Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@@H:12]([CH2:14]N3CCN(C(C(OCC4C=CC=CC=4)=O)CC(OCC4C=CC=CC=4)=O)CC3)[O:11][C:10]2=[O:43])=[CH:5][CH:4]=1.ClCC1C=CC(N)=CC=1.[O:53]1CC1CO.ClC1C=CC(NCC(O)CO)=C(C)C=1.C(=O)(OCC)OCC.CC(C)([O-])C>>[Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][OH:53])[O:11][C:10]2=[O:43])=[CH:7][CH:8]=1
Reactant: O=C(CC(C(=O)OCc1ccccc1)N1CCN(C[C@@H]2CN(c3ccc(CCl)cc3)C(=O)O2)CC1)OCc1ccccc1
Reactant: OCC1CO1
Agent: CC(C)(C)[O-]
Agent: Cc1cc(Cl)ccc1NCC(O)CO
Agent: Nc1ccc(CCl)cc1
Solvent: CCOC(=O)OCC
Product: O=C1OC(CO)CN1c1ccc(CCl)cc1

Procedure:
1.1 g of 3-(4-chloromethylphenyl)-5(R)-[4-(1,2di-benzyloxycarbonylethyl)piperazinomethyl]oxazolidin-2-one [obtainable by reaction of 4-chloromethylaniline with 2,3-epoxypropan-1-ol to give N-(4-chloro-methylphenyl)-2,3-dihydroxypropylamine, reaction with diethyl carbonate in the presence of K tert-butoxide to give 3-(4-chloromethylphenyl)-5-hydroxymethyl-oxazolidin-2-one, subsequent esterification with methanesulfonyl chloride and reaction with 1-(1,2-dibenzyloxycarbonylethyl)piperazine], dissolved in 30 ml of DMF, are treated at room temperature with 0.9 g of freshly prepared guanidine, dissolved in 10 ml of DMF, and the mixture is stirred for two hours. After removal of the solvent and customary working up, 3-(4-guanidinylmethylphenyl)-5(R)-[4-(1,2-dibenzyloxycarbonylethyl)piperazinomethyl]oxazolidin-2-one is obtained.
Reaction SMILES: N([O-])=O.[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]3[CH:18]=[CH:19][C:20](N)=[CH:21][C:16]=3[O:15][C:14]([CH3:24])([CH3:23])[N:13]=2)=[CH:8][CH:7]=1.[ClH:25].[S:26](=[O:28])=[O:27]>O.C(O)(=O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]3[CH:18]=[CH:19][C:20]([S:26]([Cl:25])(=[O:28])=[O:27])=[CH:21][C:16]=3[O:15][C:14]([CH3:24])([CH3:23])[N:13]=2)=[CH:8][CH:7]=1
Reactant: Cl
Reactant: CC1(C)N=C(c2ccc(F)cc2)c2ccc(N)cc2O1
Reactant: O=S=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)N=C(c2ccc(F)cc2)c2ccc(S(=O)(=O)Cl)cc2O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of sodium nitrite (153 mg) in water (2.4 mL) was added dropwise to a solution of 4-fluorophenyl-2,2-dimethyl-2H-1,3-benzoxazin-7-amine (an objective compound of Reference Example 38(3); 600 mg) in acetic acid (18 mL) and concentrated hydrochloric acid (6 mL) at −5° C. and the mixture was stirred at the same temperature for one hour. To the reaction mixture was added a mixture of sulfur dioxide, acetic acid, cupric chloride and water at 0° C. and the mixture was stirred at the same temperature for one hour. The reaction mixture was poured into ice water (200 mL) and the mixture was extracted with ether (50 mL×3). The combined organic layer was washed successively with brine (50 mL) and a saturated aqueous solution of sodium bicarbonate (50 mL×2), dried over sodium sulfate and concentrated in vacuo to give the titled compound (400 mg) as a yellow oil, which was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[N:26]=[C:27]([CH3:35])[N:28]2[C:33]=1[C:32](=O)[NH:31][CH:30]=[N:29]2>C(#N)C>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[N:26]=[C:27]([CH3:35])[N:28]2[C:33]=1[C:32]([N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)=[N:31][CH:30]=[N:29]2
Reactant: Cc1nc(-c2ccccc2F)c2c(=O)[nH]cnn12
Reactant: c1nc[nH]n1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(-c2ccccc2F)c2c(-n3cncn3)ncnn12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1H-1,2,4-Triazole (15.1 g, 219 mmol) in acetonitrile (220 mL) was cooled to 0° C. and treated slowly with phosphorus oxychloride (5.99 mL, 65.4 mmol). After 10 minutes, triethylamine (36.5 mL, 262 mmol) was slowly added; the reaction was stirred for an additional 10 minutes at 0° C., then slowly warmed to room temperature over 15 minutes. C5 (5.33 g, 21.8 mmol) was added to the reaction mixture and stirring was continued at room temperature for 2 hours. After concentration in vacuo, the residue was diluted with ethyl acetate (˜250 mL) and poured into ice-cold stirring aqueous potassium phosphate solution (25%, 250 mL). After stirring for 10 minutes, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel chromatography (small plug of silica gel employed; Eluent: 2:1 heptane/ethyl acetate) provided the product as a bright yellow solid. Yield: 6.50 g, 21.8 mmol, 100%. LCMS m/z 296.0 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 9.06 (s, 1H), 8.35 (s, 1H), 7.77 (s, 1H), 7.74 (ddd, J=7.6, 7.4, 1.8 Hz, 1H), 7.35-7.40 (m, 1H), 7.26 (ddd, J=7.6, 7.5, 1.2 Hz, 1H), 6.88 (ddd, J=10.2, 8.3, 1.1 Hz, 1H), 2.87 (s, 3H).
Reaction SMILES: Cl.[C:2]1([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23]N4CCC(C5N=C(C6C=CC=CN=6)NN=5)CC4)=[CH:19][CH:18]=3)=[N:10][C:11]3[N:12]([N:14]=[CH:15][CH:16]=3)[CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:41]N1C(=O)CCC1=O.[OH2:49]>C(Cl)(Cl)Cl.ClCCl>[Br:41][C:16]1[CH:15]=[N:14][N:12]2[CH:13]=[C:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]=[O:49])=[CH:19][CH:18]=3)=[N:10][C:11]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: O
Reactant: c1ccc(-c2cn3nccc3nc2-c2ccc(CN3CCC(c4n[nH]c(-c5ccccn5)n4)CC3)cc2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=Cc1ccc(-c2nc3c(Br)cnn3cc2-c2ccccc2)cc1

