Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[C:17](Cl)=[O:18].[N:20]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[S:22][C:21]=1[C:29]1[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=1[NH2:31].CCN(C(C)C)C(C)C>C(#N)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[C:17]([NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=1[C:21]1[S:22][C:23]2[C:28]([N:20]=1)=[CH:27][CH:26]=[CH:25][N:24]=2)=[O:18]
Reactant: Nc1ccccc1-c1nc2cccnc2s1
Reactant: COCCCc1sc(-c2ccccc2)nc1C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCCCc1sc(-c2ccccc2)nc1C(=O)Nc1ccccc1-c1nc2cccnc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.3 %

Procedure:
5-(3-methoxypropyl)-2-phenylthiazole-4-carbonyl chloride (229 mg, 0.774 mmol) was added to a suspension of 2-(thiazolo[5,4-b]pyridin-2-yl)aniline (141 mg, 0.619 mmol) in acetonitrile (15 mL). DIPEA (162 μL, 0.929 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The resulting ppt was collected by filtration, and rinsed with acetonitrile to give the title compound as a white solid (260 mg, 86% yield). MS Calcd for C26H22N4O2S2: 486.12. Found (M+H)+ m/z=487.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:27][C:26]1[C:21]([NH:20][C:17]([CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:16][CH2:15]2)=[O:19])=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cccnc1N
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cccnc1NC(=O)C1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
The benzyl 4-{[(3-methyl-2-pyridinyl)amino]carbonyl}-1-piperidinecarboxylate was prepared as described in EXAMPLE 1, except that 1-[(benzyloxy)carbonyl]-4-piperidinecarboxylic acid (5.00 g, 18.99 mmol), 2-amino-3-methylpyridine (2.16 g, 19.94 mmol), EDC (4.37 g, 22.79 mmol), and HOAt (2.71 g, 19.94 mmol) and DMF (3 mL) were used as starting materials. Benzyl 4-{[(3-methyl-2-pyridinyl)amino]carbonyl}-1-piperidine was isolated as an off-white solid and used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH2:25].C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH:25][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(O)c1ccccn1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1F)c1ccccn1
Reaction time: 24 h
Yield: 75.7 %

Procedure:
Picolinic acid (10.0 g, 81 mmol) was added to a solution of 1,1'-carbonyldiimidazole (13.13 g, 81 mmol) in dimethylformamide (80 mL) and the reaction mixture was stirred for 1 hour before introduction of 2,4-difluoroaniline (9.06 mL, 89 mmol). After 24 hours, the reaction mixture was poured into saturated sodium bicarbonate solution, extracted into ether, dried, concentrated, and recrystallized using a mixture of ether and petroleum ether to yield N-(2,4-difluorophenyl)-2-pyridine-carboxamide as a white solid (14.37 g, 76.0%) m.p. 90.5°-95° C.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[CH3:34][C:35]1[C:43]2[CH:42]=[C:41]([C:44](=[O:47])[CH2:45][CH3:46])[S:40][C:39]=2[CH:38]=[CH:37][CH:36]=1>O1CCCC1>[Br:1][CH:45]([CH3:46])[C:44]([C:41]1[S:40][C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:34])[C:43]=2[CH:42]=1)=[O:47]
Reactant: CCC(=O)c1cc2c(C)cccc2s1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: Cc1cccc2sc(C(=O)C(C)Br)cc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 46.7 %

Procedure:
Phenyltrimethylammonium tribromide (1.47 g) was added in portions under nitrogen at 0° C. over 10 minutes to a stirred solution of 1-(4-methylbenzo[b]thiophen-2-yl)propan-1-one (0.53 g) in tetrahydrofuran (15 ml), then the mixture was stirred at 0° C. for 3 hours and at ambient temperature for 16 hours. Further phenyltrimethylammonium tribromide (0.49 g) was added, then the mixture was stirred at ambient temperature for 26 hours and filtered. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica using a 4:1 mixture of petroleum ether (b.p. 60-80° C.) and dichloromethane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 2-bromo-1-(4-methylbenzo[b]thiophen-2-yl)propan-1-one (0.3 g) as a yellow solid which was used without further purification.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:12](=O)([O-:14])[O-:13].[K+].[K+].C(=O)=O>O.CC(C)=O>[OH:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:12]([OH:14])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc2c1CCCC2
Agent: O=C=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1ccc2c(c1O)CCCC2
Temperature: 145 °C
Yield: 90 %

