Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[CH:8][CH:9]=2)[O:4][CH2:3]1.BrC1(Br)C(=O)C2C(=CC(O[Si](C(C)C)(C(C)C)C(C)C)=CC=2)OC1.[OH:48][C:49]1([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C(N(CC)CC)C>C(O)C>[OH:48][C:49]1([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:54][CH2:53][N:52]([CH:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][C:7]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[CH:8][CH:9]=3)[O:4][CH2:3]2)[CH2:51][CH2:50]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CC(C)[Si](Oc1ccc2c(c1)OCC(Br)C2=O)(C(C)C)C(C)C
Agent: CC(C)[Si](Oc1ccc2c(c1)OCC(Br)(Br)C2=O)(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)[Si](Oc1ccc2c(c1)OCC(N1CCC(O)(c3ccccc3)CC1)C2=O)(C(C)C)C(C)C
Yield: 3 %

Procedure:
7-(Triisopropylsilyloxy)-4-chromanone (2.0 g, 6.2 mmol) was dissolved in CCl4 (45 ml). Bromine (0.3 ml, 6.4 mmol) in CCl4 (5 ml) was added dropwise at ambient temperature over 10 minutes. The reaction initially turned dark red but after stirring for 10 minutes the color changed to light yellow. This yellow solution was washed with dilute NaHSO3, saturated NaHCO3 and brine, dried by filtering through phase separatory paper, and concentrated to yield a brown oil (2.3 g, 93%) which NMR showed was a 2.5:1:1 mixture of 3-bromo-7-(triisopropylsilyloxy)-4-chromanone, 3,3-dibromo-7-(triisopropylsilyloxy)-4-chromanone and starting material. This crude mixture (2.3 g, 5.6 mmol) was combined with 4-hydroxy-4-phenyl piperidine (1.0 g, 5.8 mmol), triethylamine (0.9 ml, 6.5 mmol) and ethanol (50 ml). The reaction was refluxed for 3 hours, then cooled and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over CaSO4, concentrated and the residue chromatographed on silica gel using gradient elution with ethyl acetate/hexanes to give 80 mg (3%) of present title product as a yellow solid, mp 132°-132.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:9]([CH2:12][CH:13]3[CH2:15][CH2:14]3)=[N:10][N:11]=2)[CH:5]=[CH:6][C:7]=1Cl.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].O1CCOCC1>C([O-])(O)=O.[Na+].CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH:25]=[C:26]([C:7]2[CH:6]=[CH:5][N:4]3[C:9]([CH2:12][CH:13]4[CH2:15][CH2:14]4)=[N:10][N:11]=[C:3]3[C:2]=2[CH3:1])[CH2:27][CH2:28]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1c(Cl)ccn2c(CC3CC3)nnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(C2=CCN(C(=O)OC(C)(C)C)CC2)ccn2c(CC3CC3)nnc12
Temperature: 150 °C

Procedure:
A mixture of D98 (0.358 mg, 1.614 mmol), N-(tert-butoxycarbonyl)-3,6-dihydro-2H-pyridine-4-boronic acid pinacol ester (0.6 g, 1.937 mmol) and Pd(PPh3)4 (0.0933 g, 0.0801 mmol) in NaHCO3, (3.5 ml, aqueous sat. solution) and 1,4-dioxane (9 ml) was heated at 150° C. under microwave irradiation for 5 min. After cooling, the mixture was refilled with additional N-(tert-butoxycarbonyl)-3,6-dihydro-2H-pyridine-4-boronic acid pinacol ester (0.5 g) and Pd(PPh3)4 (0.072 g) and NaHCO3, (1 ml, aqueous sat. solution). The mixture was heated at 150° C. under microwave irradiation for 20 min. After cooling to r.t. the mixture was diluted with EtOAc/H2O, filtered through a pad of diatomaceous earth and washed with EtOAc. The organic phase was collected, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; EtOAc/7M solution of NH3 in MeOH up to 6% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate D99 (0.458 g, 77%).
