Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(O)(=O)C>N1C=CC=CC=1.O>[F:21][C:3]1[C:2]([N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccncc1
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(c5ccc(F)cc5)CC4)cc3nc21
Temperature: 115 °C
Yield: 62.5 %

Procedure:
A suspension of 3.07 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 7.21 g of 4-(4-fluorophenyl)-piperazine in 30 cm3 of pyridine was heated at a temperature around 115° C. for 84 hours. The reaction mixture was concentrated under reduced pressure (20 kPa) at approximately 60° C. The solid obtained was taken up in 50 cm3 of water and 3.5 cm3 of 10% acetic acid were added. The suspension was brought to approximately 100° C. The solidified product was filtered off and washed 3 times with 30 cm3 and 3 times 30 cm3 of warm ethanol. After recrystallizing twice from 65 cm3 of dimethylformamide on each occasion, 2.82 g of 7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid were obtained in the form of a yellow solid melting at about 318-319° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Br.Br.Br[CH2:24][C:25]1[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([CH2:24][C:25]3[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Reactant: Nc1ncc(CBr)c(N)n1
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncc(CN2CC=C(c3ccc(F)cc3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.5 %

Procedure:
A solution of 3.6 g (0.020 mol) of 4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine in 100 ml of tetrahydrofuran was treated with 13.9 ml (0.10 mol) of triethylamine and 7.3 g (0.020 mol) of 5-bromomethyl-pyrimidine-2,4-diamine dihydrobromide and the mixture was stirred at room temperature under argon for 16 hours. The suspension obtained was suction filtered and the filtrate was completely freed from the solvents. The residue was chromatographed over silica gel with acetonitrile/methanol 1:1 as the eluent and digested in diethyl ether. 3.5 g (58%) of 5-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-pyrimidine-2,4-diamine were obtained as brownish crystals; m.p. 265°.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:15][C:16]1[CH:17]=[C:18]([CH2:24][OH:25])[CH:19]=[C:20]([F:23])[C:21]=1[F:22]>>[CH3:12][N:11]1[C:4]2[N:5]([C:6](=[O:8])[N:7]=[C:2]([O:25][CH2:24][C:18]3[CH:19]=[C:20]([F:23])[C:21]([F:22])=[C:16]([F:15])[CH:17]=3)[CH:3]=2)[CH2:9][C:10]1([CH3:14])[CH3:13]
Reactant: OCc1cc(F)c(F)c(F)c1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCc3cc(F)c(F)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3,4,5-trifluorophenyl)methanol.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][C:8]2[CH:9]=[C:10]([F:29])[C:11]([N:14]3[CH2:20][CH:19]4[N:21](C(OC(C)(C)C)=O)[CH:16]([CH2:17][CH2:18]4)[CH2:15]3)=[N:12][CH:13]=2)[CH2:4][O:3]1.[ClH:31].CCOCC>ClCCl.CO.O1CCOCC1>[ClH:31].[ClH:31].[CH:19]12[NH:21][CH:16]([CH2:17][CH2:18]1)[CH2:15][N:14]([C:11]1[N:12]=[CH:13][C:8]([CH2:7][C@@H:5]([OH:6])[CH2:4][OH:3])=[CH:9][C:10]=1[F:29])[CH2:20]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1ncc(C[C@@H]3COC(C)(C)O3)cc1F)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: OC[C@H](O)Cc1cnc(N2CC3CCC(C2)N3)c(F)c1
Yield: 95 %

Procedure:
A solution of 109 (0.70 g, 1.67 mmol) in dichloromethane (4.0 mL) and methanol (1.0 mL) was treated at room temperature with 4 mol/L HCl in dioxane (2.5 mL) in a closed vessel for 16 hrs. The resulting suspension was stirred with ether (10 mL). The solid precipitate was collected on filter paper and washed several times with ether to afford a tan solid 110 (95% yield) which was confirmed by LC/MS and used directly for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNC1
Reactant: ClCc1ccccc1Cl
Solvent: Cc1ccccc1
Product: Clc1ccccc1CN1CCCC1
Yield: 75.7 %

