperidin-1-yl-propoxy)-benzoic acid (70 mg, 0.25 mmol) and 1-(2-aminoethyl)piperidine (450 □L, 0.3 mmol) in DMF (5 mL) was added EDC (58 mg, 0.3 mmol), HOBT (40 mg, 0.3 mmol), and diisopropylethyl amine (52 □1, 0.3 mmol). The mixture was stirred at room temperature overnight. The mixture was partitioned between EtOAc and water. The organic phase was washed with brine, dried (MgSO4), and concentrated. The residue was purified by flash chromatography (Biotage 12 M, elute 90/10/1 CH2Cl2/MeOH/NH4OH) to yield the title compound. MS (ES+) 392.3
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:9]=1[CH3:10])=[O:4].C1C(=O)N([Br:35])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O.CCCCCC>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:15][CH:16]=2)[C:9]=1[CH2:10][Br:35])=[O:4]
Reactant: COC(=O)c1sc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: COC(=O)c1sc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)c1CBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
A solution of 404 mg of the product of Step 5, 200 mg of NBS, and 5 mg of benzoylperoxde in 10 mL of CCl4 was heated in a 80° C. oil bath under light from a W-lamp. After 30 min, the reaction mixture was cooled to room temperature, diluted with 10 mL of 3:1 EtOAc/hexane, and filtered through a pad of silica gel. The filtrate was concentrated in vacuo to give 400 mg of the crude title compound which was used for the next step without further purification.
Reaction SMILES: [CH:1]12[N:7]([C:8](=[O:42])[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][C:16]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=3)=[C:15]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)([CH3:11])[CH3:10])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.C=O.[C:45](O)(=O)C.C([BH3-])#N.[Na+].[NH4+].[OH-]>O1CCCC1.CO>[CH:4]12[N:7]([C:8](=[O:42])[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][C:16]([C:21]3[CH:22]=[C:23]([CH3:28])[CH:24]=[C:25]([CH3:27])[CH:26]=3)=[C:15]4[CH2:29][CH2:30][N:31]([CH3:45])[CH2:32][CH2:33][CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)([CH3:11])[CH3:10])[CH:1]([CH2:2][CH2:3]1)[CH2:6][CH2:5]2
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCNCCCCc2ccncc2)c1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCN(C)CCCCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A dry flask containing 120 mg (0.21 mmol) of 1-(7-azabicyclo[2.2.1]hept-7-yl)-2-[2-(3,5-dimethylphenyl)-3-[2-[4-(pyridin-4-yl)butylamino]ethyl]-1H-indol-5-yl)-2-methylpropan-1-one (prepared essentially as described in EXAMPLE 2), 63.0 mg (2.1 mmol) of paraformaldehyde, and 200 mg of powdered 3A molecular sieves was fitted with a septum and purged thoroughly with nitrogen. Next, 5 mL of methanol and 0.121 mL (126.1 mg, 2.1 mmol) of glacial acetic acid were added, and the mixture was stirred at room temperature for 15 minutes. Then 52.8 mg (0.84 mmol) of sodium cyanoborohydride was added, followed after an additional 25 minutes by 2.5 mL of anhydrous tetrahydrofuran. After 1 day, the mixture was filtered, and the filter cake was washed thoroughly with methylene chloride. The filtrate was shaken in a separatory funnel with water. The aqueous phase was extracted an additional 3 times with methylene chloride. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was flash chromatographed on silica gel (gradient elution with 99:1:0.1 to 95:5:0.5 CH2Cl2-MeOH-concd. NH4O) to yield 95.4 mg (79%) of a yellow, stiff foam; homogeneous by TLC in 95:5:0.5 CH2Cl2-MeOH-concd. NH4OH. