Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][N:8]1[CH:12]=[N:11][N:10]=[CH:9]1.F[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17].Cl>CS(C)=O.O>[C:16]([C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[NH:7][N:8]1[CH:12]=[N:11][N:10]=[CH:9]1)#[N:17]
Reactant: N#Cc1ccccc1F
Reactant: Nn1cnnc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccccc1Nn1cnnc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.5 %

Procedure:
6.67 Grams of potassium tert-butoxide was dissolved in 36 ml of anhydrous dimethylsulfoxide, and 5.00 g of 4-amino-4H-1,2,4-triazole was added thereto and the mixture was stirred for 15 minutes at room temperature. Subsequently, 9 ml of an anhydrous dimethylsulfoxide solution containing 3.23 g of 2-fluorobenzonitrile was added dropwise to the solution over a period of 10 minutes, and the mixture was stirred for further 15 minutes. The reaction mixture was poured into 90 ml of water and 90 g of ice, and the solution was then adjusted to have pH of 5.7 with 1N hydrochloric acid. The crystals precipitated out were collected by filtration and dried to give 2.64 g of 4-[(2-cyanophenyl)amino]-4H-1,2,4-triazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17](C1C=CC=CC=1)[C:18](=O)[O-:19])[CH2:6][CH2:5]2.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18]([N:31]1[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]1)=[O:19])[CH2:6][CH2:5]2
Reactant: O=C([O-])N(c1ccccc1)c1ccccc1N1CCc2cc(Br)ccc21
Reactant: CN1CCNCC1
Solvent: CCOCC
Product: CN1CCN(C(=O)Nc2ccccc2N2CCc3cc(Br)ccc32)CC1
Yield: 90 %

Procedure:
A solution of N-[2-(5-bromo-1-indolinyl)phenyl]phenylcarbamate (11.5 g, 28.5 mmoles), N-methylpiperazine (15 ml) and ether (50 ml) was stirred at room temperature for 2 hours. The ether was evaporated. The mixture was filtered through a silica gel column (150 g), packed with dichloromethaane, and the column was washed with 2% methanol-dichloromethane solution (2 l). The solvent was evaporated. The residue was purified by flash chromatography on a silica gel column (150 g, 230-400 mesh), eluted with 1% methanol/dichloromethane (4 l), 1.5% methanol/dichloromethane (2 l), and 2% methanol/dichloromethane. The fractions containing the desired material were collected and evaporated to give 10.9 g (90%) of product. Crystallization from chloroform and hexane afforded the analytical sample, mp 108°-110° C.
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2]2.[N:14]([Si](C)(C)C)=[N+:15]=[N-:16].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[N:14]([C@H:1]1[C@H:5]([OH:6])[CH2:4][N:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2]1)=[N+:15]=[N-:16]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.7 %

Procedure:
A 500 mL round-bottomed flask was charged with tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (15.42 g, 83.25 mmol), (1S,2S)-(−)-[1,2-cyclohexanediamino-N,N′-bis(3,5-di-t-butylsalicylidene)]chromium (III) chloride (1.18 g, 1.67 mmol) and azidotrimethylsilane (12.8 mL, 91.58 mmol) and the resulting mixture was stirred at ambient temperature under a nitrogen atmosphere for 48 hours. The dark red-brown mixture was diluted with chloroform (250 mL) and washed sequentially with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was dissolved in methanol (830 mL) and treated with potassium carbonate (11.51 g, 83.25 mmol) and the mixture was stirred at ambient temperature for 5 hours. The methanolic solution was filtered through a pad of Celite washed with methanol and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous back extracted with EtOAc. The combined organic extracts were washed with saturated sodium bicarbonate solution, water and brine, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (Biotage 40M; 20% ethyl acetate/hexanes) to give (3R,4R)-tert-butyl 3-azido-4-hydroxypyrrolidine-1-carboxylate (18 g, 95%). Enantiomeric excess was determined by Chiral HPLC (AD-H, Chiralcel, 10% EtOH: 90% hexanes at 0.80 mL/min, 94.5% e.e.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+].Cl.[CH3:22][O:23][CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1>>[CH3:22][O:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:25]1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: COC1CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC1CCCN(c2nnc(N)nc2-c2ccccc2)C1
Yield: 4.2 %