Procedure:
A mixture of 5,6,7,8-tetrahydro-1-naphthol (7.42 g, 50 mmol) and potassium carbonate (25.5 g, 185 mmol) were placed in a glass tube inside a stainless steel pressure reactor. The reactor was charged with CO2 at 40 bar and then heated to 145° C. The pressure rose to 60 bar and then slowly dropped to 20 bar over the 3 day reaction period. The bomb was cooled and the solid product was taken up in water (˜500 ml) and acetone (˜500 ml). The mixture was evaporated in vacuo to remove the acetone and then washed with DCM (3×150 ml). The aqueous was acidified with 2M hydrochloric acid to give a white suspension. This was extracted with DCM (4×250 ml), which was then dried over sodium sulphate and evaporated in vacuo to give the crude product. This was recrystallised from aqueous ethanol and dried under high vacuum to provide 8.64 g (45 mmol, 90% yield) of the title compound as a pale brown powder. 1H NMR (200 MHz., d6-DMSO) δ 1.81 (4H, m); 2.67 (2H, m); 2.81 (2H, m); 6.73 (1H, d); 7.61 (1H, d); 11.78 (1H, bs). EIMS m/z=192 (M+); 174; 146
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([Cl:20])[N:12]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([Cl:20])[N:12]=2)=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Cl)nc1NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.3 %

Procedure:
4-Chlorobenzylamine (7.3 mL, 60 mmol) was added dropwise to a stirred, cooled (˜0° C.), solution of 2,6-dichloro-3-nitropyridine (10.1 g, 52.2 mmol) and K2CO3 (7.93 g, 57.4 mmol) in MeCN (60 mL). After stirring for 5 hours at ambient temperature, the mixture was concentrated in vacuo and then partitioned between EtOAc and water. The EtOAc layer was then washed successively with aqueous potassium hydrogen sulfate solution, brine and then dried (MgSO4). The solution was evaporated in vacuo to give a yellow solid which was recrystallised from heptane/EtOAc (1:2) to give (4-chloro-benzyl)-(6-chloro-3-nitro-pyridin-2-yl)-amine as a yellow solid (7.67 g). The mother liquor was evaporated and the residue recrystallised from EtOH to give a second crop of product (3.39 g). MS: [M+H]+=298
Reaction SMILES: [Na].C(O[C:5](=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[C:12]([C:16](C)=[O:17])([CH3:15])([CH3:14])[CH3:13]>C(O)C>[CH2:9]([O:8][C:6](=[O:7])[CH2:5][C:16](=[O:17])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)C(C)(C)C
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC(=O)C(C)(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 106.5 %

Procedure:
Sodium pellets (4.6 g, 200 mmol) were dissolved in ethanol (165 ml) under nitrogen at room temperature and a solution of diethyloxalate (27.2 ml, 200 mmol) in tert-butyl-methyl ketone (20.1 g, 200 mmol) was added dropwise at room temperature over 15 minutes. The reaction was diluted with ethanol (100 ml), heated to 60° C. and stirred at this temperature for 2 hours. After cooling to room temperature the reaction was stirred for 64 hours, poured onto ice-cold 2N HCl (200 ml) and extracted with diethylether (3×200 ml). The combined organic extracts were washed with water, dried over MgSO4 and concentrated under reduced pressure to give 4,4-dimethyl-3-oxo-pentanoic acid ethyl ester (36.7 g) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ=6.48 (1H, s), 4.26-4.37 (2H, quart), 1.29-1.38 (3H, t), 1.17 (9H, s) ppm. LRMS (electrospray): m/z [M+Na]+ 223, [M−H]+ 199.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[CH2:3][NH:2]1.[N+:19]([O-:22])([OH:21])=[O:20].CC1([C:30]([NH2:32])=[NH:31])C=C(C)N=N1>C(O)C>[N+:19]([O-:22])([OH:21])=[O:20].[C:30]([N:2]1[CH2:3][C:4]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)(=[NH:31])[NH2:32]
Reactant: CC1=CC(C)(C(=N)N)N=N1
Reactant: c1ccc2c(c1)CC1(CNCc3ccccc31)O2
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: N=C(N)N1Cc2ccccc2C2(Cc3ccccc3O2)C1
Yield: 42.9 %

