Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:33])[N:11]([CH:30]([CH3:32])[CH3:31])[C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[C:14]([N:19](CC2C=CC(OC)=CC=2)[CH3:20])[CH:13]=3)[CH:5]=[CH:6][C:7]=1[F:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:33])[N:11]([CH:30]([CH3:31])[CH3:32])[C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[C:14]([NH:19][CH3:20])[CH:13]=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2ccc(F)c(N)c2)c(=O)n3C(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc2c(cn1)cc(-c1ccc(F)c(N)c1)c(=O)n2C(C)C
Yield: 32.5 %

Procedure:
The above prepared 3-(3-amino-4-fluoro-phenyl)-1-isopropyl-7-[(4-methoxy-benzyl)-methyl-amino]-1H-[1,6]naphthyridin-2-one (5.3 g) was combined with TFA (50 mL) in DCM (150 mL) and heated at reflux overnight. The volatiles were removed under reduced pressure, the residue dissolved in 10% HCl and washed with EtOAc (3×). The aqueous layer was made basic (pH=11), extracted with EtOAc and the combined organics were dried (Na2SO4) and concentrated to give 3-(3-amino-4-fluoro-phenyl)-1-isopropyl-7-methylamino-1H-[1,6]naphthyridin-2-one (1.26 g, 32% yield over two steps). 1H NMR (400 MHz, DMSO-d6): δ 8.36 (s, 1H), 7.70 (s, 1H), 7.06 (dd, J=8.4, 2.0 Hz, 1H), 6.94 (dd, J=11.6, 8.4 Hz, 1H), 6.88 (m, 1H), 6.72 (m, 1H), 6.39 (s, 1H), 5.07 (m, 1H), 5.06 (s, 2H), 2.83 (d, J=4.8 Hz, 1H), 1.51 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 327.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12](S(C)(=O)=O)[N:13]=1.[CH3:30][N:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12]([NH:37][CH:34]2[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]2)[N:13]=1
Reactant: CN1CCC(N)CC1
Reactant: CS(=O)(=O)c1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Product: CN1CCC(Nc2nc(-c3ccccc3Cl)c3ccc(=O)n(-c4ccccc4Cl)c3n2)CC1

Procedure:
The product of Example 47, and 1-methylpiperidin-4-ylamine were reacted by the procedure of Example 60 to afford the title compound 4,8-bis-(2-chloro-phenyl)-2-(1-methyl-piperidin-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 1.42 (m, 2H), 1.79 (m, 4H), 2.25 (s, 3H), 2.75 (m, 2H), 3.15 (m, 1H), 5.33 (s, 1H), 6.39 (d, 1H, J=9.8 Hz), 7.24-7.59 (m, 9H). LC MS (m/e)=480 (MH+).
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11](Cl)[N:10]=1>>[Cl:8][C:9]1[N:10]=[C:11]([NH:7][CH2:1][C:2]2[O:6][CH:5]=[CH:4][CH:3]=2)[CH:12]=[N:13][CH:14]=1
Reactant: Clc1cncc(Cl)n1
Reactant: NCc1ccco1
Product: Clc1cncc(NCc2ccco2)n1
Yield: 98 %

Procedure:
In a procedure analogous to Example 1, reaction of furfurylamine and 2,6-dichloropyrazine furnished the product (98%).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:10]1([C:13](Cl)=O)[CH2:12][CH2:11]1>>[CH:10]1([CH:13]2[C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:2][CH2:1][NH:9]2)[CH2:12][CH2:11]1
Reactant: O=C(Cl)C1CC1
Reactant: NCCc1ccccc1
Product: c1ccc2c(c1)CCNC2C1CC1