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[C:7]([CH3:11])([CH3:10])[NH:6][C:5]1=[O:12])[C:2]#[CH:3].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]#[CH:21]>C(C(C)=O)C.O>[CH2:21]([N:6]1[C:7]([CH3:10])([CH3:11])[C:8](=[O:9])[N:4]([CH2:1][C:2]#[CH:3])[C:5]1=[O:12])[C:20]#[CH:19]
Reactant: C#CCBr
Reactant: C#CCN1C(=O)NC(C)(C)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: C#CCN1C(=O)N(CC#C)C(C)(C)C1=O
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a stirred solution of 3-(2-propynyl)-5,5-dimethylhydantoin (3 g, 18.1 mmole) in methyl ethyl ketone (125 mL) at room temperature was added K2CO3 (2.8 g, 20.3 mmole), followed by propargyl bromide (3 g, 80% in toluene, 20.2 mmole). The reaction mixture was then refluxed for 24 hr. The reaction mixture was cooled to room temperature and was diluted with water and extracted with methylene chloride (3×125 mL). The organic layer was washed with saturated NaCl and dried over MgSO4. Evaporation of the volatiles yielded 3.3 g (89 %) of 1,3-di-propargyl-5,5-dimethylhydantoin as a light yellow semi-solid. An NMR spectrum showed the desired structure. This intermediate was subjected to the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16])[NH:11][C:10](=[O:19])[N:9]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:8]2=[O:25].C=O.[C:28](O)(=O)C.O1CCCC1>[Pd].C(#N)C.O.O>[OH:1][CH2:2][CH2:3][N:4]([CH3:28])[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([F:18])([F:16])[F:17])[NH:11][C:10](=[O:19])[N:9]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:8]2=[O:25]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(NCCO)cc2c1=O
Reactant: CC(=O)O
Agent: [Pd]
Agent: C=O
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: CN(CCO)c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F

Procedure:
A mixture of 370 mg (0.968 mmol) of N-[6-(2-hydroxy-ethylamino)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide, 0.074 ml (0.912 mmol) of formaldehyde solution (37% in water), 4 ml of acetic acid, 15 ml of tetrahydrofuran and 15 ml of water is hydrogenated in presence of 115 mg of palladium on carbon for 3 days. After day 1 and 2 another portion of formaldehyde (0.074 ml) is added. After filtration of the reaction mixture the tetrahydrofuran is evaporated and the remaining aqueous phase extracted with ethyl acetate. The organic phase is washed with brine, dried over Na2SO4 and concentrated to dryness leaving a brown oil that is fractionated by medium pressure chromatography on a RP-18 column (20 μm particle size) with acetonitril/water 1:2. The fractions containing the product are combined and extracted with ethyl acetate, the organic phase dried over Na2SO4 and concentrated yielding 165 mg of N-{6-[(2-hydroxy-ethyl)-methyl-amino]-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl}-methanesulfonamide as yellow powder, m.p. 220-224° C.
