Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([F:30])[C:22]=1[F:31])[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:17][CH2:16][C:11]4([O:15][CH2:14][CH2:13][O:12]4)[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)=[C:23]([F:30])[C:22]=1[F:31])[CH3:19]
Reactant: Brc1ccc(C2=CCC3(CC2)OCCO3)cc1
Reactant: CCOc1ccc(B(O)O)c(F)c1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1ccc(-c2ccc(C3CCC4(CC3)OCCO4)cc2)c(F)c1F
Temperature: 25 °C
Yield: 75.7 %

Procedure:
8-(4-Bromophenyl)-1,4-dioxaspiro(4.5)dec-7-ene (s71) (30.0 g), 4-ethoxy-2,3-difluorophenylboronic acid (s70) (24.6 g), potassium phosphate (K3PO4; 64.7 g), dichlorobistriphenylphosphine palladium (II) (Pd(Ph3P)2Cl2; 2.1 g) and 1,4-dioxane (300 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and heated to reflux for 2 hours. After the reaction mixture had been cooled to 25° C., it was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder. Pd/C (1.5 g) was added to the purified product, and the mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder, and then by recrystallization from a mixed solvent of toluene and heptane (toluene:heptane=1:1 by volume) to give 8-(4′-ethoxy-2′,3′-difluoro-(1,1′-biphenyl)-4-yl)-1,4-dioxaspiro(4.5)decane (s72) (28.8 g). The yield based on the compound (s71) was 75.7%.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH:18]=O.N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[Br:1][C:2]1[S:6][C:5]([C:7](/[C:8](=[CH:18]/[C:17]2[CH:20]=[CH:21][C:22]([Cl:23])=[C:15]([Cl:14])[CH:16]=2)/[C:9]([O:11][CH3:12])=[O:10])=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)CC(=O)c1ccc(Br)s1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COC(=O)/C(=C\c1ccc(Cl)c(Cl)c1)C(=O)c1ccc(Br)s1
Temperature: 110 °C
Yield: 91.5 %

Procedure:
To a 250 mL round bottom flask was added a solution of methyl 3-(5-bromo-2-thienyl)-3-oxopropanoate (25.11 g, 95.44 mmol), 3,4-dichloro-benzaldehyde (21.71 g, 124.1 mmol) and piperidine (0.944 mL, 9.54 mmol) in anhydrous benzene (682 mL). Acetic acid (3.80 mL, 66.8 mmol) was added and the reaction mixture was fitted with a Dean-Stark trap. The oil bath was heated to 110° C. and the reaction stirred at reflux for 18 hours. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The crude material was dry loaded onto silica gel and purified by silica gel chromatography to afford the product as a yellow oil (36.7 g, 91.6%). LCMS: (AA) ES+: 421. 1H NMR (400 MHz, d6-DMSO) δ 7.83 (s, 1H), 7.53-7.45 (m, 1H), 7.34 (t, J=10.0 Hz, 1H), 7.24 (dd, J=8.4, 2.7 Hz, 2H), 7.03 (d, J=4.1 Hz, 1H), 3.81 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:37]=[C:38]([Cl:40])[CH:39]=1)[O:28][C:29]1[O:33][C:32]([C:34](Cl)=[O:35])=[CH:31][CH:30]=1>C1COCC1.C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([CH:37]=[C:38]([Cl:40])[CH:39]=1)[O:28][C:29]1[O:33][C:32]([C:34]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=3)[CH2:10][CH2:11]2)=[O:35])=[CH:31][CH:30]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Reactant: O=C(Cl)c1ccc(Oc2cc(Cl)cc(Cl)c2)o1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC(=O)c3ccc(Oc4cc(Cl)cc(Cl)c4)o3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 5-(3,5-dichlorophenoxy)-2-furoyl chloride: ESMS m/e: 572.0 (M+H)+.
Reaction SMILES: [CH:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].ClCCl.O1CCOCC1.[Br:29]Br>O>[Br:29][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:1]=[O:19]
Reactant: CCCCCCCCCCCCCCCCCC=O
Reactant: BrBr
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCC(Br)C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a stirred solution of 21 parts of octadecanal in 65 parts of dichloromethane and 50 parts of 1,4-dioxane there were added dropwise 34.1 parts of bromine. After stirring for 4 hours at room temperature, the reaction mixture was poured into 250 parts of water. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated, yielding 28 parts (95%) of 2-bromooctadecanal (interm. 1).
Reaction SMILES: C(O)=O.[O:4]1CCCO[CH:5]1[CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([CH:18]2[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[CH2:20][CH2:19]2)[CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[F:34][C:33]([F:35])([F:36])[O:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][CH:21]2[CH2:20][CH2:19][CH:18]([CH:15]3[CH2:16][CH2:17][CH:12]([CH2:11][CH2:10][CH:5]=[O:4])[CH2:13][CH2:14]3)[CH2:23][CH2:22]2)=[CH:31][CH:30]=1
Reactant: FC(F)(F)Oc1ccc(CCC2CCC(C3CCC(CCC4OCCCO4)CC3)CC2)cc1
Solvent: Cc1ccccc1
Solvent: O=CO
Product: O=CCCC1CCC(C2CCC(CCc3ccc(OC(F)(F)F)cc3)CC2)CC1
Yield: 94.8 %