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (ESI): m/e=577.5 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:11](=[O:18])[N:10]([CH2:19][C:20]3[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=3)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:9]2)=[CH:4][CH:3]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:42][CH2:43][CH2:44][N:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]2([CH2:55][CH2:54]2)[C:46]1=[O:56]>CC(=O)CC.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3([CH2:13][CH2:14][N:15]([CH2:42][CH2:43][CH2:44][N:45]4[C:53]5[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=5)[C:47]5([CH2:55][CH2:54]5)[C:46]4=[O:56])[CH2:16][CH2:17]3)[C:11](=[O:18])[N:10]([CH2:19][C:20]3[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=3)[C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCNCC3)C2=O)c1
Reactant: O=C1N(CCCCl)c2ccccc2C12CC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCN(CCCN4C(=O)C5(CC5)c5ccccc54)CC3)C2=O)c1
Temperature: 78 °C
Reaction time: 16 h
Yield: 65.3 %

Procedure:
To a solution of tert-butyl 3-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (3 g, 6.81 mmol, 1 equiv), sodium iodide (0.408 g, 2.72 mmol, 0.4 equiv) and potassium carbonate (2.35 g, 13.62 mmol, 2 equiv) in 2-butanone (5 mL), was added 1′-(3-chloropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one (1.61 g, 6.81 mmol, 1 equiv). After stirring at 78° C. for 16 hours, the reaction mixture was filtered and isolated using the Biotage flash chromatography system (SNAP 100 g cartridge, Rf=0.5, gradient—50%-100% ethyl acetate in hexanes) to obtain the title compound (2.84 g, 63%); 1H NMR (DMSO-d6): δ 1.52 (s, 9H), 1.57-1.65 (m, 6H), 1.77 (t, 2H, J=6.4 Hz), 2.25-2.37 (m, 4H), 2.64-2.68 (m, 4H), 3.79 (t, 2H, J=6.8 Hz), 4.57 (d, 4H, J=13.2 Hz), 6.91-7.20 (m, 8H), 7.48-7.51 (m, 2H), 7.78 (s, 1H), 7.83 (d, 1H, J=7.2 Hz); MS for C38H43FN4O4 m/z 639.14 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:23][C:24]1[CH:37]=[CH:36][C:35]2[C:34](=[O:38])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27](=[O:39])[C:26]=2[CH:25]=1>>[CH:25]1[C:26]2[C:27](=[O:39])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34](=[O:38])[C:35]=2[CH:36]=[CH:37][C:24]=1[CH2:23][N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20]
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: O=C1c2ccccc2C(=O)c2cc(CCl)ccc21
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccc3c(c2)C(=O)c2ccccc2C3=O)c1
Yield: 38 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2-chloromethyl anthraquinone were reacted by the same way with the example 1 to obtain the titled compound (193 mg, yield: 38.0%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:15]([Cl:16])=[C:14]([O:17][CH3:18])[CH:13]=[CH:12][C:11]=1[C:19](=[O:23])[CH2:20][CH2:21][CH3:22].[OH-].[Na+]>C(O)C>[Cl:16][C:15]1[C:10]([Cl:9])=[C:11]([C:19](=[O:23])[C:20](=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:21][CH3:22])[CH:12]=[CH:13][C:14]=1[O:17][CH3:18]
Reactant: O=Cc1ccccc1
Reactant: CCCC(=O)c1ccc(OC)c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(=Cc1ccccc1)C(=O)c1ccc(OC)c(Cl)c1Cl

Procedure:
To a mixture of benzaldehyde (19.4 g., 0.183 mole) andd 2',3'-dichloro-4'-methoxybutyrophenone (42.2 g., 0.183 mole) in absolute ethanol (350 ml.) a 20% sodium hydroxide solution (35.9 ml.) is added dropwise with stirring. The mixture is stirred for 22 hours. The white solid product that separates is collected and air dried. Yield 55.6 g. (91%), m.p. 127°-130° C.