Procedure:
1.0 g 6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (prepared as described under example 19) and 0.65 g N-bromosuccinimide are refluxed in 30 ml Chloroform for 5 h. This mixture is worked up by diluting with water and extraction with dichloromethane. The organic layers are dried over Na2SO4 and concentrated to yield the crude product, which is suspended in ethyl acetate/petrol ether. The solid desired product is isolated by filtration.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12]Br)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>CC(O)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH2:12][CH2:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(=O)Nc1ccc(CCBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(=O)Nc1ccc(CCN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C
Yield: 48.4 %

Procedure:
2-[4-(Acetylamino)phenyl]ethyl bromide (2.6 g, 10.7 mmol) was added to a mixture of N-tert-butyloxycarbonyl piperazine (2.0 g, 10.7 mmol) and K2CO3 (3.0 g, 21.7 mmol), in IPA (100 ml), and heated at 100° C. for 16 h. The mixture was filtered and the filtrate evaporated under vacuum. The residue was taken up into ethyl acetate and washed with H2O . The aqueous phase was extracted with EtOAc and the combined extracts dried (Na2SO4 /MgSO4) and evaporated. The crude product was chromatographed on silica gel eluting with ethyl acetate to give 1-tert-butyloxycarbonyl-4-[2-(4-(acetylamino)phenyl)ethyl]piperazine (1.8 g, 49%) which was shown to be pure by 1H NMR. A solution of the preceding N-Boc piperazine (1.8 g, 5.19 mmol) in 99% formic acid (30 ml) was stirred at room temperature for 16 h. The solvent was removed under vacuum and the product chromatographed on silica gel eluting with CH2Cl2 / MeOH/NH3 (50:8:1) to give the title-piperazine (1.3 g, 100%) δ(250 MHz, D6 -DMSO) 2.01 (3H, s, Me), 2.26-2.72 (12H, m, 6 of CH2), 7.12 (2H, d, J=8.5 Hz, Ar-H), 7.46 (2H, d, J=8.5 Hz, Ar-H), 9.85 (1H, s, NH).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[N:13](COCC[Si](C)(C)C)[CH:12]=1)=[O:10])[CH3:7].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[NH:13][CH:12]=1)=[O:10])[CH3:7]
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)c1ncco1
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)c1ncco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
In a round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-oxazol-2-yl-ethyl)-amide (106 mg, 0.192 mmol) was dissolved in dichloromethane (0.9 ml) and trifluoroacetic acid (0.6 ml, 7.7 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.9 ml) and ethylenediamine (0.8 ml, 11.7 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 66 mg (82%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-oxazol-2-yl-ethyl)-amide as an off-white powder. MS: (M+H)+=422; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.91 (br. s., 1H), 9.13 (s, 1H), 8.66 (d, J=8.3 Hz, 1H), 8.51 (s, 1H), 8.46 (d, J=8.3 Hz, 1H), 8.11 (s, 1H), 8.00 (s, 1H), 7.23 (s, 1H), 7.15-7.21 (m, 1H), 5.47-5.61 (m, 1H), 4.18 (s, 3H), 1.66 (d, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(Cl)Cl.C(N(CC)CC)C.