Procedure:
In accordance with the same procedures as in Preparation 1-1, except that 12.5 ml of phenethylamine (0.1M) and 10 ml of cyclopropane carbonylchloride(0.11M) were used as starting materials, 2.5 g of the title compound was prepared.
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[CH:5][C:4]3=[C:3]([C:21]#[C:22][C:23]2[C:24](=[O:43])[NH:25][C:26](=[O:42])[N:27]([CH:41]=2)[C@@H:28]2[O:40][C@H:31]([CH2:32][O:33]C(=O)C(C)(C)C)[CH2:30][CH2:29]2)[CH:2]=1.CO>C(O)(=O)C>[CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[CH:5][C:4]3=[C:3]([C:21]#[C:22][C:23]2[C:24](=[O:43])[NH:25][C:26](=[O:42])[N:27]([CH:41]=2)[C@@H:28]2[O:40][C@H:31]([CH2:32][OH:33])[CH2:30][CH2:29]2)[CH:2]=1
Reactant: CC(C)(C)C(=O)OC[C@@H]1CC[C@H](n2cc(C#Cc3ccc4c5cccc6cccc(c7cccc3c74)c65)c(=O)[nH]c2=O)O1
Solvent: CO
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)n([C@H]2CC[C@@H](CO)O2)cc1C#Cc1ccc2c3cccc4cccc(c5cccc1c52)c43
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a suspension of 5-(perylen-3-ylethynyl)-5′-O-pivaloyl-2′,3′-dideoxyuridine (350 mg, 0.613 mmol) in 80 mL of MeOH solid KOH (310 mg, 5.517 mmol) was added, and the mixture was stirred overnight. The mixture was then neutralized with acetic acid, evaporated under reduced pressure, co-evaporated with MeOH twice to give a crude product, which was chromatographically purified on a silica gel column using a 0 to 3% EtOH/CHCl3 gradient to give a chromatographically homogeneous (Rf 0.46, 37.5% acetone/CHCl3) product as orange solid (130 mg, 43%). 1H-NMR (DMSO-d6): 11.74 (s, 1H, NH), 8.76 (s, 1H, H-6), 8.45 (d, 1H, J 7.7), 8.41-8.38 (m, 2H), 8.36 (d, 1H, J 7.7), 8.30 (d, 1H, J 7.7), 7.71-7.54 (m, 6H) (perylenyl), 5.99-5.98 (m, 1H, H-1′), 5.35 (br. s, 1H, OH), 4.15-4.10 (m, 1H, H-4′), 3.70 (app. d, 1H, H-5′), 3.63 (app. d, 1H, H-5′), 2.38-2.31 (m, 1H, H-2′), 2.17-2.13 (m, 1H, H-2′), 2.01-1.94 (m, 1H, H-3′), 1.91-1.86 (m, 1H, H-3′).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[C:14]3[NH:21][CH:20]=[C:19]([C:22](O)=[O:23])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.C(OC(=O)[NH:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([C:38](=[O:43])[NH:39][CH:40]2[CH2:42][CH2:41]2)[CH2:34][CH2:33]1)(C)(C)C>>[CH:40]1([NH:39][C:38]([C@H:35]2[CH2:36][CH2:37][C@H:32]([NH:31][C:22]([C:19]3[C:15]4[N:16]=[CH:17][N:18]=[C:13]([C:7]5[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=5[O:5][CH2:4][CH:1]5[CH2:3][CH2:2]5)[C:14]=4[NH:21][CH:20]=3)=[O:23])[CH2:33][CH2:34]2)=[O:43])[CH2:42][CH2:41]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)NC2CC2)CC1
Reactant: O=C(O)c1c[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12
Product: O=C(N[C@H]1CC[C@H](C(=O)NC2CC2)CC1)c1c[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A77) and trans-(4-cyclopropylcarbamoyl-cyclohexyl)-carbamic acid tert-butyl ester (A195) the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][OH:10])[C:5]([CH:11](Br)[CH2:12]Br)=[CH:4][N:3]=1.[OH-].[K+]>>[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][OH:10])[C:5]([C:11]#[CH:12])=[CH:4][N:3]=1
Reactant: Cc1ncc(C(Br)CBr)c(CO)c1O
Agent: [K+]
Agent: [OH-]
Product: C#Cc1cnc(C)c(O)c1CO