Reaction SMILES: Cl[C:2](=[N:15]OS(C)(=O)=O)[CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.N1C=CC=CC=1.[N:27]([Na])=[C:28]=[S:29].[Br:31][C:32]1[CH:33]=[C:34]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:35]([NH2:38])=[N:36][CH:37]=1>O.C(#N)C>[Br:31][C:32]1[CH:33]=[C:34]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:35]([NH:38][C:28]2[S:29][N:15]=[C:2]([CH:3]3[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4]3)[N:27]=2)=[N:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(Cl)=NOS(C)(=O)=O)C1
Reactant: Nc1ncc(Br)cc1Oc1ccccc1
Reactant: [Na]N=C=S
Solvent: c1ccncc1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2nsc(Nc3ncc(Br)cc3Oc3ccccc3)n2)C1
Temperature: 25 °C

Procedure:
A 40 mL flask was charges with tert-butyl 3-(chloro(methylsulfonyloxyimino)methyl)pyrrolidine-1-carboxylate (1.60 g, 4.90 mmol) and acetonitrile (25 mL). Added pyridine (1.22 mL, 15.1 mmol) and isothiocyanatosodium (0.398 g, 4.90 mmol) and heated to 40° C. for 45 minutes. Added 5-bromo-3-phenoxypyridin-2-amine (1.00 g, 3.77 mmol) and heated at 60° C. overnight. The reaction was cooled to ambient temperature, poured into water and extracted with EtOAc (100 mL). The organic layer were dried with sodium sulfate, filtered and concentrated. The residue was purified by MPLC (Biotage) eluting with 3:1 hexane:ethyl acetate to afford tert-butyl 3-(5-(5-bromo-3-phenoxypyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)pyrrolidine-1-carboxylate as a light yellow/off white solid: 1H NMR (d6-DMSO) δ 12.21 (s, 1H), 8.34 (s, 1H), 7.48 (s, 1H), 7.39 (t, 2H), 7.18 (t, 1H), 7.07 (d, 2H), 3.42-3.63 (m, 3H), 3.36 (m, 1H), 2.02-2.21 (m, 3H), 1.35 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])/[C:3](=[CH:7]\[CH3:8])/[C:4]([OH:6])=O.CCOC(OC(OCC)=O)=O.[F:30][C:31]([F:48])([F:47])[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[C:43]([CH2:45][NH2:46])[CH:42]=[CH:41][N:40]=2)=[CH:35][CH:34]=1>C1COCC1>[CH3:1][N:2]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])/[C:3](=[CH:7]\[CH3:8])/[C:4]([NH:46][CH2:45][C:43]1[CH:42]=[CH:41][N:40]=[C:39]([C:36]2[CH:35]=[CH:34][C:33]([O:32][C:31]([F:48])([F:30])[F:47])=[CH:38][CH:37]=2)[CH:44]=1)=[O:6]
Reactant: NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1
Reactant: C/C=C(/C(=O)O)N(C)S(=O)(=O)c1ccc(F)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C/C=C(/C(=O)NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1)N(C)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
Acid 11A (515 mg, 2.5 mmol) was dissolved in 10 ml of THF and at rt DEPC (1.1 equiv, 0.38 ml) and [2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (1.1 equiv., 737 mg) were added to the solution. The mixture was stirred at rt overnight then evaporated. The residue was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (1:1 EtOAc:petroleum ether) afforded 200 mg of a pale yellow solid. Yield=15% 1HNMR (DMSO, 200 MHz) δ 1.74 (3H, d J=7.4 Hz), 3.06 (3H, s), 4.40 (2H, d, J=6 Hz), 6.83 (1H, q, J=7 Hz), 7.44 (5H, m), 7.83 (3H, m), 8.18 (2H, d, J=8.2 Hz), 8.59 (1H, d, J=5.2 Hz), 8.70 (1H, bt) [M+1] 524.3 (C24H21F4N3O4S requires 523.50).
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[CH2:15][N:14]([S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:36])([CH3:35])[C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)C1C=CC=CC=1.C(Cl)Cl.B(Cl)(Cl)Cl>CO>[F:34][C:31]([F:32])([F:33])[C:30]([C:27]1[CH:28]=[CH:29][C:24]([N:11]2[CH2:12][CH2:13][N:14]([S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:18])[CH2:15][C@@H:10]2[CH2:9][OH:8])=[CH:25][CH:26]=1)([OH:36])[CH3:35]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COCc2ccccc2)cc1)C(F)(F)F
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CO)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
A 2-L round-bottomed flask was charged with 2-(4-((2R)-2-((benzyloxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (54.4 g, 101 mmol) and 200 mL of CH2Cl2. After cooling to 0° C., BCl3 (1M in CH2Cl2, 302 mL, 302 mmol, Sigma-Aldrich, St. Louis, Mo.) was added over 10 min. After 30 min at 0° C., the mixture was carefully diluted with MeOH and then concentrated and purified via column chromatography on silica gel (0 to 3% MeOH in CH2Cl2) to give 1,1,1-trifluoro-2-(4-((2R)-2-(hydroxymethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (42.7 g) as a tan foam.