Procedure:
6-(3-Methoxypiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (33 mg, 4%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.70 g, 2.78 mmol), K2CO3 (0.80 g, 5.85 mmol) and 3-methoxy piperidine HCl (0.52 g, 3.34 mmol) according to the general procedure of Example 2.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1.O>CN(C)C=O>[O:1]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: OCc1ccccn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-hydroxymethylpyridine (19.3 ml), t-butyldimethylsilyl chloride (36.2 g) and imidazole (27.2 g) in dimethylformamide (190 ml) was stirred for two hours at room temperature. Water was added to the reaction mixture and extracted with n-hexane. The organic layer was washed with water, dried over magnesium sulfate and then evaporated. The residue was distilled to give 2-t-butyldimethylsiloxymethylpyridine (42.30 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[C:13]([CH:20]=[CH:21][CH:22]=3)[O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:10]=[C:4]2[CH:3]=1.[CH2:23]([N:25]([CH3:37])[C:26]([C:28]1[CH:29]=[N:30][N:31]([CH3:36])[C:32]=1[C:33](O)=[O:34])=[O:27])[CH3:24]>>[CH3:19][O:18][C:16](=[O:17])[CH2:15][O:14][C:13]1[CH:20]=[CH:21][CH:22]=[C:11]([C:9]2[N:10]=[C:6]3[N:7]=[C:2]([NH:1][C:33]([C:32]4[N:31]([CH3:36])[N:30]=[CH:29][C:28]=4[C:26](=[O:27])[N:25]([CH2:23][CH3:24])[CH3:37])=[O:34])[CH:3]=[CH:4][N:5]3[CH:8]=2)[CH:12]=1
Reactant: CCN(C)C(=O)c1cnn(C)c1C(=O)O
Reactant: COC(=O)COc1cccc(-c2cn3cnc(N)cc3n2)c1
Product: CCN(C)C(=O)c1cnn(C)c1C(=O)Nc1ccn2cc(-c3cccc(OCC(=O)OC)c3)nc2n1

Procedure:
The title compound was prepared in analogy to example 82 from methyl 2-(3-(7-aminoimidazo[1,2-c]pyrimidin-2-yl)phenoxy)acetate (105 mg, 352 μmol) and 4-(ethyl(methyl)carbamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid (74.3 mg, 352 μmol). Light yellow solid (30 mg, 16%). MS (m/z)=492.2 [M+H+].
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[CH:34](=O)[CH2:35][CH2:36]/[CH:37]=[CH:38]/[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[CH2:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH:34][CH2:35][CH2:36]/[CH:37]=[CH:38]/[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCC/C=C/CCC=O
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: CCCCC/C=C/CCC=CCc1ccccc1
Yield: 62.3 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (3.20 g, 7.15 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 4.5 mL, 7.15 mmol, 1.0 equiv.) and (E)-dec-4-enal (1.66 g, 10.7 mmol, 1.5 equiv.), 1.08 g (62%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3).
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH2:12][CH:11]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:23](O)=[O:24])=[CH:18][CH:17]=3)=[O:14])[O:10][N:9]=2)[CH:3]=1>C(Cl)Cl>[Cl:1][C:23]([CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13]([CH:11]2[O:10][N:9]=[C:8]([C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)[CH2:12]2)=[O:14])=[CH:17][CH:18]=1)=[O:24]
Reactant: Cl
Reactant: O=C(Nc1ccc(C(C(=O)O)c2ccccc2)cc1)C1CC(c2cccnc2)=NO1
Solvent: ClCCl
Product: O=C(Nc1ccc(C(C(=O)Cl)c2ccccc2)cc1)C1CC(c2cccnc2)=NO1