Procedure:
Formic acid (3.0 g, 66 mmol) and toluene (20 ml) were added to the above 4-(4-(1,3-dioxan-2-ylethyl)cyclohexyl)-1-(2-(4-trifluoromethoxyphenyl)ethyl)cyclohexane (3.25 g, 6.94 mmol), followed by refluxing the mixture for 5 hours, washing the organic layer successively with a saturated, aqueous solution of sodium bicarbonate and water, drying over magnesium sulfate, and distilling off the solvent, to obtain 3-(4-(4-(2-(4-trifluoromethoxyphenyl)ethyl)cyclohexyl)cyclohexyl)propanal (2.70 g, 6.58 mmol). Yield: 94.8%.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:9]1[N:18]=[C:17]2[C:12]([C:13](=[O:25])[C:14]([C:22]([OH:24])=[O:23])=[CH:15][N:16]2[CH:19]2[CH2:21][CH2:20]2)=[CH:11][C:10]=1[F:26].[Br:27][CH2:28][CH2:29][OH:30].C(N(CC)CC)C>CN(C=O)C>[BrH:27].[CH:19]1([N:16]2[C:17]3[C:12](=[CH:11][C:10]([F:26])=[C:9]([N:2]4[CH2:3][CH:4]5[CH2:7][CH2:8][CH:1]4[CH2:6][N:5]5[CH2:28][CH2:29][OH:30])[N:18]=3)[C:13](=[O:25])[C:14]([C:22]([OH:24])=[O:23])=[CH:15]2)[CH2:20][CH2:21]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(N3CC4CCC3CN4)c(F)cc2c1=O
Reactant: OCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Br
Product: O=C(O)c1cn(C2CC2)c2nc(N3CC4CCC3CN4CCO)c(F)cc2c1=O
Yield: 63.1 %

Procedure:
A solution of 0.77 g (2.0 mmol) of 7-(2,5-diazabicyclo[2.2.2]oct-2-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 0.70 ml (8.0 mmol) of 2-bromoethanol, 1.30 ml (8.0 mmol) of triethylamine, and 20 ml of DMF was heated at 100° C. for 18 hours. The reaction solution was evaporated to dryness and the residue was triturated ethanol. The solid was collected by filtration to give 0.61 g of the title product, mp 290° C. dec (a).
Reaction SMILES: [Na].[F:2][CH:3]([F:9])[PH:4](=[O:8])[O:5][CH2:6][CH3:7].[C:10](#[N:12])[CH3:11].[C:13](O)(=O)C>C(O)C>[C:10]([CH2:11][CH2:13][P:4]([CH:3]([F:9])[F:2])(=[O:8])[O:5][CH2:6][CH3:7])#[N:12]
Reactant: CCO[PH](=O)C(F)F
Reactant: CC(=O)O
Reactant: CC#N
Agent: [Na]
Solvent: CCO
Product: CCOP(=O)(CCC#N)C(F)F
Temperature: 25 °C

