Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1SC=C(C(=O)C(N[C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15](CSC2N4N=C(C(=O)N)N=C4N=C(C)C=2)=[C:16]3[C:20]([OH:22])=[O:21])=O)N=1.NOC(C)(C)C(NNS(C1C=CC(O)=C(O)C=1)(=O)=O)=O>>[O:19]=[C:18]1[N:17]2[CH:12]([S:13][CH2:14][CH:15]=[C:16]2[C:20]([OH:22])=[O:21])[CH2:11]1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)n2nc(C(N)=O)nc2n1
Agent: CC(C)(ON)C(=O)NNS(=O)(=O)c1ccc(O)c(O)c1
Product: O=C(O)C1=CCSC2CC(=O)N12

Procedure:
34 mg of (6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[(2-carbamoyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid were reacted with 28 mg of 2-[2-(aminooxy)-2-methylpropionyl]-1-[(3,4-dihydroxyphenyl)sulphonyl]hydrazine according to the procedure described in Example 7. After purification of the crude product with the chromatographic procedure described in Example 1 and lyophilization of the product, there was obtained (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[3-[(3,4-dihydroxy-phenyl)sulphonyl]carbazolyl]-1-methylethoxy]imino]aceta-mido]-3-[[(2-carbamoyl)-5-methyl-s-triazolo[1,5-a]-pyrimidin-7-yl)-thio]methyl]8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid as a white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)(=[O:20])=[O:19].C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:24]4[CH:25]=[CH:26][C:21]([S:18]([CH3:17])(=[O:20])=[O:19])=[CH:22][CH:23]=4)[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2nccc(Nc3cc(C4CC4)[nH]n3)n2)cc1
Temperature: 100 °C
Yield: 5.4 %

Procedure:
A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (200 mg, 0.85 mmol, 1.0 equiv.), 4-(methylsulfonyl)phenylboronic acid (187 mg, 0.93 mmol, 1.1 equiv.), Pcy3 (57 mg, 0.204 mmol, 0.24 equiv.), Pd2 (dpa)3 (78 mg, 0.085 mmol, 0.1 equiv.), K3PO4 (722 mg, 3.4 mmol, 4 equiv.), dioxane (5 ml) and water (1 ml) was added to the filtrate. The reaction mixture was heated to 100° C. for 15 h under nitrogen atmosphere. The residue was purified by silica gel chromatography (CH2Cl2/methanol 500:1 to 100:1) to afford title compound N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-(methylsulfonyl)phenyl) pyrimidin-4-amine (Compound 15) (16.2 mg, 5.4%) as white solid. LC-MS (m/z)=356.0 [M+H]+; 1H NMR (300 MHz, DMSO-d6): δ 0.73 (m, 2H), 0.94 (m, 2H), 1.91 (m, 1H), 3.26 (s, 3H), 8.06 (d, J=8.7 Hz, 2H), 8.40 (d, J=6 Hz, 2H), 8.53 (d, J=8.4 Hz, 2H), 9.99 (s, 1H), 12.10 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]=[CH:8][C:9]2=[O:14])([O-:3])=[O:2].[N+]([C:19]1[CH:20]=C2C(=[CH:27][CH:28]=1)C(=O)C=CC2=O)([O-])=O.C=CC=C.ClC=C(Cl)Cl>O>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[C:7]1[CH2:20][CH2:19][CH2:28][CH2:27][C:8]=1[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: O=C1C=CC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Agent: C=CC=C
Solvent: O
Solvent: ClC=C(Cl)Cl
Product: O=C1C2=C(CCCC2)C(=O)c2c1cccc2[N+](=O)[O-]
Reaction time: 2.5 h
Yield: 88 %