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C@H:30]1[CH2:35][CH2:34][C@H:33]([CH:36]=O)[CH2:32][CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29].CCCCCC>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:31][CH2:32]1
Reactant: CCCCC[C@H]1CC[C@H](C=O)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCC[C@H]1CC[C@H](C=C(Br)Br)CC1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
A solution, cooled to -20° C., of 331.6 g of tetrabromomethane in 1 l of dry methylene chloride was treated dropwise under nitrogen gasification within 30 minutes with a solution of 524.6 g of triphenylphosphine in 1 l of methylene chloride. The mixture was subsequently stirred at -5° C. for a further 30 minutes, then treated dropwise at this temperature within 30 minutes with a solution of 91.2 g of trans-4-pentylcyclohexanecarboxaldehyde in 500 ml of methylene chloride and stirred at -5° C. for a further 2 hours. The mixture was poured into 6 l of hexane, the mixture was stirred at -20° C. for 1 hour and then the precipitate was filtered off under suction and washed well with about 1 l of cold (-20° C.) hexane. The filtrate was concentrated to a volume of about 1 l on a rotary evaporator, dilued with 2 l of hexane, again concentrated to a volume of about 1 l and stirred at -20° C. for a further 1 hour. The precipitate was filtered off under suction and rinsed well with about 500 ml of cold (-20° C.) hexane. The filtrate was freed from solvent on a rotary evaporator and the yellow oil obtained was filtered chromatographically on silica gel with about 3 l of hexane. The eluate was evaporated up to constant weight on a rotary evaporator, there being obtained 122.8 g (72.6%) of trans-1-(2,2-dibromovinyl)-4-pentylcyclohexane as a colourless oil; Rf-value (hexane) 0.55.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:23])[C:10]([CH3:22])([CH3:21])[CH2:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[F:20])=[CH:4][CH:3]=1.C(O)(=O)C.C(N(CC)CC)C.Br[CH:36]([CH:39]=O)[CH:37]=[O:38]>C(O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:36]([CH:37]=[O:38])=[CH:39][N:23]=[C:9]2[C:10]([CH3:21])([CH3:22])[CH2:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[F:20])=[CH:4][CH:3]=1
Reactant: CC(C)(Cc1c(F)ccc(F)c1F)C(=N)Nc1ccc(F)cc1
Reactant: O=CC(Br)C=O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(C)(Cc1c(F)ccc(F)c1F)c1ncc(C=O)n1-c1ccc(F)cc1

Procedure:
A solution of N-(4-fluorophenyl)-2,2-dimethyl-3-(2,3,6-trifluorophenyl) propanimidamide (35) (72.8 mg, 0.22 mmol), acetic acid (14 μL, 0.24 mmol), triethylamine (33 μL, 0.24 mmol), and bromomalonaldehyde (33.9 mg, 0.22 mmol) in isopropyl alcohol (1 mL) was refluxed for 4 h. The reaction was concentrated in vacuo, dichloromethane was added and washed with water. The aqueous phase was extracted with dichloromethane and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to afford 1-(4-fluorophenyl)-2-(2-methyl-1-(2,3,6-trifluorophenyl)propan-2-yl)-1H-imidazole-5-carbaldehyde (36).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C([O:49]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N1C[CH2:76][CH2:75][N:74]([CH:78]2[CH2:83][CH2:82][CH:81]([NH2:84])[CH2:80][CH2:79]2)[CH2:73][CH2:72]1)C1C=CC=CC=1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]([CH3:13])([CH3:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:84][C@H:81]5[CH2:82][CH2:83][C@H:78]([N:74]6[CH2:75][CH2:76][O:49][CH2:72][CH2:73]6)[CH2:79][CH2:80]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCC(N2CCCN(Cc3ccccc3)CC2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCOCC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(9-Cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (Intermediate 6) (66 mg, 0.15 mmol, 1 eq), DIPEA (52 μl, 0.3 mmol, 2 eq) and TBTU (54 mg, 0.17 mmol, 1.1 eq) were added to 1.5 mL DMF and the resulting solution was stirred at rt for 20 min before the addition of 4-morpholinocyclohexanamine (Intermediate 16) (33 mg, 0.18 mmol, 1.2 eq). The RM was then stirred at rt for 2 hours before purifying by preparative RP-HPLC-MS (Preparative—2) to provide 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-((trans)-4-morpholinocyclohexyl)benzamide (off-white solid, 10 mg, 11%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:13][CH2:14][C:15](Cl)=[O:16]>ClCCl>[Cl:13][CH2:14][C:15]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:16]