Procedure:
660 mg (28.8 mmol) of sodium are dissolved in 40 ml of ethanol. The solution is cooled to -10° and 8.6 g (57.6 mmol) of ethyl P-difluoromethylphosphinate and 3.8 ml (57.6 mmol) of acetonitrile are added with stirring. The reaction mixture is then allowed to warm up to room temperature and stirred for additional 17 hours and then adjusted to pH 6 by addition of glacial acetic acid. The solvents are evaporated and the residue is dissolved in dichloromethane, washed twice with water, dried over magnesium sulphate and evaporated to dryness. The crude product is purified by chromatography on silica gel with ethyl acetate/dichloromethane (7:3) as eluent. The fractions containing the desired product are combined and evaporated to dryness yielding ethyl P-(2-cyanoethyl)-P-difluoromethyl-phosphinate as an oil of Rf =0.54 (above eluent).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@H:13]([C:21]([NH:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH:35]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][C:37](O)=[O:38].ON1C(=O)CCC1=O.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[NH:35]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][C:37]([NH:12][C@H:13]([C:21]([NH:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])=[O:22])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:38]
Reactant: N[C@@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCC(=O)N1O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Temperature: 4 °C
Yield: 65.5 %

Procedure:
A mixture of p-toluenesulfonic acid salt of Phe-Gly-OBzl (3.06 g), Boc-Gly-OH (1.10 g), N-hydroxysuccinimide (941 mg), N-methylmorpholine (0.725 ml), and N,N-dimethylformamide (40 ml) was cooled to 4° C., and added with N,N′-dicyclohexyl-carbodiimide (1.56 g). The mixture was allowed to react overnight at room temperature with stirring, and then evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol=98:2 solution) to give Boc-Gly-Phe-Gly-OBzl (1.93 g).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([CH3:22])[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=2)[CH2:9][CH2:8]1>O>[OH:3][CH:4]([CH3:22])[CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][CH:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=2)[CH2:11][CH2:12]1
Reactant: CC(=O)CCN1CCC(c2cc3ccccc3o2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(O)CCN1CCC(c2cc3ccccc3o2)CC1

Procedure:
A solution of 6.0 g of sodium borohydride in 25 ml of water is added dropwise, with stirring and external cooling, to a solution of 6.0 g of 1-(3-oxobutyl)-4-(2-benzofuranyl)-piperidine (cp. Example 8), the manner of addition being such that the reaction temperature does not exceed 30°. The mixtuure is subsequently stirred for 15 hours at room temperature. The methanol is then evaporated off in vacuo, the aqueous phase remaining behind extracted twice with 250 ml of chloroform each time, the chloroform solution dried over sodium sulphate, filtered, and concentrated by evaporation. The residue is dissolved in 500 ml of 2 N hydrochloric sacid, and the acid solution washed with ether. The aqueous solution is subsequently adjusted by addition of 10% sodium hydroxide solution to have a pH value of 12, and extracted with 1 liter of chloroform. The chloroform solution is dried with sodium sulphate, filtered, and concentrated by evaporation to obtain crude 1-(3-hydroxybutyl)-4-(2-benzofuranyl)-piperidine (4-(2 -benzofuranyl)-α-methyl-1-piperidine-propanol). The hydrochloride of this is prepared with hydrogen chloride in ethyl acetate, and recrystallised from ethyl acetate, whereupon it melts at 194°-195°.
Reaction SMILES: S(O)([O:4][CH2:5][CH2:6][NH2:7])(=O)=O.O1[CH:11]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10]1.[OH-].[Na+].C1(C)C=CC=CC=1>O.CO>[O:13]([CH2:12][CH:11]1[O:4][CH2:5][CH2:6][NH:7][CH2:10]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: NCCOS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: c1ccc(OCC2CNCCO2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
2-Aminoethyl hydrogen sulphate (49 g, 0.347 mol) was added in portions to a mixture of (±)-1,2-epoxy-3-phenoxypropane (11.2 ml, 0.083 mol), sodium hydroxide (26.4 g, 0.66 mol) in water (50 ml) and methanol (20 ml). After addition the reaction mixture was stirred at 40° C. (oil bath temperature) for 2 hours. The reaction mixture was cooled, sodium hydroxide pellets (20.65 g, 0.516 mol) and toluene (80 ml) were added, then the reaction mixture stirred, whilst heating at 65° C. (oil bath temperature) for 7.5 hours. The reaction mixture was cooled, toluene (40 ml) and water (140 ml) were added. The toluene phase was extracted with 2M hydrochloric acid (2×60 ml). The acid extracts were combined, 40% sodium hydroxide solution added to pH=11, then extracted with toluene (2×60 ml). The combined organics were dried (sodium sulphate) then evaporated to give a colourless gum (10 g) which was purified by column chromatography on silica, using neat ethyl acetate to remove the lipophilic impurities then ethyl acetate/methanol/ammonia (9:1:0.1) to elute the required product as a colourless oil (7.0 g, 44%). Rf 0.22 in dichloromethane/methanol (9:1) on silica plates MS CI+, m/z=194 for (M+H)+. 1H NMR (360 MHz, CDCl3) δ2.54-2.85 (2H, m), 2.92 (1H, ddd, J1 =2, J2 =J3 =12 Hz), 3.05 (1H, dd, J1 =2, J2 =12 Hz), 3.67 (1H, ddd, J1 =2, J2 =J3=12 Hz), 3.83-4.03 (4H, m), 6.88-6.97 (3H, m), 7.23-7.30 (2H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:16]=O>C(O)=O>[CH3:16][N:13]1[CH2:12][CH2:11][CH:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14]1
Reactant: C=O
Reactant: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Solvent: O=CO
Product: CN1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 110 °C