Procedure:
41.3 g of a crude 5-nitronaphthoquinone cake (having a water content of 40 wt% and a dry weight of 24.8 g, and comprised of 75 wt% of 5-nitronaphthoquinone and 15 wt% of 6-nitronaphthoquinone when determined under dried conditions), 13.1 g of 1,3-butadiene and 124 g of trichloroethylene were introduced into an autoclave. The autoclave was hermetically sealed and the reaction was effected at 80°C for 2.5 hours. Then, Example 1 was repeated to obtain 20.7 g of 5-nitrotetrahydroanthraquinone. The yield was 88.0%. The thus obtained 5-nitrotetrahydroanthraquinone was oxidized and reduced in accordance with the standard method to obtain 1-aminoanthraquinone having a purity above 98 wt% and a 2-aminoanthraquinone content of 0.5 wt%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[N:11]([CH3:12])[C:10](=[O:13])[N:9]([CH3:14])[C:8](=[O:15])[C:7]=1[CH2:16][CH2:17][C:18]#[N:19].[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:21].C(N(CCC)CCC)CC>C1(C)C(C)=CC=CC=1>[C:18]([CH2:17][CH2:16][C:7]1[C:8](=[O:15])[N:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:6]=1[NH:5][CH2:4][CH2:3][CH2:2][N:32]1[CH2:31][CH2:30][N:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][CH2:20][CH3:21])[CH2:34][CH2:33]1)#[N:19]
Reactant: Cn1c(NCCCCl)c(CCC#N)c(=O)n(C)c1=O
Reactant: CCOc1ccccc1N1CCNCC1
Agent: CCCN(CCC)CCC
Solvent: Cc1ccccc1C
Product: CCOc1ccccc1N1CCN(CCCNc2c(CCC#N)c(=O)n(C)c(=O)n2C)CC1
Yield: 57 %

Procedure:
4.3 g (15 mmol) of 6-(3-chloropropylamino)-5-cyanoethyl-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione and 4.2 g (15 mmol) of 1-(2-ethoxyphenyl)piperazine are heated at 140° C. for 14 h with 11.4 ml (60 mmol) of tripropylamine in 50 ml of xylene. The reaction mixture is concentrated in vacuo, the residue is taken up with 50 ml of water and 200 ml of ethyl acetate, and the mixture is treated with 300 ml of 1N NaOH, extracted and separated. The organic extract is washed with saturated NaCl solution and dried and the oil obtained after removing the solvent is purified by column chromatography (neutral silica gel, eluent initially ethyl acetate/petroleum ether 1:1, later only petroleum ether). The title compound of m.p. 133-136° C. (from ether) is obtained from the product fractions in a yield of 57%.
Reaction SMILES: N1(CCO[C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]([C:21]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=4)=[CH:19][N:20]=3)=[CH:11][CH:10]=2)CCCC1.COC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.B(Br)(Br)Br>C(Cl)Cl.CO>[C:12]1([NH:15][C:16]2[S:17][C:18]([C:21]3[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=3)=[CH:19][N:20]=2)[CH:11]=[CH:10][CH:9]=[CH:14][CH:13]=1
Reactant: Oc1ccc(-c2cnc(Nc3ccc(OCCN4CCCC4)cc3)s2)cc1
Agent: BrB(Br)Br
Agent: COc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc(-c2cnc(Nc3ccccc3)s2)cc1

Procedure:
The title compound is prepared as described in Example 7 for 4-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-thiazol-5-yl}-phenol but starting from [5-(4-methoxy-phenyl)-thiazol-2-yl]-phenyl-amine and using 2 equivalents of BBr3. Title compound: ES-MS: 269.0 [M+H]+; single peak at tR=6.65 min (System 1); Rf=0.05 (CH2Cl2/MeOH, 98/2).
Reaction SMILES: [CH3:1][NH2:2].F[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[N+:14]([O-:16])=[O:15]>CN(C)C=O>[CH3:1][NH:2][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[N+:14]([O-:16])=[O:15]
Reactant: CN
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: CN(C)C=O
Product: CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 86 %

Procedure:
A stream of methylamine was bubbled through a solution of 1.3 g (6.2 mmol) 4-fluoro-3-nitrobenzotrifluoride in 25 ml dimethylformamide at 25° C. for 5 min. Stirring was continued at 25° C. for 2 h, and then the reaction mixture was evaporated in vacuo. The residue was stirred with water, and the precipitate was filtered off to give 1.17 g (86%) 4-methylamino-3-nitrobenzotrifluoride. NMR (CDCl3): 8.4 (1H, s), 8.2 (1H, broad s), 7.6 (1H, dd), 6.9 (1H, d), 3.1 (3H, d).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][N:7]([CH3:15])[CH2:6]1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH3:15][N:7]1[CH2:6][C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:4][CH2:3][CH2:2][NH:1][C:29]([NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1
Reactant: CN1Cc2ccccc2C(CCCN)(c2ccccc2)C1
Reactant: O=C=Nc1ccccc1
Solvent: ClC(Cl)Cl
Product: CN1Cc2ccccc2C(CCCNC(=O)Nc2ccccc2)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.4 %