Procedure:
The oily product from Step A was refluxed in 15 ml. of 10% (w/v) ethanolic potassium hydroxide under nitrogen for 10 minutes. After cooling the solvent was evaporated. The residue was extracted with 2 × 20 ml. of hot isopropanol which was then filtered and evaporated to give solid 2-methyl-3-hydroxy-4-hydroxymethyl-5-ethynyl-pyridine, m.p. 170°-171° C.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:28])=[CH:6][C:7]([F:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17](F)[C:18]=3[Br:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1>N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:28])=[CH:6][C:7]([F:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17]([NH:2][CH3:1])[C:18]=3[Br:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1
Reactant: CN
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)c(F)cc1F
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 40% aqueous solution (150 mg) of methylamine and 1-(5-amino-2,4-difluorophenyl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg) were added to pyridine (3 ml), and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, a mixed liquid of ethanol and diethyl ether was added to the residue, and solids were collected by filtration to obtain the title compound (40 mg) as a light brown powder.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:13][CH2:12][O:11][C:9](=[O:10])[CH2:8][CH2:7]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl.O1CCCC1>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([NH:24][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]2[CH2:13][CH2:12][O:11][C:9](=[O:10])[CH2:8][CH2:7]2)(=[O:22])=[O:23])=[CH:19][CH:20]=1
Reactant: O=C1CCC(CCCCO)CCO1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1CCC(CCCCNS(=O)(=O)c2ccc(Cl)cc2)CCO1
Temperature: 25 °C

Procedure:
To a solution of 3.53 g of 4-(4-hydroxybutyl)-epsilon-caprolactone in 14 mL methylene chloride and 14 mL tetrahydrofuran is added 4.24 g p-chlorophenylsulfonamide followed by 7.44 g triphenylphosphine. The reaction mixture is stirred at room temperature for one half hour and then 6.1 mL diethyl azodicarboxylate is added slowly with cooling. After the addition, the cooling bath is removed and the solution is stirred at room temperature overnight. The reaction mixture is evaporated to dryness to yield 4-[4-(p-chlorophenylsulfonamido)butyl]-epsilon-caprolactone.
Reaction SMILES: C([O-])(O)=O.[Na+].OC(C(F)(F)F)=O.[CH2:13]([O:20][N:21]1[C:27](=[O:28])[N:26]2[CH2:29][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:30]([NH:32][NH2:33])=[O:31])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N:34]#[C:35]Br>O1CCOCC1>[NH2:34][C:35]1[O:31][C:30]([C@@H:25]2[CH2:24][CH2:23][C@@H:22]3[CH2:29][N:26]2[C:27](=[O:28])[N:21]3[O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:32][N:33]=1
Reactant: N#CBr
Reactant: NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31.8 %

Procedure:
Saturated NaHCO3 (7.0 mL, 6.26 mmol) was added to a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide TFA salt (2.3 g, 5.69 mmol) in dioxane (11.4 mL) and the reaction mixture was stirred at rt for 5 minutes. Cyanic bromide (3 M solution, 2.3 mL, 6.90 mmol) was added and the reaction mixture was stirred at rt for 30 minutes. The reaction mixture was then loaded on a silica gel cartridge and purified by silica gel column chromatography (gradient elution 0-10% MeOH/DCM) to give (2S,5R)-2-(5-amino-1,3,4-oxadiazol-2-yl)-6-(benzyloxy)-1,6-diazabicyclo[3.2.1]octan-7-one (0.57 g, 32%). ESI-MS (EI+, m/z): 316.4 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[OH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32]O)=[CH:25][CH:24]=1.N1C=CN=C1>C(Cl)Cl>[OH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][Br:20])=[CH:25][CH:24]=1
Reactant: BrBr
Reactant: OCCCCc1ccc(O)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Oc1ccc(CCCCBr)cc1
Reaction time: 0.25 h
Yield: 87.7 %