Procedure:
A solution of spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (4.2 g), 3,5-dimethylpyrazole carboxamidine nitrate (3.6 g) in 95% ethanol (80 ml) is heated under reflux for 7 hours. The mixture is evaporated to dryness in vacuo and the viscous residue is triturated with ether. After filtration, the precipitate is twice recrystallized from ethyl acetate/methanol to yield product (2.6 g, 42%) as a solid, mp 188°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][CH2:8][CH2:7]2.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][C:26](Cl)=[O:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].C(=O)(O)[O-].[K+]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][C:26]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][C:12]=2[O:13][CH3:14])[CH2:9][CH2:8][CH2:7]3)=[O:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: COc1cc2c(cc1CCN)CCC2
Agent: O=C([O-])O
Agent: [K+]
Product: COc1cc2c(cc1CCNC(=O)Cc1ccc(OC)c(OC)c1)CCC2

Procedure:
5-Aminoethyl-6-methoxyindan and 3,4-dimethoxyphenylacetyl chloride were reacted following the procedure of Example 1, except that potassium bicarbonate was used in place of triethylamine, to produce the desired product. After recrystallization from ethanol it melted at 115° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]([C:25]3[CH:26]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=4[Cl:44])[C:27]([C:33]([O:35][CH3:36])=[O:34])=[C:28]([CH3:32])[NH:29][C:30]=3[CH3:31])=[O:24])[CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H].C>C(O)C.[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]([C:25]3[CH:26]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=4[Cl:44])[C:27]([C:33]([O:35][CH3:36])=[O:34])=[C:28]([CH3:32])[NH:29][C:30]=3[CH3:31])=[O:24])[CH:11]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCOc2cc(-c3ccc([N+](=O)[O-])cc3)[nH]n2)C1c1cccc(Cl)c1Cl
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCOc2cc(-c3ccc(N)cc3)[nH]n2)C1c1cccc(Cl)c1Cl
Yield: 54 %

Procedure:
12.86 g (20 mmole) of 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5-p-nitrophenyl-3-pyrazolyloxy)hexyl ester (Example 60) was dissolved in 100 ml of ethanol, to which was added 5 ml of Raney nickel, and catalytic hydrogenation was effected at room temperature and atmospheric pressure, thereby 1350 ml (60 mmole) of hydrogen was absorbed. The Raney nickel was filtered off from the reaction mixture, and the filtrate was concentrated under reduced pressure to obtain a pale yellow oily residue. This residue was purified by chromatography on a silica gel column using a mixed solution of chloroform-methanol (the ratio by volume of 3:1) as an eluent, and the fractions containing the intended compound were concentrated under reduced pressure to obtain a pale yellow oily residue. This residue was dissolved in ethyl acetate, and after adding 5 g of activated charcoal, stirred well, and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain 6.63 g (yield 54.0%) of the 1,4-dihydro-2,6-dimethyl-4 -(2,3-dichlorophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5-p-aminophenyl-3-pyrazolyloxy)hexyl ester as a pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[C:17]([O:24][CH3:25])=[CH:16][C:3]=1[CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8]([NH2:15])=[N:9][C:10]=2[Cl:14].OS(O)(=O)=O.[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[Br:1][C:2]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[C:17]([O:24][CH3:25])=[CH:16][C:3]=1[CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8]([NH:15][C:31](=[O:33])[CH3:32])=[N:9][C:10]=2[Cl:14]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(Cn2cnc3c(Cl)nc(N)nc32)c(Br)c(OC)c1OC
Agent: O=S(=O)(O)O
Product: COc1cc(Cn2cnc3c(Cl)nc(NC(C)=O)nc32)c(Br)c(OC)c1OC

Procedure:
A suspension of 9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purin-2-ylamine (example 51) in acetic anhydride was treated with a catalytic amount of conc. H2SO4 at r.t. for 3 h. Work-up and purification by preparative TLC (EtOAc:hexane 9:1) gave the title compound. HPLC Rt: 5.603 min. 1H-NMR (CDCl3): δ 8.20 (s, 1H), 8.10 (s, 1H), 7.00 (s, 1H), 5.47 (s, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.86 (s, 3H), 2.51 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:18])[S:9][C:10]=1[NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:5])C.[OH-].[K+]>CO.O>[CH3:18][C:8]1[S:9][C:10]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1
Reactant: CCOC(=O)c1nc(C)sc1Nc1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc(C(=O)O)c(Nc2cccnc2)s1
Temperature: 55 °C
Reaction time: 0.67 h
Yield: 70.8 %