Procedure:
To a solution of 4-(3-aminopropyl)-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (0.4 g) in chloroform (10 ml) was added phenyl isocyanate (0.25 g) and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated to dryness and the residue was crystallized from methanol-isopropyl ether to provide the title compound (0.39 g) as colorless powder.
Reaction SMILES: C(C1NC=CN=1)(C1[NH:4]C=CN=1)=O.[CH3:13][C:14]1[CH:35]=[CH:34][CH:33]=[CH:32][C:15]=1[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:29]#[C:30][CH3:31])[CH2:25][C:26](O)=[O:27])=[CH:20][CH:19]=1.[NH4+].[OH-].Cl>C1COCC1.O>[CH3:13][C:14]1[CH:35]=[CH:34][CH:33]=[CH:32][C:15]=1[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:29]#[C:30][CH3:31])[CH2:25][C:26]([NH2:4])=[O:27])=[CH:20][CH:19]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC#CC(CC(=O)O)c1ccc(OCc2ccccc2C)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC#CC(CC(N)=O)c1ccc(OCc2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
Carbonyl diimidazole (0.46 g, 2.84 mmol) was added to a solution of 3-[4-(2-Methyl-benzyloxy)-phenyl]-hex-4-ynoic acid (See Example 13) (0.73 g, 2.37 mmol) in anhydrous THF (10 mL). The mixture was stirred at room temperature for 2 hours. Concentrated NH4OH (10 mL) was then added to the mixture, and the reaction was stirred at room temperature overnight. The reaction mixture was poured into water (300 mL) and the solution was adjusted to pH=7 with conc. HCl. The aqueous layer was then extracted with 3×25 mL ethyl acetate. The combined organic layers were washed with water, followed by brine. The organic layer was then dried (Na2SO4) and concentrated under reduced pressure to yield 0.48 g (70%) of 3-[4-(2-Methyl-benzyloxy)-phenyl]-hex-4-ynoic acid amide (23.2) as a light yellow solid. LC/MSD m/e: 308.4 (M+H)
Reaction SMILES: Cl[C:2](=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:10]>ClCCl>[CH2:9]([N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2](=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH3:10]
Reactant: CCNc1ccccc1
Reactant: COC(=O)CC(=O)Cl
Solvent: ClCCl
Product: CCN(C(=O)CC(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
Dichloromethane was added to a dry round bottom flask at 20-25° C. under nitrogen atmosphere. Methyl 3-chloro-3-oxo-propanoate (2.59 ml, 24.15 mmol) was added, followed by N-ethylaniline (2.97 ml 24.13 mmol), and the solution was stirred at r.t. for 14 h, then the solvent was removed under reduced pressure to obtain a yellowish oil. Yield: 100%. The purity of the isolated product: 98% (HPLC, area %).
Reaction SMILES: C[C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:3]=1[OH:4].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)([CH3:19])[CH3:18])=[CH:13][CH:12]=1.[C:27](=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>>[CH3:19][C:17]([C:14]1[CH:13]=[CH:12][C:11]([OH:10])=[CH:16][CH:15]=1)([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[CH3:18].[CH3:27][O:9][C:7]1[CH:8]=[CH:2][C:3]([OH:4])=[CH:5][CH:6]=1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: Cc1cc(O)ccc1O
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Product: COc1ccc(O)cc1
Temperature: 180 °C
Reaction time: 0.08 h