Procedure:
A solution of triphenylphosphine (144.1 mmole, 37.80 g) in methylene chloride (556 ml) was treated with bromine (144.1 mmole, 23.03 g) until a pale yellow color persisted. After stirring approximately 15 minutes, a solution of 4-(4-hydroxyphenyl)butanol (96.1 mmole, 15.97 g) and imidazole (192.2 mmole, 13.08 g) in methylene chloride (355 ml) was added over a 15 minute period. Approximately 4 hours later, the reaction suspension was filtered and the filtrate was reduced in volume. To the reduced filtrate was added silica gel and the suspension was reduced to dryness. This material was filtered and the first six fractions were eluted with 10% ethyl acetate:hexane. Fractions 7 through 12 were eluted with 20% ethyl acetate:hexane. Fractions 7 through 10 were combined, reduced in volume, dried over sodium sulfate, filtered and concentrated in vacuo to afford 19.32 g (88%) of the title compound as an oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:18]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[O:30])=[C:23]([CH3:37])[CH:22]=3)=[O:20])[CH2:17][C:16]3[CH:15]=[N:14][N:13]([CH3:38])[C:12]=3[NH:11][C:10]=2[CH:39]=1>ClCCl.C(N(CC)CC)C>[C:1]([N:34]1[CH2:33][CH2:32][N:31]([C:29](=[O:30])[CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:19]([N:18]3[CH2:17][C:16]4[CH:15]=[N:14][N:13]([CH3:38])[C:12]=4[NH:11][C:10]4[CH:39]=[C:6]([Cl:5])[CH:7]=[CH:8][C:9]3=4)=[O:20])=[CH:22][C:23]=2[CH3:37])[CH2:36][CH2:35]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3cc(Cl)ccc32)ccc1CCC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)CCc2ccc(C(=O)N3Cc4cnn(C)c4Nc4cc(Cl)ccc43)cc2C)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of acetyl chloride (0.39 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of 3-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-phenyl]-1-piperazin-1-yl-propan-1-one (2.47 mg, 0.005 mmol) in di-chloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 20 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=535.5
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[NH:10][CH:11]=O.P(Cl)(Cl)(Cl)=O>COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([N+:10]#[C-:11])[S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2cc(F)ccc2F)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: COCCOC
Product: [C-]#[N+]C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(C)cc1
Temperature: -5 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
To a solution of N-((2,5-difluorophenyl)(tosyl)methyl)formamide (5.92 g, 18.2 mmol) in DME (100 mL) at about −10° C. was added phosphorus oxychloride (Fluka, 5.09 mL, 54.6 mmol) followed by dropwise addition of TEA (12.7 mL, 91.0 mmol) in DME (10 mL). The reaction mixture was stirred at about −5° C. for about 3 h. The reaction mixture was poured into ice-cold water (250 mL) and extracted with EtOAc (3×50 mL). The organic layer was dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography using heptane/EtOAc (gradient; 1:0 to 1:1) to give the title compound (1.90 g, 34.0%) as a yellow solid. LC/MS (Table 1, Method a) Rt=2.94 min; MS m/z: 306.1 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:8][NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[N:8][N:9]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([O:20][C:19]([F:18])([F:30])[F:31])[CH:22]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccncc2)n[nH]c1C
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccncc2)nn(-c2cccc(OC(F)(F)F)c2)c1C
Temperature: 25 °C
Reaction time: 120 h
Yield: 53.8 %