Procedure:
4-(4-Nitrophenyl)piperidine (515 mg) was added to 4 mL 90% formic acid and 1.5 mL formalin added. The solution was stirred and heated at 110° C. for 17 h, evaporated and the solids dissolved in 20 mL water. After basification to pH 14 with 5M sodium hydroxide solution the precipitated solid was extracted into t-butyl methyl ether (3×30 mL). Drying (sodium sulphate) and evaporating gave pure product as pale cream solid. NMR δ 8.15(d,2H), 7.39(d, 2H), 3.00(m,2H), 2.60(m,1H), 2.31(s, 3H), 2.08 (m, 2H), 1.86 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:20]2[S:24][C:23]([C@@:25]3([OH:36])[CH2:30][CH2:29][C@H:28]([C:31]([OH:33])=[O:32])[C:27]([CH3:35])([CH3:34])[CH2:26]3)=[N:22][CH:21]=2)[CH:6]=[C:7]([NH:9][C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=2)[CH:8]=1.[C:37]([OH:40])(=[O:39])[CH3:38].[CH2:41](Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>C1COCC1>[C:37]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:20]2[S:24][C:23]([C@@:25]3([OH:36])[CH2:30][CH2:29][C@H:28]([C:31]([OH:33])=[O:32])[C:27]([CH3:34])([CH3:35])[CH2:26]3)=[N:22][CH:21]=2)[CH:6]=[C:7]([NH:9][C:10]2[N:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:13]=[CH:12][N:11]=2)[CH:8]=1)(=[O:39])[CH3:38].[C:37]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:20]2[S:24][C:23]([C@@:25]3([OH:36])[CH2:30][CH2:29][C@H:28]([C:31]([O:33][CH3:41])=[O:32])[C:27]([CH3:34])([CH3:35])[CH2:26]3)=[N:22][CH:21]=2)[CH:6]=[C:7]([NH:9][C:10]2[N:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:13]=[CH:12][N:11]=2)[CH:8]=1)(=[O:40])[CH3:38]
Reactant: ClCCCl
Reactant: CC1(C)C[C@@](O)(c2ncc(-c3cc(CN)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC[C@@H]1C(=O)O
Reactant: CC(=O)O
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]3(O)CC[C@H](C(=O)O)C(C)(C)C3)s2)c1
Product: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(CNC(C)=O)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Temperature: 23 °C
Reaction time: 14 h
Yield: 184.7 %