Procedure:
A solution of 50 g of 2-chlorobenzyl chloride in 100 ml of toluene is added in portions under agitation to a solution of 55 g of pyrrolidine in 150 ml of toluene, maintaining the temperature below 40° C. When all has been added, the mixture is brought to boiling point and heated under reflux for three hours. After cooling, it is washed twice with water, the toluene solution is dried over K2CO3, and the solvent is removed under reduced pressure. The residue is distilled under vacuum. B.P.=102°-104° C. 46 grams of N-(2-chlorobenzyl)-pyrrolidine are obtained. The analytical and spectral (I.R., N.M.R.) data agree with the proposed formula. Treating a solution in ether with gaseous HC1 gives the hydrochloride, M.P. 170° C.
Reaction SMILES: [NH2:1][S:2](Cl)(=[O:4])=[O:3].CC(N(C)C)=O.[N:12]1([CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C:21]([C:31]#[N:32])=[CH:20][CH:19]=2)[CH:16]=[N:15][CH:14]=[N:13]1>CCOC(C)=O>[S:2](=[O:4])(=[O:3])([O:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[CH:23]=[C:18]([CH2:17][N:12]3[CH:16]=[N:15][CH:14]=[N:13]3)[CH:19]=[CH:20][C:21]=2[C:31]#[N:32])=[CH:25][CH:26]=1)[NH2:1]
Reactant: NS(=O)(=O)Cl
Reactant: N#Cc1ccc(Cn2cncn2)cc1-c1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Cn2cncn2)cc1-c1ccc(OS(N)(=O)=O)cc1

Procedure:
As general method using H2NSO2Cl (4.63 mL, 1.39 mmol), DMA (1.5 mL) and 19 (0.077 g, 0.279 mmol). The reaction mixture was poured into EtOAc (30 mL). The organic layer separated was washed with distilled H2O (30 mL×4), brine (30 mL), dried (MgSO4) and evaporated in vacuo to give white residues. Column chromatography (CH2Cl2/acetone 80:20) eluted 15 as a white solid (0.074 g, 75%), mp 159-162° C.; 1H NMR δH (270 MHz, DMSO-d6) 5.60 (s, 2H), 7.41-7.46 (m, 314), 7.51 (s, 1H), 7.67 (d, J=8.2, 2H), 7.98 (d, J=7.9, 1H), 8.03 (s, 1H), 8.17 (br s, 214) and 8.73 (s, 1H);
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:31]=[C:10]3[CH:11]=[CH:12][C:13]([O:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:30])=[C:20]([NH:22]C(=O)OC(C)(C)C)[CH:21]=4)=[CH:14][N:9]3[N:8]=2)=[O:5])[CH2:3][CH2:2]1>FC(F)(F)C(O)=O>[NH2:22][C:20]1[CH:21]=[C:16]([CH:17]=[CH:18][C:19]=1[CH3:30])[O:15][C:13]1[CH:12]=[CH:11][C:10]2[N:9]([N:8]=[C:7]([NH:6][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[N:31]=2)[CH:14]=1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Yield: 88.6 %

Procedure:
In the same manner as in Example 29 and using tert-butyl [5-({2-[(cyclopropylcarbonyl)amino][1,2,4]triazolo[1,5-a]pyridin-6-yl}oxy)-2-methylphenyl]carbamate (3.78 g, 8.48 mmol) and trifluoroacetic acid (20 mL) as starting materials, the title compound (2.43 g, 89%) was obtained as a white solid.
Reaction SMILES: [C:1]([F:16])([O:5][C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])=[C:2]([F:4])[F:3].[Si]([F:21])(C)(C)C>>[C:6]([O:5][CH:1]([C:2]([F:21])([F:4])[F:3])[F:16])([C:7]([C:8]([F:10])([F:9])[F:11])([F:12])[F:13])([F:14])[F:15]
Reactant: C[Si](C)(C)F
Reactant: FC(F)=C(F)OC(F)(F)C(F)(F)C(F)(F)F
Product: FC(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Yield: 1 %

Procedure:
Example 8 was repeated using the same reactor and catalyst/support charge. CF3CF2CF2OCF(CF3)CO2SiMe3 (16.20 g, 40.3 mmol) was added dropwise over 1.5 hr. There was obtained 13.94 g of liquid product consisting of an equimolar mixture of PPVE and TMSF. Less than 0.2% starting TMS ester remained, and less than 1% C3F7OCHFCF3 was produced.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([O:48][C:49]([NH:51][CH2:52][CH:53]1[CH2:57][CH2:56][CH2:55][NH:54]1)=[O:50])([CH3:47])([CH3:46])[CH3:45].ClCl>O1CCCC1.ClCCl.C(O)C>[C:44]([O:48][C:49]([NH:51][CH2:52][CH:53]1[CH2:57][CH2:56][CH2:55][N:54]1[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]#[N:12])=[CH:10][C:2]=1[Cl:1])=[O:6])=[O:50])([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)NCC1CCCN1
Reactant: N#Cc1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC1CCCN1C(=O)c1ccc(C#N)cc1Cl