Procedure:
) HCl (gaseous) (excess) was bubbled through a suspension of (±)-4-[[[4,5-dihydro-3-(3-pyridinyl)-5-isoxazolyl]carbonyl]amino]-α-phenylbenzeneacetic acid (0.005 mol) in CH2Cl2 (100 ml) for 10 minutes. The solvent was removed under reduced pressure. The white solid was co-evaporated twice with toluene. Thionyl chloride (50 ml) was added. The reaction mixture was heated and refluxed for 1 hour. The solvent was evaporated. The reaction mixture was co-evaporated three times with toluene, yielding N-[4-[(chlorocarbonyl)phenylmethyl]phenyl]4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide (compound 493).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[C:19]4[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[Cl:32][C:27]1[CH:26]=[C:25]([CH:20]2[C:19]3[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=3[C:17]3[N:16]=[C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][N:41]5[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]5)=[CH:9][CH:10]=4)[N:24]=[CH:23][C:22]=3[CH2:21]2)[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccc(Cl)c(Cl)c2)C3)cc1
Product: CN1CCN(CCc2ccc(Nc3ncc4c(n3)-c3ccccc3C(c3ccc(Cl)c(Cl)c3)C4)cc2)CC1

Procedure:
This product was synthesized as described in general procedure 2 except 4-(6-(3,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate was used instead of 4-(6-(3-bromophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate and N-methyl piperazine was used instead of piperidine to afford 6-(3,4-dichlorophenyl)-N-(4-(2-(4-methylpiperazin-1-yl)ethyl)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine M.p.=119-121° C. 1H NMR 400 MHz (CDCl3) δ 13.02 (br s, 3H), 11.07 (br s, 1H), 8.42-8.35 (m, 1H), 7.97 (s, 1H), 7.74 (d, J=8.2 Hz, 2H), 7.6-7.5 (m, 2H), 7.38-7.34 (m, 1H), 7.28-7.23 (m, 2H), 7.18 (d, J=2.0 Hz, 1H), 7.12-7.07 (m, 1H), 6.9-6.8 (m, 1H), 4.35 (t, J=6.7 Hz, 1H), 3.48 (br s, 8H), 3.3-2.96 (m, 6H), 2.83 (s, 3H). LCMS m/e 545 (M+H).
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[CH3:10])[CH2:2][C:3]#[CH:4].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14](I)[CH:13]=1>>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([C:4]#[C:3][CH2:2][CH2:1][N:5]2[CH2:9][CH2:8][CH2:7][CH:6]2[CH3:10])[CH:13]=1
Reactant: Nc1ccc(Br)cc1I
Reactant: C#CCCN1CCCC1C
Product: CC1CCCN1CCC#Cc1cc(Br)ccc1N

Procedure:
The compound of formula (43) can be prepared from 3-butynyl p-toluenesulfonate (42) and 2(R)-methylpyrrolidine L-tartrate (40) as shown in Scheme 5. 2(R)-Methylpyrrolidine L-tartrate (40) is treated with potassium carbonate in acetonitrile to provide 2(R)-methylpyrrolidine (41), which is combined with 3-butynyl p-toluenesulfonate (42) to give 1-but-3-ynyl-2-methyl-pyrrolidine (43). Compound (43) is reacted with 4-bromo-2-iodo-phenylamine (44) to provide 4-bromo-2-[4-(2-methyl-pyrrolidin-1-yl)-but-1-ynyl]-phenylamine (45). Compound (45) undergoes cyclization to compound (46) in the presence of a strong base, such as potassium t-butoxide. Compound (46) then is subjected to the Suzuki reaction conditions with an aryl or heteroaryl boronic acid, such as 4-cyanophenylboronic acid, to give compound (47) and (47a). Alternatively, in the presence of base and an alkylating agent, compounds (45) and (46) are alkylated with an alkyl halide such as methyl iodide to give an N-alkyl indole compounds, such as compound (48). Compound formula (48) is then subjected to the Suzuki reaction conditions with an aryl or heteroaryl boronic acid, such as 4-cyanophenylboronic acid, to give compounds such as compound (49) and (49a). Similarly, the compounds (40) and (41) can be substituted with any other suitable amine to provide the corresponding amine-substituted indole compound. In addition, the 4-cyanophenylboronic acid can be substituted with other boronic acids of the formula RcB(OH)2, wherein Rc is aryl or heteroaryl, to provide compounds of general structures (47a) and (49a), wherein R1 is aryl, heteroaryl, or heterocycle.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:14][O:15][N:16]=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:30][OH:31]>C1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:14][O:15][N:16]=2)=[N:30][OH:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NO
Reactant: CCOC(=O)CCc1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: c1ccccc1
Product: CCOC(=O)CCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Reaction time: 1 h
Yield: 30.2 %