Procedure:
A blue-green suspension of 5-methyl-3-pyridin-4-yl-1H-pyrazole-4-carboxylic acid ethyl ester (700 mg, 3.03 mmol), molecular sieves 4A, 3-(trifluoromethoxy)benzeneboronic acid (1.25 g, 6.05 mmol), copper (II) acetate (824 mg, 4.54 mmol) and pyridine (0.48 ml, 6.05 mmol) in 14 ml CH2Cl2 was stirred under argon atmosphere and at room temperature for 5 days. The reaction mixture was diluted with CH2Cl2 and washed with a saturated solution of NaHCO3 and brine. The aqueous phases were extracted twice with CH2Cl2, the combined organic layers dried over magnesium sulfate, and evaporated. The residue was treated with EtOAc:toluene, 1:9, filtered off. The filtrate was evaporated and chromatographed twice (amino-phase silica gel, toluene:EtOAc 9:1) to afford the title compound as a colorless oil (638 mg, 54%). MS: 392.1 (MH+).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]2)=[CH:13][CH:12]=1)#[N:10]>CS(C)=O>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][C:22]3([CH2:4][O:25]3)[CH2:21][CH2:20]2)=[CH:15][CH:16]=1)#[N:10]
Reactant: N#Cc1ccc(CCN2CCC(=O)CC2)cc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1ccc(CCN2CCC3(CC2)CO3)cc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
60% sodium hydride (1.89 g) was added to anhydrous dimethylsulfoxide (42 mL) and the mixture was stirred at room temperature for ten minutes under nitrogen atmosphere. After gradually adding trimethylsulfoxonium iodide (10.4 g) to the mixture at 10 to 19° C., the mixture was stirred at 8 to 10° C. for thirty minutes and at room temperature for sixty minutes. An anhydrous dimethylsulfoxide solution (42 mL) of the compound (9.00 g) obtained in Step 2 was added dropwise to the mixture. After stirring the resulting mixture at room temperature for one and half hours, the reaction mixture was poured into an ice water (250 mL) gradually with stirring. The mixture was extracted with ethyl acetate, and the organic layer was combined and washed with water and brine successively. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The residue was crystallized from hexane and collected by filtration to obtain the titled compound (8.61 g) as crystals.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][N:13]1[C:17]([CH3:18])=[C:16]([CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:26]3[C:31]([N:32]4[CH2:37][CH2:36][CH:35]([CH2:38][OH:39])[CH2:34][CH2:33]4)=[N:30][CH:29]=[CH:28][N:27]=3)[CH2:22][CH2:21]2)[CH:15]=[N:14]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:12][N:13]1[C:17]([CH3:18])=[C:16]([CH2:19][N:20]2[CH2:21][CH2:22][N:23]([C:26]3[C:31]([N:32]4[CH2:37][CH2:36][CH:35]([CH2:38][O:39][S:7]([C:4]5[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=5)(=[O:9])=[O:8])[CH2:34][CH2:33]4)=[N:30][CH:29]=[CH:28][N:27]=3)[CH2:24][CH2:25]2)[CH:15]=[N:14]1
Reactant: Cc1c(CN2CCN(c3nccnc3N3CCC(CO)CC3)CC2)cnn1C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CCN(c3nccnc3N3CCN(Cc4cnn(C)c4C)CC3)CC2)cc1
Reaction time: 20.5 h
Yield: 51 %

Procedure:
Add p-toluenesulfonyl chloride (272 mg, 1.43 mmol, 1.1 eq) to a solution of {1-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-piperidin-4-yl}-methanol (0.5 g, 1.30 mmol, 1 eq, free base and triethylamine (1.43 mL, 10.24 mmol, 1.1 eq) in DCM (3 mL) at 0° C. Stir the mixture under nitrogen for 20.5 hr. Add a further portion of p-toluenesulfonyl chloride (0.13 g, 0.682 mmol, 0.5 eq) to the reaction mixture and continue stirring for a further 4.5 hr. Quench the reaction with saturated aqueous sodium bicarbonate solution (20 mL), and then pass through a hydrophobic frit to separate. Wash the aqueous layer twice with DCM (20 mL), combine the organic extracts and concentrate. Purify by flash chromatography on 40 g silica gel column, eluting with 0-10% methanol in DCM to give toluene-4-sulfonic acid 1-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-piperidin-4-ylmethyl ester (0.36 g, 51%). MS (m/z): 540.2 (M+1).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C@@H:11]2[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]3[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=3)=[O:17])[CH2:12]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:32][C:33]([O:36][C:37]([NH:39][CH2:40][C@@H:41]1[CH2:46][CH2:45][C@H:44]([C:47](O)=[O:48])[CH2:43][CH2:42]1)=[O:38])([CH3:35])[CH3:34]>>[CH3:35][C:33]([O:36][C:37]([NH:39][CH2:40][C@@H:41]1[CH2:46][CH2:45][C@H:44]([C:47]([N:14]2[CH2:15][C@@H:11]([N:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]3)[CH2:12][C@H:13]2[C:16]([NH:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[CH:21][CH:20]=2)=[O:17])=[O:48])[CH2:43][CH2:42]1)=[O:38])([CH3:32])[CH3:34]
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCN(S(C)(=O)=O)CC3)CN2)cc1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](C(=O)O)CC1
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](C(=O)N2C[C@@H](N3CCN(S(C)(=O)=O)CC3)C[C@H]2C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)CC1