Reaction SMILES: C(O[CH2:4][NH:5][C:6]1[CH:27]=[CH:26][C:9]([C:10]([NH:12][CH2:13][C:14]2[S:15][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:17][CH:18]=2)=[O:11])=[CH:8][N:7]=1)C.[BH4-].[Na+].O.C(OCC)(=O)C>CS(C)=O>[CH3:4][NH:5][C:6]1[CH:27]=[CH:26][C:9]([C:10]([NH:12][CH2:13][C:14]2[S:15][C:16]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:17][CH:18]=2)=[O:11])=[CH:8][N:7]=1
Reactant: CCOCNc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CNc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)cn1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 48.1 %

Procedure:
To a solution of 6-(ethoxymethyl-amino)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-153 (427 mg, 0.92 mmol) in dimethylsulfoxide (5 mL) was added sodium borohydride (100 mg, 2.7 mmol), and the solution was stirred for 15 minutes at 100° C. Water and ethyl acetate were added to the reaction solution, which was then partitioned, and the organic layer was washed with water three times. Silica gel was added to the organic layer, the solvent was evaporated in vacuo for adsorption, and purified by silica gel column chromatography (ethyl acetate). The solvent was evaporated in vacuo, hexane, diethyl ether and ethyl acetate were added to the residue for solidification, and the title compound (150 mg, 0.44 mmol, 48.1%) was obtained as a white solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([O:6][C:7]2[C:12](Br)=[CH:11][N:10]=[C:9]([NH:14][C@H:15]3[CH2:20][CH2:19][C@@H:18]([CH3:21])[CH2:17][CH2:16]3)[N:8]=2)[CH2:2]1.[O:22]1[CH2:26][CH2:25][C@H:24]([O:27][C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)[CH2:23]1>>[O:1]1[CH2:5][CH2:4][C@@H:3]([O:6][C:7]2[C:12]([C:31]3[CH:32]=[CH:33][C:28]([O:27][C@H:24]4[CH2:25][CH2:26][O:22][CH2:23]4)=[CH:29][CH:30]=3)=[CH:11][N:10]=[C:9]([NH:14][C@H:15]3[CH2:20][CH2:19][C@@H:18]([CH3:21])[CH2:17][CH2:16]3)[N:8]=2)[CH2:2]1
Reactant: C[C@H]1CC[C@@H](Nc2ncc(Br)c(O[C@@H]3CCOC3)n2)CC1
Reactant: CC1(C)OB(c2ccc(O[C@H]3CCOC3)cc2)OC1(C)C
Product: C[C@H]1CC[C@@H](Nc2ncc(-c3ccc(O[C@H]4CCOC4)cc3)c(O[C@@H]3CCOC3)n2)CC1

Procedure:
Using the procedure of Example 1, Step 3, 4-((R)-tetrahydrofuran-3-yloxy)-5-bromo-N-(cis-4-methylcyclohexyl)pyrimidin-2-amine was reacted with 2-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane to provide the title compound as a free base.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].C(Br)C=C.[Cl:10][C:11]1[S:15][C:14]([CH2:16]Cl)=[CH:13][CH:12]=1>CCOCC>[Cl:10][C:11]1[S:15][C:14]([CH2:16][CH2:3][CH:2]=[CH2:1])=[CH:13][CH:12]=1
Reactant: C=CC[Mg]Br
Reactant: ClCc1ccc(Cl)s1
Solvent: CCOCC
Solvent: C=CCBr
Product: C=CCCc1ccc(Cl)s1
Temperature: 0 °C
Yield: 195.9 %

Procedure:
A solution of allyl magnesium bromide (from 14.6 g of magnesium and 24.2 g (0.2 M) of allyl bromide) in 100 ml ether is added dropwise with stirring to 29.9 g of 5-chloro-2-chloromethylthiophene in 10 ml ether over half an hour and the resulting mixture heated under reflux overnight. The mixture is then poured into 300 ml ice cold dilute sulfuric acid, the ether layer separated and the aqueous phase extracted with 200 ml of ether. The combined ethereal solutions are washed with aqueous potassium carbonate, dried over MgSO4 and evaporated to give crude 4-(5-chloro-2-thienyl)-1-butene as a yellow oil (34 g).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([I:19])[CH:8]=[C:9]([CH2:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:20](OCC)=[O:21].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:20]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([CH2:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:8][C:7]=3[I:19])=[O:21])=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cnc2c(I)cc(CC3CCOCC3)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CC3CCOCC3)cc2c1O
Temperature: 180 °C
Yield: 75 %

Procedure:
A suspension of ethyl 4-hydroxy-8-iodo-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-quinolinecarboxylate (0.8 g) and 4-chlorobenzylamine (1.54 mL) is heated to 180 ° C. for 1 h. The reaction is cooled to room temperature. The resulting solid is collected and washed with Et2O. The crude solid is adsorbed onto silica and chromatographed (Biotage flash 40S, eluent 1% MeOH/CH2Cl2 then 2% MeOH/CH2Cl2). Fractions homogeneous by TLC are combined and concentrated. The resulting solid is triturated with EtOAc/hexanes to yield 0.73 g (75%) of the desired product as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][NH2:28])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][NH:28][C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: COc1ccc(CCN)cc1OC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CCNC(=O)Cc2ccc(C)cc2)cc1OC