Procedure:
Ethyl 3-(4-[(3-chloro-4-fluorophenyl)amino]carbonyl-1,2,5-oxadiazol-3-yl)propanoate (27 mg, 0.079 mmol) was suspended in benzene (1 mL) under an atmosphere of nitrogen and phosphorus pentachloride (18.0 mg, 0.086 mmol) was added. The solution was heated to reflux for 2.5 h. The solvent was removed in vacuo. The residue was dissolved in EtOH (1.0 mL) and hydroxylamine (100 μL, 2 mmol) (50% solution in water) was added to the reaction. After stirring 1 h, the solution was diluted with MeOH and purified by preparative LCMS to give the desired product (8.5 mg, 30%). 1H NMR (400 MHz, CD3OD): δ 7.03 (t, J=8.9 Hz, 1 H), 6.95 (dd, J=6.4, 2.7 Hz, 1 H), 6.71 (m, 1 H), 4.12 (q, J=7.2 Hz, 2 H), 3.11 (t, J=7.2 Hz, 2 H), 2.80 (t, J=7.2 Hz, 2 H), 1.23 (t, J=7.2 Hz, 3 H); LCMS for C14H15ClFN4O1(M+H)+: m/z=357.1.
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[C:17]([NH:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25])(=[O:20])[CH2:18][CH3:19]>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[NH:21][C:17](=[O:20])[CH2:18][CH3:19])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: CCC(=O)Nc1ccccc1C(=O)Cl
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Agent: Cl
Product: CCC(=O)Nc1ccccc1C(=O)Oc1ccc(C(=O)CNC(C)C)cc1O

Procedure:
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and o-propionamidobenzoyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(o-propionamidobenzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with methanesulfonic acid there is obtained the methanesulfonate salt. When this methanesulfonate is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(o-propionamidobenzoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol and methanesulfonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccc(O)c(Cl)c1
Solvent: CC(=O)O
Product: O=Cc1cc(Cl)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.4 %

Procedure:
To a solution of 3-chloro-4-hydroxybenzaldehyde (400 mg, 2.55 mmol) in acetic acid (5 mL) was added concentrated nitric acid (0.1 mL) and at 0° C., the resulting suspension was stirred at 25° C. for 6 h. The mixture was poured into ice water; the solid was collected by filtration, washed with water (30 mL) and dried in vacuo to give Intermediate 59 (300 mg, 58.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[N:13]1([C:9]2[CH2:8][CH2:7][C:6]3[C:11]([CH:10]=2)=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNC1
Reactant: O=C1CCc2cccc(Cl)c2C1
Solvent: Cc1ccccc1
Product: Clc1cccc2c1C=C(N1CCCC1)CC2
Yield: 92.3 %