Reactant: O=C(Cl)CCl
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of pyrrolidine (5 g, 0.07 mol) in dichloromethane (100 ml) at 0° C. was added triethylamine (11.8 ml, 0.084 mol) followed by dropwise addition of chloroacetyl chloride (6.2 ml 0.077 mol) in dichoromethane (20 ml), stirred for 2 hrs, left to warm to room temperature. The reaction was washed with water (2×100 ml), brine (1×100 ml), the organic layers were dried (MgSO4), filtered and evaporated to give the required product (9.8 g) which was used without purification.
Reaction SMILES: [C:1]([S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][C:19]3([C:33]4[CH:32]=[N:31][N:30]([CH3:34])[C:29]=4[C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:22]3)[CH2:18][CH2:17]2)=[O:15])=[CH:10][C:9]=1OC)(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].Br[C:38]1[CH:43]=[CH:42][C:41]([C:44]([N:46]2[CH2:51][CH2:50][C:49]3([C:63]4[CH:62]=[N:61][N:60]([CH3:64])[C:59]=4[C:58]4[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=4[O:52]3)[CH2:48][CH2:47]2)=[O:45])=[CH:40][C:39]=1[CH3:65]>>[C:1]([S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:17][CH2:18][C:19]3([C:33]4[CH:32]=[N:31][N:30]([CH3:34])[C:29]=4[C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:22]3)[CH2:20][CH2:21]2)=[O:15])=[CH:10][C:9]=1[CH3:38])(=[O:7])=[O:6])([CH3:3])([CH3:2])[CH3:4].[CH2:1]([S:5]([C:38]1[CH:43]=[CH:42][C:41]([C:44]([N:46]2[CH2:51][CH2:50][C:49]3([C:63]4[CH:62]=[N:61][N:60]([CH3:64])[C:59]=4[C:58]4[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=4[O:52]3)[CH2:48][CH2:47]2)=[O:45])=[CH:40][C:39]=1[CH3:65])(=[O:7])=[O:6])[CH3:2]
Reactant: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1S(=O)(=O)C(C)(C)C
Reactant: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1Br
Product: CCS(=O)(=O)c1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)cc1C
Product: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1S(=O)(=O)C(C)(C)C

Procedure:
(4-Isopropylsulfanyl-3-methoxy-phenyl)-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (291 mg, 0.6277 mmol) was dissolved in acetic acid (3 mL) and hydrogen peroxide (200 μL, 6.527 mmol) was added. The reaction mixture was heated at 80° C. for 40 minutes before it was partitioned between ethyl acetate (15 mL) and water (10 mL). The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and then purified by column chromatography utilizing a gradient of 0-5% methanol in dichloromethane to yield (4-isopropylsulfonyl-3-methoxy-phenyl)-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (51 mg, 24%) as a white solid. ESI-MS m/z calc. 495.2. found 496.5 (M+1)+. Retention time: 1.52 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.83 (d, J=8.0 Hz, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.45 (s, 1H), 7.34 (s, 1H), 7.29 (t, J=7.8 Hz, 1H), 7.22 (d, J=8.0 Hz, 7.15-7.06 (m, 2H), 4.45-4.31 (m, 1H), 4.10 (s, 3H), 3.97 (s, 3H), 3.68 (septet, J=6.7 Hz, 1H), 3.59-3.22 (m, 3H), 2.10-1.82 (m, 4H), 1.17 (d, J=6.9 Hz, 6H). (4-(tert-Butylsulfonyl)-3-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone was also synthesized using the procedures described above. (4-(tert-Butylsulfonyl)-3-methylphenyl)(1-methyl-1H-spiro-[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone and (4-(ethylsulfonyl)-3-methylphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone were synthesized from (4-bromo-3-methylphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone using the procedures described above.