[F:30][C:31]([F:37])([F:36])[S:32](Cl)(=[O:34])=[O:33]>O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][S:32]([C:31]([F:37])([F:36])[F:30])(=[O:34])=[O:33])[N:13]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=S(=O)(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The operation is carried out as in Stage 1 of Example 10 starting from 280 mg of the product obtained in Stage 1 of Example 7, 3 ml of methylene chloride, 0.17 ml of triethylamine, 0.128 ml of trifluoromethanesulphonic acid chloride in place of the 4-methyl-benzenesulphonic acid chloride then the reaction medium is agitated at ambient temperature for approximately 30 min. Then 2 ml of water is added, followed by extracting with 3×5 ml of methylene chloride, washing with 5 ml of saturated sodium chloride, drying, evaporating, impasting in 5 ml of ether then in 5 ml of pentane, separating and drying. In this way 315 mg of expected product is obtained in the form of a beige solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[NH:4][N:3]=1.C([O-])(O)=O.[Na+].[F:17][C:18]1[C:19](Cl)=[N:20][C:21]([Cl:24])=[N:22][CH:23]=1>C1COCC1.CCO>[Cl:24][C:21]1[N:22]=[C:23]([NH:11][C:7]2[CH:6]=[C:5]3[C:10]([C:2]([CH3:1])=[N:3][NH:4]3)=[CH:9][CH:8]=2)[C:18]([F:17])=[CH:19][N:20]=1
Reactant: Cc1n[nH]c2cc(N)ccc12
Reactant: Fc1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1n[nH]c2cc(Nc3nc(Cl)ncc3F)ccc12
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a stirred solution of 3-methyl-6-aminoindazole (2.71 g, 0.015 mol) and NaHCO3 (1.26 g, 0.045 mol) in THF (15 mL) and EtOH (60 mL) was added 5-fluoro-2,4-dichloropyrimidine (3.2 g, 0.019 mol) at room temperature. After the reaction was stirred overnight, the brown suspension was filtered and washed thoroughly with EtOH. The filtrate was concentrated under reduced pressure, and the resulting solid was washed with ether to remove excess pyrimidine to yield 3.7 g of the desired product (89%). HNMR: δ 12.57 (s, 1H), 10.01 (s, 1H), 8.28 (d, 1H), 7.93 (s, 1H), 7.60 (d, 1H), 7.27 (dd, 1H) 3.11 (s, 1H).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[C:3]#[CH:4].I[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[C:3]#[C:4][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2
Reactant: C#CC(O)c1ccccn1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccccn3)c21

Procedure:
Using Method C above, 3-hydroxy-3-(2-pyridinyl)-1-propyne (133 mg, 1 mmol) (from Example 36 above) was coupled to (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (147 mg, 0.4 mmol) using (Starting Material 2) (Ph3P)2PdCl2 (40 mg) (Aldrich) and CuI (20 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 19 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(2-pyridinyl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 84 mg, 56%).
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH:17]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:34][CH2:35][C:36]1[C:37]([C:42]2[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[C:44]([O:52][CH3:53])[CH:43]=2)=[N:38][CH:39]=[CH:40][CH:41]=1>>[ClH:34].[ClH:34].[ClH:34].[ClH:34].[CH2:1]([N:8]([CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH:17]=2)[CH2:13][CH2:14]1)[CH2:35][C:36]1[C:37]([C:42]2[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[C:44]([O:52][CH3:53])[CH:43]=2)=[N:38][CH:39]=[CH:40][CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2ncccc2CCl)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCC(NCc4ccccc4)CC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCC(N(Cc4ccccc4)Cc4cccnc4-c4cc(OC)c(OC)c(OC)c4)CC3)ccn2)cc(OC)c1OC
Product: Cl