Procedure:
To a 1 L glass reaction vessel, methylhydroquinone (1.07 moles, 133.14 g), bisphenol-A (0.03 moles, 6.28 g) and diphenyl carbonate (1.19 moles, 254.50 g) were added. The system was purged and backfilled with nitrogen three times. After heating the system to about 180° C., the system underwent a modified series of the 11 segments described in Table 1 where Segments 7 and 9 were shortened to about 5 minutes and the temperature for Segment 11 was 310° C. After a total of almost 3 hours, the polymer was stranded to give about 124 g and about 132 g each for two batches.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[O:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH:50](O)[CH3:51])[CH2:45][CH2:44]1>>[CH3:51][CH:50]([O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)[CH2:49][N:46]1[CH2:47][CH2:48][O:43][CH2:44][CH2:45]1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CC(O)CN1CCOCC1
Product: COc1cc(C(=O)OC(C)CN2CCOCC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 1-morpholinopropan-2-ol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-methyl-2-morpholin-4-yl-ethyl ester. MS (ES+) m/z calcd. for C38H43Cl2F2N4O5: [(M+H)+]: 743. found: 743.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:5]=1[NH2:6])([O-:3])=[O:2].[Br:14]Br.O>C(O)(=O)C>[Br:14][C:9]1[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([NH2:6])=[C:7]([N+:11]([O-:13])=[O:12])[CH:8]=1
Reactant: Nc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Nc1c([N+](=O)[O-])cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A stirred suspension of 2,6-dinitroaniline (5 g, 27.3 mmol) in glacial acetic acid (50 ml) was treated, dropwise, with bromine (1.5 ml, 30 mmol) and heated at 120° C. for 2 h. After cooling to ambient temperature, the resultant mixture was poured into water (500 ml). The precipitated solid was collected by filtration, washed with water and dried in vacuo to give 4-Bromo-2,6-dinitroaniline as a yellow solid (6.5 g, 91%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=2)[N:5]=1.[CH:21]1([Mg]Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1>[CH:21]1([CH:9]([C:8]2[C:4]([CH2:3][O:2][CH3:1])=[N:5][N:6]([C:11]3[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[CH:13][N:12]=3)[CH:7]=2)[OH:10])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COCc1nn(-c2cc(C(F)(F)F)ccn2)cc1C=O
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: COCc1nn(-c2cc(C(F)(F)F)ccn2)cc1C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30 %

Procedure:
To a solution (10 mL) of 3-(methoxymethyl)-1-[4-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carbaldehyde (0.59 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise under ice-cooling cyclohexylmagnesium bromide (4.0 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (0.23 g, 30%) as a pale-yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=2)[CH:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)#[CH:13]>>[CH3:11][C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:13]#[C:12][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:7][N:6]2[N:8]=1
Reactant: Cc1cc2ncc(Br)cn2n1
Reactant: C#Cc1ccncc1
Product: Cc1cc2ncc(C#Cc3ccncc3)cn2n1

Procedure:
The title compound, light brown solid, MS: m/e=235.1 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and 4-ethynylpyridine.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][N:6](C(OC(C)(C)C)=O)[C@@H:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:4]1)#[N:2].[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>C(Cl)Cl>[F:25][C:24]([F:27])([F:26])[C:22]([OH:28])=[O:23].[F:21][C:17]1[CH:16]=[C:15]([C@@H:5]2[NH:6][CH2:7][C@@H:3]([C:1]#[N:2])[CH2:4]2)[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C#N)C[C@@H]1c1cccc(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#C[C@@H]1CN[C@@H](c2cccc(F)c2)C1

Procedure:
To a solution of (2R,4S)-tert-butyl 4-cyano-2-(3-fluorophenyl)-pyrrolidine-1-carboxylate (I-30) (72 mg, 0.25 mmol) in DCM (0.5 mL) was added TFA (0.5 mL) with stirring. After 1 hour the volatile organics were removed under reduced pressure. The residue was triturated with Et2O and the resulting solids collected and dried under vacuum to give (3S,5R)-5-(3-fluorophenyl)pyrrolidine-3-carbonitrile 2,2,2-trifluoroacetate (I-31), which was used without purification. MS m/z 191.1 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO.[NH3:14]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: N
Solvent: CO
Product: NS(=O)(=O)c1ccc(Br)cc1
Reaction time: 8 h
Yield: 100 %

Procedure:
4-Bromobenzenesulfonyl chloride (1.0 g, 3.9 mmol), methanol/ammonia solution (5 mL, excess), and methanol (5 mL) were mixed together in a 25 mL-single neck flask and stirred overnight under a nitrogen atmosphere. In the morning, the reaction was concentrated under reduced vacuum to yield intermediate title compound (1.13 g, 100%) as a white solid. This material was used without further purification. Ion spray M.S. 235.9 (M*).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH2:12][CH2:13][NH2:14])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH2:12][CH2:13][NH:14][C:23](=[O:24])[O:25][CH2:26][CH3:27])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)Cl
Reactant: COc1cccc2cc(CCN)oc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)NCCc1cc2cccc(OC)c2o1
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.8 %