Procedure:
To 100 ml of toluene were added 5.0 g (27.8 mmol) of 8-chloro-2-tetralone. To the resulting solution then were added 3.5 g of pyrrolidine, and the mixture was heated to reflux for three hours after which the solvent was removed in vacuo to give 3-pyrrolidino-5-chloro-1,2-dihydronaphthalene as a dark oil (about 6 g).
Reaction SMILES: C[N:2]([CH:4]=[O:5])C.[C:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)C(O)=O)(=[O:8])[CH3:7].C(N(CC)CC)C.ClC(OCC)=O.[OH-].[NH4+]>>[C:6]([C:9]1[CH:17]=[C:16]([CH:15]=[CH:11][CH:10]=1)[C:4]([NH2:2])=[O:5])(=[O:8])[CH3:7]
Reactant: CN(C)C=O
Reactant: CC(=O)c1cccc(C(=O)O)c1
Agent: CCOC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc(C(N)=O)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
General Procedure FF: Into DMF (11 ml, 140 mmol) solution of 3-acetylbenzoic acid (706 mg, 4.30 mmol) which was cooled in ice/water bath was added triethylamine (602 μl, 4.30 mmol) followed by addition of ethyl chloroformate (424 μl, 4.30 mmol) dropwise in 5 min under an atmosphere of nitrogen. The mixture was stirred at 0° C. for 30 min and then at rt for 30 min. Ammonium hydroxide (28% aq. solution; 1.15 ml) was added, and the mixture was stirred at rt for 3 h. After that time, the mixture was poured into ice/water, extracted with EtOAc (3×50 ml). The extracts were washed with water (2×30 ml), brine (30 ml), dried over MgSO4, filtered and concentrated in vacuo, giving the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ=2.66 (s, 3H), 7.58 (dt, J=0.4 & 8.0 Hz, 1H), 8.05 (md, J=8.0 Hz, 1H), 8.12 (md, J=8.0 Hz, 1H), 8.38-8.41 (m, 1H). MS (ES+): m/z 164.10 [MH+]. HPLC: tR=1.89 min (polar—5 min, ZQ3).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[C:19]([C:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=3)[CH:18]=[CH:17][C:16]=2[F:27])[CH2:13][C:12]([C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[N:11]1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[C:19]([C:21]3[CH2:22][CH2:23][N:24]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:25][CH:26]=3)[CH:18]=[CH:17][C:16]=2[F:27])[CH2:13][C:12]([C:28]([F:33])([F:34])[C:29]([F:30])([F:32])[F:31])=[N:11]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(C3=CCNCC3)ccc2F)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CC=C(c2ccc(F)c(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[2-fluoro-5-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 148, triethylamine (41.0 uL, 0.30 mmol) and methanesulfonyl chloride (8.1 mg, 0.07 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 3 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 15 mg of the titled compound as a yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C.CN(C)C=O>O>[O:19]=[C:20]1[N:3]2[CH:4]=[N:5][C:6]3[CH:7]=[CH:8][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:10][C:11]=3[C:2]2=[N:1][CH:27]=[C:21]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CS(=O)(=O)Nc1ccc2ncnc(N)c2c1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2c3cc(NS(C)(=O)=O)ccc3ncn2c1=O
Temperature: 155 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
A mixture of 4-amino-6-methanesulfonamidoquinazoline (6.89 g), diethyl ethoxymethylenepropanediate (15.5 g) and N,N-dimethylformamide (55 ml) was stirred at 155° C. for 2.5 hours. The reaction mixture was cooled to ambient temperature. To the mixture was added water to give precipitates, which were separated by filtration and washed with water. To the crystals was added a mixture of methanol and chloroform (1:4) (400 ml). After stirring under heating, insoluble materials (6.95 g) were filtered off and recrystallized from N,N-dimethylformamide to give crystalline ethyl 4-oxo-10-methanesulfonamido-4H-pyrimido [1,2-c]quinazoline-3-carboxylate (5.76 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.O.[NH:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: COc1ccc(S(=O)(=O)N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 4-methoxybezenesulfonyl chloride and 4-piperidone monohydrate hydrochloride according to the procedure of Intermediate 22 as an off-white solid; 1H NMR (CDCl3) δ 2.54 (t, J=4.80 Hz, 4H), 3.37 (t, J=4.80 Hz, 4H), 3.88 (s, 3H), 7.01 (dt, J=1.50 Hz, 3.90 Hz, 2H), 7.73 (dt, J=1.50 Hz, 3.60 Hz, 2H); MS (ES) m/z 269.8 (MH+); HRMS for C12H15NO4S: 269.0722; Anal. Calcd. for C12H15NO4S: C, 53.52; H, 5.61; N, 5.20. Found: C, 53.35; H, 5.60; N, 5.15.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:10])([CH2:6][CH2:7][CH2:8][F:9])[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O1CCCC1.O>[C:4]([C:3]([NH:2][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH2:6][CH2:7][CH2:8][F:9])[CH3:10])#[N:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(N)(C#N)CCCF
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C#N)(CCCF)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude rac-2-amino-5-fluoro-2-methylpentanonitrile hydrochloride product from Example 76A was initially charged in 185 ml of tetrahydrofuran/water (1:1), and 32.09 g (232.18 mmol) of potassium carbonate and 10.63 g (62.29 mmol) of benzyl chloroformate were added. The reaction mixture (biphasic mixture) was stirred at room temperature overnight. Another 1.93 g (11.33 mmol) of benzyl chloroformate were added to the reaction and the mixture was stirred at room temperature for a further 2 h. Subsequently, the biphasic system was separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, and then dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate gradient=20/1 to 5/1). 11.77 g of the target compound were obtained (72% of theory over two stages, 92% purity).