Temperature: 100 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
A mixture of 5.00 g (33.3 mmol) of (4-methylphenyl)acetic acid, 5.94 g (49.9 mmol) of thionyl chloride, 0.12 g (1.6 mmol) of N,N-dimethylformamide and 20 ml of toluene was stirred at 100° C. for 1 hour, cooled and concentrated under reduced pressure. The residue was added to a mixture of 6.34 g (35.0 mmol) 2-(3,4-dimethoxyphenyl)ethylamine, 8.6 g (67 mmol) of diisopropylethylamine and 25 ml of toluene at 0° C. and kept at 0° C. for 30 minutes and at room temperature for 6 hours. Water and ethyl acetate were added to the reaction mixture and precipitated solid was collected with filtration. The obtained solid was dried to give 5.76 g of N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(4-methylphenyl)acetamide.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:38]3=[N:39][S:40](=[O:44])(=[O:43])[CH2:41][CH2:42][N:37]3[CH:36]=[CH:35][CH:34]=2)=[CH:29][CH:28]=1)(C(C)(C)C)(C)C.[NH4+].[Cl-]>C1COCC1>[O:44]=[S:40]1(=[O:43])[CH2:41][CH2:42][N:37]2[CH:36]=[CH:35][CH:34]=[C:33]([C:30]3[CH:31]=[CH:32][C:27]([OH:26])=[CH:28][CH:29]=3)[C:38]2=[N:39]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
TBAF (1 M in THF) (40.0 mL) was added to a solution of 9-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (14.9 g) in THF (dry)(2.0 L) at 0° C. and the mixture was stirred at ambient temperature for 30 min. The mixture was neutralized with sat. NH4Cl aq. and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was washed with EtOAc/hexane to give the title compound (10.2 g) as an off-white crystal.
Reaction SMILES: CS(C)=O.[OH:5][CH:6]1[CH2:29][CH2:28][C:9]2([C:13](=[O:14])[N:12]([C:15]3[CH:16]=[N:17][C:18]([O:21][C@@H:22]([CH3:27])[C:23]([F:26])([F:25])[F:24])=[CH:19][CH:20]=3)[CH2:11][CH2:10]2)[CH2:8][CH2:7]1.C(Cl)(=O)C(Cl)=O.Cl>ClCCl.C(N(CC)CC)C>[F:26][C:23]([F:24])([F:25])[C@H:22]([CH3:27])[O:21][C:18]1[N:17]=[CH:16][C:15]([N:12]2[CH2:11][CH2:10][C:9]3([CH2:8][CH2:7][C:6](=[O:5])[CH2:29][CH2:28]3)[C:13]2=[O:14])=[CH:20][CH:19]=1
Reactant: C[C@H](Oc1ccc(N2CCC3(CCC(O)CC3)C2=O)cn1)C(F)(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: C[C@H](Oc1ccc(N2CCC3(CCC(=O)CC3)C2=O)cn1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
DMSO (16.3 ml) was added dropwise over a period of 5 minutes to a solution of 8-hydroxy-2-[6-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-3-yl]-2-aza-spiro[4.5]decan-1-one (39.3 g) in dichloromethane (400 ml) that was cooled down to −78° C. in a CO2/acetone-bath. After 5 minutes, oxalylchloride (15.6 ml) was added dropwise over a period of 15 minutes and stirring was continued for 30 minutes at −78° C. Then, triethylamine (42.7 ml) was added dropwise over a period of 15 minutes to the reaction mixture and after 5 minutes, the mixture was allowed to warm to 20° C. and stirred further 2 h at R.T. The reaction mixture was poured into ice/water and was acidified with 2M aqueous HCl solution to pH 3. The aqueous phase was extracted two times with dichloromethane and the combined organic layers were washed with brine, dried over Na2SO4 and filtered. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, gradient 20% to 60 of AcOEt in hexane) to give the title compound as an off white solid (23.96 g). MS (m/e): 357.2 (MO.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=2)[CH2:4][O:3]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(OCC)C>[CH3:1][C:2]1([CH3:19])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][O:18][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:11][CH:10]=2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](COc2ccc(CCCO)cc2)O1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC1(C)OC[C@@H](COc2ccc(CCCOS(C)(=O)=O)cc2)O1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To (3-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-propan-1-ol (12.2 g, 46 mmol) in dry diethyl ether (150 mL) is added triethylamine (12.8 mL, 92 mmol). The mixture is cooled to 0° C. and treated dropwise with methanesulfonyl chloride (5.3 mL, 69 mmol). The reaction mixture is allowed to warm to RT and then stirring is continued for 3 h. The resulting mixture is washed with water (2×100 mL), saturated aqueous sodium hydrogen carbonate solution, brine then dried (MgSO4) and concentrated in vacuo to give the title compound as a white solid.