Procedure:
2-(7-methoxy-1-benzofuran-2-yl)ethanamine (from step 5) (100 mg, 0.523 mmol) was dissolved in THF (4 ml). To this solution triethylamine (0.211 g, 2.09 mmol) and ethyl chloroformate (0.085 g, 0.784 mmol) was added at 0° C. and then stirred at room temperature for 5 h. THF was evaporated and the residue was purified by column chromatography using 100-200 mesh silica gel and eluted in 5% ethyl acetate-petroleum ether to obtain 30 mg of yellow thick liquid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH2:18]([O:20][C:21]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][C:22]=1[NH2:23])[CH3:19].Cl.[OH-].[Na+]>O.C(O)C>[CH2:18]([O:20][C:21]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][C:22]=1[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1)[CH3:19]
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: CCOc1ccc(OCC)c(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1ccc(OCC)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1
Yield: 17.9 %

Procedure:
A mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol), 2,5-diethoxyaniline (52 mg, 0.290 mmol) and 2N HCl (150 μl) in water:ethanol (3:1, 10 ml) was refluxed for 24 h. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10-12. The resulting precipitate was filtered and isolated as a yellow solid (14 mg, 18%). 1H NMR (CDCl3): 9.67 (s, 1H), 8.74-8.71 (m, 2H), 7.93 (s, 1H), 7.64 (s, 1H), 7.43-7.39 (m, 1H), 6.91 (s, 1H), 6.86 (d, J=9.3 Hz, 1H), 6.65 (dd, J=2.7, 8.7 Hz, 1H), 4.13-4.04 (m, 4H), 1.47-1.42 (m, 6H).
Reaction SMILES: BrN1C(=O)CCC1=O.[S-:9][C:10]#[N:11].[K+].[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>CO>[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[S:9][C:10]#[N:11])[NH2:17]
Reactant: N#C[S-]
Reactant: Nc1cccc(F)c1
Agent: O=C1CCC(=O)N1Br
Agent: [K+]
Solvent: CO
Product: N#CSc1ccc(N)cc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-Bromosuccinimide (1.76 g, 9.89 mmol) and potassium thiocyanate (1.75 g, 18.0 mmol) in methanol (30 ml) were stirred for 15 minutes at room temperature. The reaction mixture was cooled to 0° C., and 3-fluoroaniline (1.00 g, 9.0 mmol) was added dropwise. The mixture was stirred at 0° C. for 2 h. Solvent was removed under vacuum, and the residue was washed with dichloromethane. The mixture was filtered to remove succinimide by-product, and the solution was washed with water, brine, and dried (MgSO4). Solvent was removed under vacuum to afford the desired product as a colorless oil. Yield 1.45 g (96%). 1H NMR.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[CH3:11][S:12][CH2:13][CH2:14][NH2:15].C(N(CC)CC)C>C(O)(C)C>[Cl:9][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:15][CH2:14][CH2:13][S:12][CH3:11])[C:7]=1[NH2:8]
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Reactant: CSCCN
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CSCCNc1nc(C)nc(Cl)c1N
Temperature: 25 °C
Yield: 93.3 %

Procedure:
Heat a solution of 4,6-dichloro-2-methyl-pyrimidin-5-amine (46.0 g, 0.258 mol), 2-(methylthio)ethyl amine (40.05 g, 0.439 mol) and triethylamine (53.3 g, 0.517 mol) in isopropanol (500 mL) at 90° C. for 30 h. Cool the reaction mixture to room temperature and concentrate. Dissolve the residue in dichloromethane (2 L) and wash with water (2×500 mL) and brine (500 mL). Dry the organic layer over solid sodium sulfate, filter, and evaporate to afford a brown solid. Purify the residue on a silica gel column eluting with ethyl acetate to give the title compound (56 g). ES/MS (m/z) 233 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH2:11][OH:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][CH2:11][OH:12]
Reactant: OCCBr
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccccc1Br
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
In a nitrogen atmosphere, 2-bromophenol 5.0 g, 2-bromoethanol 5.42 g, and potassium carbonate 12.0 g were added to N,N-dimethylformamide 30 ml, and the mixture was stirred at 100° C. After about 2.5 hours, the reaction mixture was cooled to room temperature and partitioned by adding water and diethyl ether. The organic layer was washed with water and then with brine, dried over magnesium sulfate anhydride and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system), whereby the title compound 5.09 g, 81% was obtained as a colorless oil.