Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].Cl.[F:4][C:5]1[CH:13]=[CH:12][C:11]2[N:10]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]3[CH2:21][CH2:22][NH:23][CH2:24][CH:8]3[C:7]=2[CH:6]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[O:36][CH:35](O)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1.C([BH3-])#N.[Na+]>CO>[F:4][C:5]1[CH:13]=[CH:12][C:11]2[N:10]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[CH:9]3[CH2:21][CH2:22][N:23]([CH2:35][CH2:34][CH2:33][CH:32]([OH:36])[C:29]4[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=4)[CH2:24][CH:8]3[C:7]=2[CH:6]=1
Reactant: OC1CCC(c2ccc(F)cc2)O1
Reactant: Fc1ccc(N2c3ccc(F)cc3C3CNCCC32)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CO
Product: OC(CCCN1CCC2C(C1)c1cc(F)ccc1N2c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56 %

Procedure:
To a solution of 53 mg. (0.95 mmole) of potassium hydroxide in 50 ml. of methanol under a nitrogen atmosphere was added 613 ml. (1.90 mmole) of levorotatory 8-fluoro-5-(p-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole hydrochloride, [α]D =(-)40.9 (methanol) and the mixture stirred until solution was complete. To the solution was added 346 mg. (1.90 mmole) of levorotatory 5-(p-fluorophenyl)2-hydroxytetrahydrofuran (from Example 19, Part B), dissolved in a small volume of methanol and the resulting solution stirred for 15 minutes at room temperature. The solution was cooled to 5° C. and 120 mg. (1.90 mmole) of sodium cyanoborohydride in a small amount of methanol was added over 20 minutes. The reaction mixture was stirred at room temperature for 45 minutes, then 250 mg. of potassium hydroxide was added and stirred until dissolved. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and water. After reextraction of the aqueous phase, the combined organic extracts were dried (MgSO4) and evaporated in vacuo to provide 1.014 g. of oil. This was chromatographed on 30 g. of silica gel as described above to obtain 653 mg. of the desired product as an oil. The oil was converted to the hydrochloride salt, as above, 400 mg., M.P. 252°-257° C. (dec.), [α]D23 =(-)33.7° (methanol) which was found to be 99% pure β-enantiomer by HPLC. Reworking the mother liquors afforded 80 mg. of a second crop, M.P. 254°-258° C. (dec.). Total yield 56%.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33](O)=[O:34])[CH:24]=[CH:25][C:26]=1[CH3:27]>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:23]3[CH:24]=[CH:25][C:26]([CH3:27])=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COc1cc(-c2ocnc2C(=O)O)ccc1C
Reactant: CC1(c2ccc(Cn3cc(N)cn3)s2)OCCO1
Product: COc1cc(-c2ocnc2C(=O)Nc2cnn(Cc3ccc(C(C)=O)s3)c2)ccc1C

Procedure:
Following general procedure X followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-methoxy-4-methyl-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05c: tR=0.75 min; [M+H]+=437.25.
Reaction SMILES: COC1C=C2C(=CC=1)C=C(C1C=CN=CC=1N)C=C2.BrC1C=CC(OCCN2CCCCC2)=C(F)C=1.[F:37][C:38]1[CH:39]=[C:40]([NH:53][C:54]2[CH:55]=[N:56][CH:57]=[CH:58][C:59]=2[C:60]2[CH:69]=[CH:68][C:67]3[C:62](=[CH:63][CH:64]=[C:65]([O:70]C)[CH:66]=3)[CH:61]=2)[CH:41]=[CH:42][C:43]=1[O:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>>[F:37][C:38]1[CH:39]=[C:40]([NH:53][C:54]2[CH:55]=[N:56][CH:57]=[CH:58][C:59]=2[C:60]2[CH:61]=[C:62]3[C:67](=[CH:68][CH:69]=2)[CH:66]=[C:65]([OH:70])[CH:64]=[CH:63]3)[CH:41]=[CH:42][C:43]=1[O:44][CH2:45][CH2:46][N:47]1[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]1
Reactant: COc1ccc2cc(-c3ccncc3Nc3ccc(OCCN4CCCCC4)c(F)c3)ccc2c1
Agent: COc1ccc2cc(-c3ccncc3N)ccc2c1
Agent: Fc1cc(Br)ccc1OCCN1CCCCC1
Product: Oc1ccc2cc(-c3ccncc3Nc3ccc(OCCN4CCCCC4)c(F)c3)ccc2c1
Yield: 74.5 %