Procedure:
A solution of 2-methyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester (0.24 g, 0.90 mmol) in methanol (1.6 ml) was treated with a 2.55 N solution of KOH in water (1.06 ml). The mixture was stirred at 55° C. for 40 min then cooled to room temperature. The volatiles were evaporated and the residue dissolved in water (2.00 ml) and treated with HCl 1N under vigorous stirring until pH 5 was reached. The mixture was stirred for 1 h, then the solids were filtered, washed with water and dried under high vacuum to yield 2-methyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid (0.15 g, 70%) as a light yellow solid, MS (ISP): m/e=234.1 (M−H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[F:25][C:26]1([F:38])[O:30][C:29]2[CH:31]=[CH:32][C:33](B(O)O)=[CH:34][C:28]=2[O:27]1.O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[F:38][C:26]1([F:25])[O:27][C:28]2[CH:34]=[CH:33][C:32]([C:2]3[N:7]4[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]4[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=4)[CH:3]=3)=[CH:31][C:29]=2[O:30]1
Reactant: OB(O)c1ccc2c(c1)OC(F)(F)O2
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc4c(c3)OC(F)(F)O4)n2n1
Temperature: 110 °C
Yield: 38.7 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 60 mg, 0.174 mmol), 2,2-difluorobenzo[d][1,3]dioxol-5-ylboronic acid (46 mg, 0.226 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 13.6 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.58 mL of 1,4-dioxane and 0.29 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (60-75% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (31.4 mg, 39%). 1H NMR (DMSO-d6) δ: 11.21 (s, 1H), 8.62 (d, J=1.3 Hz, 1H), 8.26 (d, J=8.6 Hz, 1H), 8.05 (s, 1H), 7.99-8.04 (m, 3H), 7.93 (d, J=5.3 Hz, 1H), 7.67 (d, J=5.6 Hz, 1H), 7.61 (d, J=8.6 Hz, 2H), 6.41 (s, 1H), 5.20 (s, 1H), 2.41 (s, 3H), 1.46 (s, 6H); ESI-MS: m/z 467.2 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([CH3:18])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([O:22][CH2:23][CH2:24][Li])(=[O:21])[CH3:20]>>[CH2:23]([O:22][C:19](=[O:21])[CH2:20][CH:16]([OH:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:18])[CH3:24]
Reactant: CC(CCCCCCCCC=O)c1ccccc1
Reactant: [Li]CCOC(C)=O
Product: CCOC(=O)CC(O)CCCCCCCCC(C)c1ccccc1
Yield: 70 %

Procedure:
When 78 g (0.317 mole) of 10-phenylundecanal was treated with lithioethyl acetate according to the procedure for the preparation of 3(R=CH3, m=12) 73.8 g (70% yield) of 3-hydroxy-12-phenyltridecanoic acid ethyl ester was obtained; δ (CDCl3) 1.28 (m, CH2), 2.1-2.6 (m, phenyl CH, CH2CO), 3.98-4.33 (CHOH, OCH2) and 7.20-7.22 (m, phenyl). This compound could be used without further purification.
Reaction SMILES: [Cl:1]C(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:35][Si:36]([CH3:49])([CH3:48])[NH:37][S:38]([C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)(=O)=[O:39]>>[CH3:35][Si:36]([CH3:49])([CH3:48])[N:37]=[S:38]([Cl:1])([C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)=[O:39]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: C[Si](C)(C)NS(=O)(=O)c1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N=S(=O)(Cl)c1ccc(F)cc1

Procedure:
The reactants used in the general procedure were hexachloroethane (0.0953 mol, 23.02 g), triphenylphosphine (0.0963 mol, 25.51 g), triethylamine (0.0991 mol, 12.5 ml), and a mixture of N-mono- and N,N-bis(trimethylsilyl)sulfonamides (3c) and (5c) containing about 89.5% monosilylsulfonamide (3c) (0.0881 mol, 21.76 g).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][C:15]2[NH:14][C:13]3[C:18](=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][CH2:20][C:12]=3[C:11]=2[CH:10]=1)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:17]=[CH:16][C:15]2[NH:14][C:13]3[CH:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][CH2:20][C:12]=3[C:11]=2[CH:10]=1
Reactant: CCOC(=O)C=C1CCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Temperature: 60 °C
Yield: 69.6 %