Procedure:
Prepared analogously to Example I d from 2-chloro-4-cyanobenzoic acid, TBTU, N,N-diisopropylethylamine, and rac.-2-(N-tert-butoxycarbonylaminomethyl)pyrrolidine in tetrahydrofuran. Yield: quantitative; Rf value: 0.52 (silica gel; dichloromethane/ethanol=95:5); C18H22ClN3O3 (363.85); mass spectrum: (M+H)+=364/366 (chlorine isotope).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:21][O:22][CH2:23][CH3:24])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=O)[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[NH2:26][OH:27]>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:21][O:22][CH2:23][CH3:24])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=[N:26][OH:27])[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC(C)=O
Reactant: NO
Agent: Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC(C)=NO

Procedure:
By the general method described in Part F of Example 30, 5-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one was reacted with hydroxylamine hydrochloride to provide 5-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one oxime in about a 3.5 to 1 mixture of E and Z isomers as a white solid after recrystallization from a mixture of toluene and methanol, mp 220-223° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]#[N:20])=[CH:16][CH:17]=3)[CH2:12][O:11]2)=[CH:6][CH:5]=1.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]Cl.CN1CCN(C)C1=O>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.COC(C)(C)C>[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][C:10]1([C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[C:18]2[C:13](=[CH:14][C:15]([C:19]#[N:20])=[CH:16][CH:17]=2)[CH2:12][O:11]1
Reactant: CN(C)CCCCl
Reactant: N#Cc1ccc2c(c1)COC2c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: CN1CCN(C)C1=O
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
60% Sodium hydride (0.96 g) was dispersed in THF (20 ml), and to this suspension was added dropwise a solution of 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (5.0 g) in THF (10 ml) at 40-50° C. under a nitrogen atmosphere. Thereto was added tetra n-butylammonium bromide (0.2 g), and a solution of 3-(dimethylamino)propyl chloride (3.4 g) in t-butyl methyl ether (18 ml) was added dropwise, which was followed by stirring for 10 min. Further, 1,3-dimethyl-2-imidazolidinone (26.1 g, 25 ml) was added and the mixture was stirred at 61-64° C. for 6 hr. The reaction mixture was poured into ice water (83 ml) and extracted 3 times with toluene (33 ml). The organic layer was extracted 3 times with 20% aqueous acetic acid (41 ml), and the obtained aqueous layer was neutralized with 25% aqueous sodium hydroxide solution (120 g) and extracted 3 times with toluene (40 ml). The obtained organic layer was washed with water, and the solvent was evaporated to give 1-(3-(dimethylamino)propyl)-1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (citalopram base) as a viscous oil (5.36 g, yield 79.1%).
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([Cl:26])[CH:19]=3)=[N:14]2)=[O:9])[CH:4]=1.[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>C(#N)C>[N:28]1([CH2:2][C:3]2[O:7][N:6]=[C:5]([C:8]([NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([Cl:26])[CH:19]=4)=[N:14]3)=[O:9])[CH:4]=2)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: c1c[nH]cn1
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(CBr)on1
Solvent: CC#N
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(Cn2ccnc2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.81 %

Procedure:
(S)-5-(bromomethyl)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)isoxazole-3-carboxamide (0.328 g, 0.731 mmol) of Example 197(a) was dissolved in acetonitrile (10 ml) and imidazole (0.31 g, 4.55 mmol) dissolved in acetonitrile (3 ml) was added. The mixture was stirred at RT overnight. The mixture was evaporated, the residue dissolved in ethyl acetate and extracted with water. The organic phase was dried, filtered and evaporated. The product was purified by recrystallization from ethyl acetate. Yield 13.81%. 1H-NMR (400 MHz; DMSO-d6): δ 1.15 (d, 3H), 4.28-4.32 (m, 2H), 4.40-4.48 (m, 1H), 5.50 (s, 2H), 6.63 (s, 1H), 6.93 (d, 1H), 6.93-6.94 (m, 1H), 7.22-7.23 (m, 1H), 7.75-7.77 (m, 1H), 7.80 (d, 1H), 7.90 (dd, 1H), 7.96 (d, 1H), 8.07 (d, 1H), 8.80 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C([Li])CCC.CN(C)[C:16](=[O:18])[CH3:17].Cl>C(OCC)C.C1COCC1.O>[C:16]([C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)(=[O:18])[CH3:17]
Reactant: Clc1ccc(Br)nc1
Reactant: CC(=O)N(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1ccc(Cl)cn1
Reaction time: 1 h