Procedure:
Following the procedure described in Example 8, the compound prepared in Example 6 was treated with cis-4-[({[(2-methyl-2-propanyl)oxy]carbonyl}amino)methyl]cyclohexanecarboxylic acid to give the title compound as a white solid.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([F:13])[C:5]=1[N:14]1[CH2:19][CH2:18][S:17][CH2:16][CH2:15]1>CO.C(OCC)(=O)C>[F:13][C:6]1[CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]([F:3])[C:5]=1[N:14]1[CH2:15][CH2:16][S:17][CH2:18][CH2:19]1
Reactant: O=[N+]([O-])c1cc(F)c(N2CCSCC2)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cc(F)c(N2CCSCC2)c(F)c1
Yield: 70 %

Procedure:
Sodium borohydride (285 mg, 7.5 mmol) was added to a stirring solution of NiCl2.6H2O (1.16 g, 5.0 mmol) and 4-(2,6-difluoro-4-nitrophenyl)thiomorpholine, obtain in Preparation 3, in methanol (30 mL). The reaction mixture was diluted with ethyl acetate (50 mL) after 0.5 h and the organic portion was washed with water (30 mL×2) followed by brine (30 mL) and dried over sodium sulfate. Evaporation of the volatiles yielded the title compound as light brown solid (400 mg, 70%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][N:12]([CH3:26])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:7][CH2:6]1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[CH3:26][N:12]([CH2:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([CH2:4][CH2:3][CH2:2][O:1][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:6][CH2:7]1)[S:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C[C@H]1CC[C@H](CCCO)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Product: CN(C[C@H]1CC[C@H](CCCOS(C)(=O)=O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 3.4, trans-N-[4-(3-hydroxy-propyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was treated with methanesulfonyl chloride to yield trans-methanesulfonic acid 3-(4-{[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-methyl}-cyclohexyl)-propyl ester as colorless solid, MS: 472 (M+).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[C:5]([O:9][C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][C:13]=1[Cl:21])=[O:11])([CH3:8])([CH3:7])[CH3:6]>C(OCC)(=O)C>[Cl:21][C:13]1[CH:14]=[C:15]([C:16](=[O:17])[N:3]([CH3:4])[CH3:2])[CH:19]=[CH:20][C:12]=1[C:10]([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11]
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)O)cc1Cl
Reactant: CNC
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(C(=O)OC(C)(C)C)c(Cl)c1

Procedure:
290 mg of dimethylamine hydrochloride was coupled to 1 g of 4-(tert-butoxycarbonyl)-3-chlorobenzoic acid via Procedure G. The reaction mixture was diluted with ethyl acetate, washed with 0.1 N HCl, 0.1 N NaOH and brine, dried (MgSO4) and evaporated to afford tert-butyl 2-chloro-4-(dimethylcarbamoyl)benzoate. 1.1 g of tert-butyl 2-chloro-4-(dimethylcarbamoyl)benzoate was treated with TFA (4 mL) containing trace amounts of H2O for 2 h. The reaction mixture was evaporated, and then added 0.1 N HCl. The resulting solid was filtered and washed with H2O to yield 2-chloro-4-(dimethylcarbamoyl)benzoic acid. 100 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to 2-chloro-4-(dimethylcarbamoyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4,N4-dimethylterephthalamide. MS (Q1) 414.1 (M)+.