Procedure:
A solution of (1S,4R)-4-{5-[3-(aminomethyl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid (40 mg, 0.075 mmol) in anhydrous THF (5 ml) was added acetic acid (6.41 μl, 0.112 mmol, 1.5 equiv), EDC (21.48 mg, 0.112 mmol, 1.5 equiv), HOBt (17.16 mg, 0.112 mmol, 1.5 equiv) and then triethylamine (0.031 ml, 0.224 mmol, 3.0 equiv). The mixture was stirred at 23° C. for 14 h. The reaction mixture was partitioned between EtOAc (2×40 ml) and water (45 ml). The combined organic layers were dried over Na2SO4 and concentrated, affording the desired product, methyl (1S,4R)-4-[5-(3-[(acetylamino)methyl]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (40 mg, 74%) as a yellow oil. 1H NMR (500 MHz, DMSO) 10.3 (s, 1H), 8.83 (d, J=4.9 Hz, 1H), 8.38 (m, 1H), 8.02 (bs, 1H), 7.90 (s, 1H), 7.68-7.66 (m, 2H), 7.52 (s, 1H), 7.28 (d, J=4.9 Hz, 1H), 5.94 (s, 1H), 4.24 (d, J=5.9 Hz, 2H), 4.12 (t, J=5.8 Hz, 1H), 3.60 (s, 3H), 3.31 (m, 2H), 1.97-1.88 (m, 5H), 1.75-1.73 (m, 2H), 1.24-1.22 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([NH:11][C:12](=[O:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:9]([CH3:19])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.[B][B][B][B][B][B][B][B][B][B]>CO>[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][CH:6]2[C:7]3[C:3](=[C:2]([CH3:1])[C:10]([NH:11][C:12](=[O:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:9]([CH3:19])[CH:8]=3)[CH2:4][CH2:5]2)=[CH:24][CH:23]=1
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)CCC2=O
Reactant: Nc1ccc(F)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)CCC2Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.7 %

Procedure:
A mixture of N-(4,6-dimethyl-1-oxo-indan-5-yl)-3,3-dimethyl-butyramide (5 g, 19 mmol), 4-fluoroaniline (5 g, 45 mmol), and decaborane (4.5 g, 36.8 mmol) in 100 ml of anhydrous methanol was stirred for 2 days at room temperature in an high pressure reaction equipment. The reaction mixture was poured into 500 ml of ice-water with strong stirring and the precipitates were filtered and washed with water. The dried solid was crystallized from hexane/ethyl acetate (5:1) to give white crystals (6 g, 86%). 1H-NMR δ (DMSO-d6, 400 MHz): 9.08 (brs, 1H, exchangeable with D2O, NH), 6.98 (s, 1H), 6.92 (t, J=8.8 Hz, 2H), 6.69 (dd, J=4.8 and 8.8 Hz, 2H), 5.76 (d, J=8.0 Hz, 1H, exchangeable with D2O, NH), 4.86 (q, J=8.0 Hz, 1H), 2.86 (ddd, J=4.8, 8.7 and 16.2 Hz, 1H), 2.70 (quint, J=8.1 Hz, 1H), 2.46 (m, 1H), 2.22 (s, 2H), 2.11 (s, 3H), 2.06 (s, 3H), 1.74 (m, 1H), 1.07 (s, 9H). MS: 369 (M+1).
Reaction SMILES: [CH2:1]([N:8]1C2C(=CC=CN=2)[C:11]([OH:18])=[C:10]([C:19](OCC)=[O:20])[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[C:27]([S:32]([NH2:35])(=[O:34])=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1.N[C:37]1[CH:42]=[CH:41][C:40](Br)=[CH:39][C:38]=1S(N)(=O)=O>>[NH2:35][S:32]([C:27]1[C:26]([NH:25][C:19]([C:10]2[C:9](=[O:24])[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:37]3[C:42]([C:11]=2[OH:18])=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:20])=[CH:31][CH:30]=[CH:29][N:28]=1)(=[O:34])=[O:33]
Reactant: CCOC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Reactant: Nc1cccnc1S(N)(=O)=O
Reactant: Nc1ccc(Br)cc1S(N)(=O)=O
Product: NS(=O)(=O)c1ncccc1NC(=O)c1c(O)c2ccccc2n(Cc2ccccc2)c1=O