Reaction SMILES: [Br:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5]([Cl:11])=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=2)=O)[CH:3]=1.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>C(Cl)Cl.CC#N>[Br:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5]([Cl:11])=[C:4]([CH2:12][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=2)[CH:3]=1
Reactant: CCOc1ccc(C(=O)c2cc(Br)c3sccc3c2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC#N
Product: CCOc1ccc(Cc2cc(Br)c3sccc3c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of (7-bromo-4-chlorobenzo[b]thiophen-5-yl)(4-ethoxyphenyl)methanone 98 (917 mg, 2.32 mmol) in a mixture of CH2Cl2 (9 mL) and CH3CN (30 mL) at 0° C. was added Et3SiH (1.6 mL, 9.27 mmol) and BF3.Et2O (0.47 mL, 3.48 mmol). The reaction mixture was warmed to room temperature, and then stirred overnight. The resulting solution was quenched with aqueous sat. NH4Cl solution (40 mL) and normal work-up with EtOAc was accomplished. After evaporating volatile solvents, the residue was purified by silica gel chromatography to afford the title compound (761 mg, 84%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=O.[F:21][C:22]([F:39])([F:38])[C:23]1[CH:24]=[C:25]([NH:29][NH:30]C(OC(C)(C)C)=O)[CH:26]=[CH:27][CH:28]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:29]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:39])[F:38])[CH:24]=2)[N:30]=1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Reactant: CC(C)(C)OC(=O)NNc1cccc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3cccc(C(F)(F)F)c3)c(=O)[nH]2)c1)C(F)(F)F
Yield: 55.5 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 0.500 g, 1.55 mmol), tert-butyl 2-[3-(trifluoromethyl)phenyl]hydrazinecarboxylate (0.428 g, 1.55 mmol), DCM (20 mL) and trifluoro acetic acid (5.0 mL) to afford 0.400 g of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH2:12]([NH:15][C:16](=[O:21])[CH2:17][C:18]([CH3:20])=[O:19])[CH:13]=[CH2:14].N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[CH2:12]([NH:15][C:16](=[O:21])[CH2:17][C:18]([CH:20]=[CH:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])=[O:19])[CH:13]=[CH2:14]
Reactant: C=CCNC(=O)CC(C)=O
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: C=CCNC(=O)CC(=O)C=Cc1ccccc1[N+](=O)[O-]
Yield: 70 %

Procedure:
o-Nitrobenzaldehyde (7.6 g, 0.05 mole) and acetoacetic allylamide (7.1 g, 0.05 mole) are dissolved in benzene (40 ml) and thereto are added piperidine (0.2 ml) and acetic acid (0.6 ml), and the mixture is refluxed for 2 hours and the produced water is removed. After the stoichiometic amount of water is distilled off, the reaction is stopped. After the reaction, the reaction mixture is washed with 5% hydrochloric acid and then with water, and the solvent is distilled off under reduced pressure, and to the residue is added diethyl ether, and the obtained crude crystals are recrystallized from ethanol to give the title compound (9.6 g, yield 69.7%) as colorless needles, m.p. 128°-129° C.