Procedure:
To a suspension of 56 g of 2-bromo-5-chloropyridine in 560 ml of dry diethylether is added a solution of 179 ml of n-butyllithium (15% solution in hexane) at -78° and under argon at such a rate that the temperature never exceeds -72°. Immediately thereafter the solution of 25.7 ml of N,N-dimethylacetamide in dry THF is added. The mixture is stirred for one hour at the same temperature and thereafter decomposed by careful addition of 100 ml of 3N hydrochloric acid, followed by 100 ml of water with vigorous cooling. Working up by process A (see Example 1) and purification by chromatogrphy over silica gel (toluene/ethyl acetate=20/1) yields the compound as white needles; m.p.: 58°-65°.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[C:4]([CH3:10])[N:3]=1.O=S(Cl)[Cl:13]>>[Cl:13][CH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([CH3:10])=[CH:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(CO)c(C)n1
Product: Cc1ccc(CCl)c(C)n1

Procedure:
The solution of compound (2,6-dimethylpyridin-3-yl)methanol (0.76 g, 5.6 mmol) in SOCl2 (5 mL) was stirred at room temperature for 1 hour and then concentrated to give the crude product 3 which was used for next step directly without further purification. LCMS (ESI) m/z=156.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=2)=[CH:6][CH:5]=1.[Cl:21][C:22]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Cl:21][C:22]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:23]=1[C:24]([N:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:19])[F:20])=[CH:5][CH:6]=1)[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1)=[O:25]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: O=C(O)c1csc(Nc2ccc(OC(F)(F)F)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)c1csc(N(C(=O)c2ccc(F)cc2Cl)c2ccc(OC(F)(F)F)cc2)n1
Temperature: 50 °C
Reaction time: 48 h
Yield: 111.8 %

Procedure:
A mixture of 2.0 g (6.6 mmol) 2-(4-(trifluoromethoxy)phenylamino)-thiazole-4-carboxylic acid, 3.17 g (16.4 mmol) 2-chloro-4-fluorobenzoyl chloride and 0.92 g (6.6 mmol) potassium carbonate in 50 mL THF was stirred at 50° C. for 48 h. After evaporation of the volatiles the residue was partitioned between water and ethyl acetate. Organic phases were pooled, dried with MgSO4 and the solvent was removed in vacuo. Crystallisation from n-heptane/ethyl acetate yielded 3.4 g of the title compound which was used without further purification.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[N:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[C:51]1([NH2:54])[CH2:53][CH2:52]1>CN(C=O)C.CCOC(C)=O>[C:10]([O:9][C:7](=[O:8])[NH:1][C@H:2]([C:4](=[O:6])[NH:54][C:51]1([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][N:45]=2)[CH2:53][CH2:52]1)[CH3:3])([CH3:13])([CH3:12])[CH3:11]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NC1(c2ccccn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1(c2ccccn2)CC1
Reaction time: 1.5 h
Yield: 74.1 %

Procedure:
To a solution of Boc-Ala (100 mg, 0.53 mmol), HATU (261 mg, 0.69 mmol) and triethylamine (0.15 mL, 1.1 mmol) in DMF (2 mL) was added a solution of 1-pyridin-2-yl-cyclopropylamine (80 mg, 0.60 mmol) in DMF (1 mL). The mixture was stirred for 1.5 h then diluted with EtOAc (30 mL), washed with water (3×30 mL), brine (1×25 mL), dried with MgSO4, filtered, and concentrated to afford a crude solid. The crude material was purified by flash chromatography on silica gel, eluting with Hex/EtOAc (50/50 to 75/25) to afford [(S)-1-(1-pyridin-2-yl-cyclopropylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (120 mg, 74%) as a white solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[N:33][CH:34]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:38]1[CH2:39][CH2:40][N:35]([C:32]2[N:33]=[CH:34][C:29]([C:2]3[C:10]4[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=4)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=3)=[CH:30][CH:31]=2)[CH2:36][CH2:37]1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(N3CCOCC3)nc2)c2ccc(C=O)cc21
Temperature: 125 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
A mixture 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (25 mg, 0.62 mmol), 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (22 mg, 0.75 mmol), PdCl2(PPh3)2 (4 mg, 0.006 mmol) and 2M Na2CO3 (0.31 mL, 0.62 mmol) in DME/H2O/EtOH (2.8 mL/0.8 mL/0.4 mL) was sealed and heated with stirring under microwave irradiation at 125° C. for 4 h. Solvent was removed and the crude product was purified by silica gel chromatography (95:5 CH2Cl2/MeOH) to yield a bright yellow foam (266 mg, 97%). 1H NMR (400 MHz, CD3OD) δ 10.02 (s, 1H), 8.60 (d, J=2.3 Hz, 1H), 8.13 (s, 1H), 7.99 (dd, J=8.9, 2.5 Hz, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.64 (dd, J=8.7, 1.1 Hz, 1H), 6.80 (d, J=9.1 Hz, 1H), 5.78 (s, 2H), 3.76 (t, J=4.7 Hz, 4H), 3.61 (t, J=8.0 Hz, 2H), 3.49 (t, J=5.1 Hz, 4H), 0.84 (t, J=8.0 Hz, 2H), −0.12 (s, 9H); MS ESI 439.3 [M+H]+, calcd for [C23H30N4O3Si+H]+ 439.21.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[CH3:14][C:15]1([CH3:23])[CH2:21][CH2:20][C:19](=[O:22])[O:18][C:16]1=[O:17]>C1C=CC=CC=1>[C:16]([C:15]([CH3:23])([CH3:14])[CH2:21][CH2:20][C:19]([N:2]([CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH3:1])=[O:22])([OH:18])=[O:17]
Reactant: CNCCc1c[nH]c2ccccc12
Reactant: CC1(C)CCC(=O)OC1=O
Solvent: c1ccccc1
Product: CN(CCc1c[nH]c2ccccc12)C(=O)CCC(C)(C)C(=O)O
Reaction time: 8 h