Procedure:
4-Benzylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (134 mg) and 3-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed in the same manner as described in Example 9. A free base obtained was converted to a tetrahydrochloride to give the title compound as yellow powder.
Reaction SMILES: C(OC([N:8]1[CH2:30][CH2:29][C:11]2([O:16][C:15]([F:18])([F:17])[CH2:14][N:13]([C:19]([C:21]3[N:22]=[C:23]([CH:26]([CH3:28])[CH3:27])[S:24][CH:25]=3)=[O:20])[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].C1(C)C=CC=CC=1>C(Cl)Cl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[F:18][C:15]1([F:17])[CH2:14][N:13]([C:19]([C:21]2[N:22]=[C:23]([CH:26]([CH3:28])[CH3:27])[S:24][CH:25]=2)=[O:20])[CH2:12][C:11]2([CH2:29][CH2:30][NH:8][CH2:9][CH2:10]2)[O:16]1
Reactant: CC(C)c1nc(C(=O)N2CC(F)(F)OC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)c1nc(C(=O)N2CC(F)(F)OC3(CCNCC3)C2)cs1
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl-2,2-difluoro-4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 44, step a) (0.78 g) in DCM (20 mL) was treated with trifluoroacetic acid (5 mL) and the reaction mixture allowed to stand at 20° C. for 30 minutes. Toluene (40 mL) was added and the solvents evaporated under reduced pressure. The residue was azeotroped twice with acetonitrile to afford the subtitled compound. Yield 0.8 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[Cl:20][C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[C:23](Cl)[N:22]=1.C(N(CC)CC)C>CN1CCCC1=O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:8]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([F:29])([F:30])[F:28])=[C:21]([Cl:20])[N:22]=2)[CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=2)=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ccc(C(F)(F)F)c(Cl)n2)cc1
Temperature: 120 °C

Procedure:
Add bis(4-methoxybenzyl)amine (35.7 g, 138.9 mmol) in 20 mL of N-methylpyrrolidone to a solution of 2,6-dichloro-3-trifluoromethylpyridine (20 g, 92.6 mmol) and triethylamine (19.4 mL, 138.9 mmol) in 100 mL of N-methylpyrrolidone. Raise the temperature to 120° C., and stir the reaction for 14 hours. Quench the reaction mixture by the addition of water (80 mL), followed by extraction with EtOAc (3×70 mL). Wash the combined organic extracts with water (2×70 mL) and brine (70 mL), and dry over anhydrous Na2SO4. Filter the dried extract and concentrate under vacuum to afford the crude product, which is purified by column chromatography to give a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, 1H, J=8.4 Hz), 7.15 (m, 4H), 6.85 (m, 4H), 6.31 (d, 1H, J=8.8 Hz), 4.70 (s, 4H), 3.80 (s, 6H). Mass spec. (436.99, M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:27]=[CH:26][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18]C(=O)OC(C)(C)C)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:4][C:5]1[CH:27]=[CH:26][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(=O)Nc2ccccc2N)cc1
Temperature: 23 °C

Procedure:
To a 0° C. solution of tert-butyl (2-(4-acetamidobenzamido)phenyl) carbamate 1.5 (3.5 g, 9.5 mmol) in dry dichloromethane (55 mL) was added trifluoroacetic acid (22 mL) dropwise. The mixture was allowed to slowly warm to 23° C. for 2 hours until the reaction was complete. The solvents were removed in vacuo. The reaction mixture was diluted with water and the pH was adjusted to ˜8 with a saturated aqueous solution of sodium bicarbonate. The resulting precipitate was filtered, washed with water and ether, and dried under vacuum to afford 4-acetamido-N-(2-aminophenyl)benzamide 1.6 as an off-white solid. Yield 1.6=2.4 g (96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[CH:5]2.[C:17](#[N:19])C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[C:5]2[C:17]#[N:19]
Reactant: CC#N
Reactant: Clc1ccc2[nH]c(-c3cccnc3)cc2c1
Product: N#Cc1c(-c2cccnc2)[nH]c2ccc(Cl)cc12