Procedure:
To a 200 liter Hastelloy reactor was added ethyl 2-(7-(benzyloxy)-1,2-dihydrocyclopenta[b]indol-3(4H)-ylidene)acetate (E/Z mixture, 12 kg), 10% Pd/C (50% wet with H2O; 1.80 kg) and ethyl acetate (108 kg). The suspension was degassed 3× with N2 and triethylamine (1.76 kg) was added. To the resulting mixture was added formic acid (3.34 kg) while maintaining the internal temperature at below 35° C. The reaction progression was followed by HPLC to monitor the complete consumption of starting material (i.e., E/Z mixture of ethyl 2-(7-(benzyloxy)-1,2-dihydrocyclopenta[b]indol-3(4H)-ylidene)acetate) and the debenzylated intermediate. After approximately 30 minutes an additional amount of formic acid (0.50 kg) was added and the combined peak area of ethyl 2-(7-(benzyloxy)-1,2-dihydrocyclopenta[b]indol-3(4H)-ylidene)acetate and the related debenzylated intermediate was determined to be <1% area by HPLC. The reactor contents were filtered through a 1.2 μm cartridge filter followed by an in-line 0.2 μm inline polishing filter. To the filtrate was added water (60 kg) and the biphasic mixture was partitioned. The organics were separated and concentrated under vacuum at approximately 60° C.±5° C. to a minimum stir volume, ethyl acetate (21.6 kg) was added and the mixture was further concentrated under vacuum to a minimum stir volume. Once again ethyl acetate (16.8 kg) was charged to the crude mixture and the resulting solution was heated to approximately 60° C. Heptanes (37.2 kg) were charged maintaining the internal temperature at 60° C. The solution was slowly cooled to approximately 0 to 5° C. and approximately 2-3 hr to facilitate crystallization. The slurry was filtered, the filter cake was reslurried in heptanes (27.12 kg) and ethyl acetate (7.08 kg). The resulting suspension was filtered and the solids dried under vacuum at approximately 40±5° C. (until the loss on drying (LOD) is <1%) to afford the title compound (6.23 kg, 70.3% yield) as a solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1>CN1CCCC1=O.C(OCC)(=O)C>[F:27][C:26]([F:28])([F:29])[C:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]2=[O:1])=[CH:20][CH:21]=1)([OH:34])[C:30]([F:31])([F:33])[F:32]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)C(=O)C1
Reaction time: 14 h
Yield: 31.6 %

Procedure:
To a stirring solution of tert-butyl 3-oxopiperazine-1-carboxylate (9.99 mmol, 2 g) in dry N-methyl-2-pyrrolidinone (2 mL) was added sodium hydride (30.0 mmol, 1.198 g). The mixture was stirred at room temperature under nitrogen for 20 min before the addition of 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (10.99 mmol, 3.70 g). The mixture was stirred for a further 14 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (4×75 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate concentrated. The resulting residue was purified by column chromatography on silica gel (eluting with dichloromethane—3.5% methanol/96.5% dichloromethane gradient) to afford the title compound (1.44 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][CH3:21])=[S:19])=[CH:13][CH:12]=3)[N:10]=[C:4]2[CH:3]=1.[Br:22]Br>C(Cl)(Cl)Cl>[Br:22][C:8]1[N:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]2=[N:10][C:9]=1[C:11]1[CH:12]=[CH:13][C:14]2[N:17]=[C:18]([NH:20][CH3:21])[S:19][C:15]=2[CH:16]=1
Reactant: CNC(=S)Nc1ccc(-c2cn3ccc(C)cc3n2)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CNc1nc2ccc(-c3nc4cc(C)ccn4c3Br)cc2s1
Temperature: 82.5 °C
Yield: 15 %

Procedure:
To a solution of 7-methyl-2-[4-(3-methylthioureido)phenyl]imidazo[1,2-a]pyridine (9.0 g) in chloroform (300 ml) was added portionwise bromine (11.5 g) at ambient temperature and the mixture was refluxed for 6 hours under stirring. The reaction mixture was evaporated in vacuo. To the residue was added 5% hydrochloric acid (300 ml) and the mixture was heated at 80 to 85° C. for 5 hours. The reaction mixture was filtered and the filtrate was adjusted to pH 7.5 with 20% potassium carbonate. From the resultant aqueous solution the product was extracted with a mixture of ethyl acetate and tetrahydrofuran. The organic extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to column chromatography on silica gel eluting with a mixture of ethyl acetate and tetrahydrofuran (8:2) and the fraction containing the desired compound was evaporated in vacuo to give 6-(3-bromo-7-methyl imidazo[1,2-a]pyridin-2-yl)- 2-methylaminobenzothiazole (1.7 g). mp. 225° C. (dec.).