Procedure:
The title compound was prepared according to the procedure of Example 84C substituting the product of Example 99A for the product of Example 84B and substituting (3-amino-pyrid-2-yl)sulfonamide for 2-amino-5-bromobenzenesulfonamide to give the crude product as an off white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[Cl:14].[Cl:15][C:16]1[CH:17]=[C:18]([C:28](O)=O)[N:19]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>C(#N)C>[Cl:14][C:3]1[CH:4]=[C:5]2[CH:6]=[N:7][NH:8][C:9]2=[C:10]2[C:2]=1[N:1]=[C:28]([C:18]1[N:19]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:20]=[C:16]([Cl:15])[CH:17]=1)[O:12][C:11]2=[O:13]
Reactant: Nc1c(Cl)cc2cn[nH]c2c1C(=O)O
Reactant: O=C(O)c1cc(Cl)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: O=c1oc(-c2cc(Cl)nn2-c2ncccc2Cl)nc2c(Cl)cc3cn[nH]c3c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
To a suspension of 1.00 g (4.58 mmol) of 6-amino-5-chloro-1H-indazole-7-carboxylic acid in 40 mL of anhydrous acetonitrile is added 1.18 g (4.58 mmol) of 5-chloro-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid followed by 1.7 mL (20.6 mmol) of pyridine. The mixture is stirred at ambient temperature during 30 minutes. Then the suspension is cooled to 0° C. and 1.25 mL (16.0 mmol) of methanesulfonyl chloride is added dropwise. The mixture is stirred at ambient temperature for 6 hours. Then the solvent is evaporated and the residue is triturated with a minimum of cold water. The precipitate, which is formed is filtrated, washed with cold water and dried. Purification by flash chromatography (SiO2, toluene/methylene chloride/ethyl acetate 10:10:3) affords 910 mg (39%) of the product as a yellowish solid; LC/MS:433/435 (M+H)+.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].[Cl:43][C:44]1[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=1[C:46](Cl)=[O:47]>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([C:46]([C:45]3[CH:49]=[CH:50][CH:51]=[CH:52][C:44]=3[Cl:43])=[O:47])[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(C(=O)c3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-chlorobenzoyl chloride and isolated as light-yellow solid. MS(m/e): 421.3 (MH+).
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:21]1[CH2:24][C:23]2([CH2:29][N:28]([C:30]([C:32]3[S:33][C:34]([CH3:37])=[CH:35][CH:36]=3)=[O:31])[CH2:27][CH2:26][O:25]2)[CH2:22]1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[ClH:1].[CH3:37][C:34]1[S:33][C:32]([C:30]([N:28]2[CH2:29][C:23]3([CH2:22][NH:21][CH2:24]3)[O:25][CH2:26][CH2:27]2)=[O:31])=[CH:36][CH:35]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: Cc1ccc(C(=O)N2CCOC3(C2)CN(C(c2ccccc2)c2ccccc2)C3)s1
Solvent: CC#N
Product: Cc1ccc(C(=O)N2CCOC3(CNC3)C2)s1
Product: Cl

Procedure:
1-Chloroethyl chloroformate (0.508 mL) was added dropwise to a solution of (2-benzhydryl-5-oxa-2,8-diazaspiro[3.5]nonan-8-yl)(5-methylthiophen-2-yl)methanone (example 33, step g) (1.5 g) in acetonitrile (30 mL) at 0° C. The mixture was then heated at reflux for 1 hour under nitrogen. The solvent was removed under reduced pressure and the residue dissolved in methanol (50 mL). This solution was heated at reflux under nitrogen for 30 minutes. The solvent was removed under reduced pressure and the residue triturated with ethyl acetate (40 mL) and then with acetonitrile (7 mL) to yield the subtitled compound. Yield 0.29 g.