Procedure:
6.97 g of 3-(2-methylaminoethyl)-indole, 100 ml of dry benzene and 5.69 g of 2,2-dimethylglutaric anhydride are introduced at ambient temperature into a 250 ml round-bottomed flask provided with a condenser, a CaCl2 drying tube and a magnetic stirrer. The reaction mixture is heated slowly at the reflux temperature for 1 hour 30 minutes with stirring. It is then left to cool and to stand overnight at ambient temperature.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH3:16])[C:3]=1[C:4]#[N:5].[S:17](Cl)(=[O:20])(=[O:19])[NH2:18].C(O)C.[OH-].[Na+]>CC(N(C)C)=O.C(OCC)(=O)C>[NH2:5][C:4]1[C:3]2[C:6]([O:10][C@@H:11]3[CH2:15][CH2:14][CH2:13][C@H:12]3[CH3:16])=[CH:7][CH:8]=[CH:9][C:2]=2[NH:1][S:17](=[O:20])(=[O:19])[N:18]=1
Reactant: C[C@@H]1CCC[C@H]1Oc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: C[C@@H]1CCC[C@H]1Oc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of 2-amino-6-(trans-2-methylcyclopentyloxy)benzonitrile (Example 236a) (150 mg, 0.694 mmol) in dimethylacetamide (3 mL) under N2 was added sulfamoyl chloride (3 equiv.). The reaction mixture was stirred at room temperature under N2 for 2 hours, diluted with ethyl acetate (50 mL) and quenched with water (20 mL). The layers were separated. The organic extract was evaporated. Ethanol (3 mL) and aqueous NaOH (2N, 2.5 equiv.) were consecutively added to the residue. The resulting mixture was heated at 90° C. for 16 hours. The workup was performed as in Example 158 to provide the desired product (160 mg, 78%) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 1.02 (d, J=6.4 Hz, 3H), 1.26 (m, 1H), 1.71 (br s, 3H), 1.89 (m, 1H), 2.12 (m, 1H), 2.24 (m, 1H), 4.55 (br s, 1H), 6.60 (d, J=8.0 Hz, 1H), 6.71 (d, J=8.0 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.73 (br s, 1H), 8.35 (br s, 1H), 10.96 (br s, 1H). MS 296 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][N:18]1[CH:22]=[CH:21][CH:20]=[N:19]1>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:17][N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: BrCn1cccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCn2cccn2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.4 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (3.1 g, 22.1 mmol) was dissolved in anhydrous DMF (150 mL), then potassium carbonate (9.1 g, 66.2 mmol) and 1-(bromomethyl)-1H-pyrazole (7.10 mg, 44.1 mmol) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 10% DCM in MeOH to afford 6-methyl-2-[(1H-pyrazol-1-ylmethyl)sulfanyl]pyrimidin-4-ol (365 mg, 7% yield for 3 steps); 1H NMR (400 MHz, DMSO-d6): δ 2.26 (s, 3H), 5.93 (s, 2H), 6.11 (bs, 1H), 6.25 (t, J=2.1 Hz, 1H), 7.50 (d, J=1.4 Hz, 1H). 7.88 (d, J=2.0 Hz, 1H); LRMS (ES+) m/z 223 (100%, M+1).