Procedure:
5-Chloro-2-pyridin-3-yl-1H-indole (Example 87) is processed according to the method described in Example 140, using acetonitrile instead of dichloromethane, to give 5-chloro-2-pyridin-3-yl-1H-indole-3-carbonitrile. 1H NMR (400 MHz, MeOD) δ ppm 7.36 (dd, J=8.6, 2.0 Hz, 1H), 7.57 (d, J=8.6 Hz, 1H), 7.65-7.77 (m, 2H), 8.43 (dt, J=8.1, 2.0 Hz, 1H), 8.72 (d, J=4.8 Hz, 1H), 9.16 (s, 1H). HRMS (ESI) m/z 254.0495 [(M+H)+ calcd for C14H9ClN3: 254.0485].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:30])[CH2:16][N:17]3[CH2:22][CH2:21][NH:20][CH:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]3=[O:29])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C=O.[C:40]([BH3-])#N.[Na+]>CO.C(O)(=O)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[N:9]2[CH2:10][CH2:11][N:12]([C:15](=[O:30])[CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH3:40])[CH:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]3=[O:29])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: O=C(CN1CCNC(c2ccccc2)C1=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(CC(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)C(=O)C1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(2-{4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}-2-oxoethyl)-3-phenylpiperazin-2-one (Example 103B, 0.1 g, 0.2 mmol) in methanol was added 30% aqueous formaldehyde solution (0.06 mL, 0.3 mmol) and sodium cyanoborohydride (0.02 g, 0.3 mmol). A few drops of acetic acid were added, and the reaction was stirred at ambient temperature overnight. The reaction mixture was diluted with methylene chloride and washed with aqueous bicarbonate solution. The organic layer was separated, dried over MgSO4, evaporated and chromatographed, eluting with 5% methanol/methylene chloride to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.37-7.42 (m, 2H), 7.26-7.35 (m, 7H), 6.94-7.01 (m, 4H), 4.22 (d, J=15.3 Hz, 1H), 4.21 (s, 1H), 4.09 (d, J=15.5 Hz, 1H), 3.79 (s, 1H), 3.73-3.83 (m, 1H), 3.60 (t, J=4.7 Hz, 2H), 3.34-3.43 (m, 3H), 3.03 (ddd, J=12.0, 4.2, 2.9 Hz, 1H), 2.78 (ddd, J=12.0, 10.7, 3.9 Hz, 1H), 2.29-2.37 (m, 4H), 2.20 (s, 3H); MS (ESI+) m/z 519 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:35])([F:34])[C:10]1[N:14]2[N:15]=[C:16]([N:19]3[CH2:25][C@H:24]4[N:26](C(OC(C)(C)C)=O)[C@H:21]([CH2:22][CH2:23]4)[CH2:20]3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1>C(Cl)Cl.CO>[C@@H:24]12[NH:26][C@@H:21]([CH2:22][CH2:23]1)[CH2:20][N:19]([C:16]1[CH:17]=[CH:18][C:13]3[N:14]([C:10]([C:9]([F:35])([F:34])[F:8])=[N:11][N:12]=3)[N:15]=1)[CH2:25]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CN(c1ccc3nnc(C(F)(F)F)n3n1)C2
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1nnc2ccc(N3C[C@H]4CC[C@@H](C3)N4)nn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.5 %

Procedure:
TFA (2.42 ml, 31.4 mmol) was added to a stirred solution of (1R,5S)-tert-butyl 3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (443 mg, 1.11 mmol) in DCM (4.50 ml) at 25° C. The resulting solution was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with methanol and the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted using 7M ammonia in methanol and evaporated to dryness to afford 6-[(1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (336 mg, 100%) as a white solid.
Reaction SMILES: [I:1]I.C[Si](C)(C)[CH:5]=[CH:6][C:7]1[C:8](=[O:14])[CH2:9][CH2:10][CH2:11][C:12]=1[CH3:13].ClCCl.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1>[I:1][CH:5]=[CH:6][C:7]1[C:8](=[O:14])[CH2:9][CH2:10][CH2:11][C:12]=1[CH3:13]
Reactant: II
Reactant: CC1=C(C=C[Si](C)(C)C)C(=O)CCC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC1=C(C=CI)C(=O)CCC1
Reaction time: 8 h

Procedure:
Iodine (750 mg, 2.96 mmol) was dissolved in 10 mL of THF and the solution was added to a solution of 2-(2-(trimethylsilyl)ethenyl)-3-methyl-2-cyclohexen-1-one (Compound 3, 560 mg, 2.70 mmol) and dichloromethane (50 mL) at room temperature. The solution was stirred overnight, and then treated with 10% aqueous Na2S2O3 to remove the excess iodine. The layers were separated and the aqueous layer was extracted 3× with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (9:1, hexane:ethyl acetate) to give the product as a brown oil.