Procedure:
Synthesized from 4-(6-methoxynaphthalen-2-yl)pyridin-3-ylamine and 1-[2-(4-bromo-2-fluorophenoxy)ethyl]piperidine according to an analogous synthetic method to Example 116, [3-fluoro-4-(2-piperidin-1-ylethoxy)phenyl][4-(6-methoxynaphthalen-2-yl)pyridin-3-yl]amine (343 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (248 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][CH2:18][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: BrCCCc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCCc2ccc3ccccc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 20.5 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.01 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.262 g), stirred for 15 minutes and treated with 2-(3-bromopropyl)naphthalene (1.7 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was purified by HPLC (dichloromethane-hexane; 4:1) and crystallized from diethyl ether-hexane to provide 0.4 g of 4-[[3-(2-naphthalenyl) propyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 97°-99° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:12][C:6]1[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccccc2)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
8 g of 2-tert-Butyl-4-methyl-phenol (49 mmol) and 16.36 g of potassium carbonate (58 mmol) were stirred in 120 ml DMF until a suspension was formed. 6.74 ml of benzylchloride were then added dropwise and the reaction mixture was stirred for 24 h at RT. After two hours heating at 60° C., the reaction mixture was cooled to RT, filtered off, diluted with ethyl acetate, and washed with water followed by brine. The organic phase was dried over magnesium sulphate, filtered off and concentrated under vacuo. The residue was purified by flash column chromatography (heptane/AcOEt 98/2) to give 8.647 g of a colorless liquid. MS (ISP) 255.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[S:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=[C:11]1[C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[O:1][CH2:42][CH2:41][N:40]([CH3:44])[CH3:39]
Reactant: O=[N+]([O-])c1ccc(-c2nc3ccccc3s2)c(O)c1
Reactant: CN(C)CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCOc1cc([N+](=O)[O-])ccc1-c1nc2ccccc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
To a stirred mixture of 2-(2-hydroxy-4-nitrophenyl)benzothiazole (0.15 g, 0.55 mmol), triphenylphosphine (0.216 g, 0.825 mmol) and N,N-dimethylethanolamine (0.059 g, 0.66 mmol) in dry THF (10 ml) at 0° C. was added dropwise DIAD (0.167 g, 0.825 mmol). The reaction mixture was stirred at 0° C. for 0.5 h, then left to rise to room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (20:1 DCM/MeOH) to give the title compound (0.089 g, 47%) as a yellow solid.
Reaction SMILES: [Br-].[C:2]1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.[CH3:27][O:28][C:29]1[C:30]([N+:37]([O-:39])=[O:38])=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=O.[Cl-].[NH4+]>O1CCCC1>[CH3:27][O:28][C:29]1[CH:36]=[CH:35][CH:34]=[C:31]([CH:32]=[CH2:2])[C:30]=1[N+:37]([O-:39])=[O:38]
Reactant: COc1cccc(C=O)c1[N+](=O)[O-]
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=Cc1cccc(OC)c1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 76.1 %

Procedure:
A suspension of 4.35 g (12.2 mmol) of triphenylmethylphosphonium bromide in 30 ml of tetrahydrofuran was cooled to -10° C. and 12.1 mmol of a 1.44M solution of butyllithium were dropwise added thereto over a period of 5 minutes. After the resulting mixture was stirred at 0° C. for 40 minutes, a solution of 1.99 g (11.0 mmol) of 3-methoxy-2-nitrobenzaldehyde in 10 ml of tetrahydrofuran was dropwise added thereto over a period of 10 minutes. The temperature of the reaction mixture was allowed to rise to room temperature. After stirring for 16 hours, the reaction mixture was poured into an aqueous solution of ammonium chloride followed by extracting with ether. The ethereal extract was washed with a saturated aqueous solution of sodium chloride and the solvent was distilled off. The residue was purified by column chromatography through 100 g of silica gel using a 15-20:100 mixture of ethyl acetate and hexane as an eluent to give 1.50 g (76%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.F[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[CH:27]=[N:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=34)[CH:23]=[CH:22][N:21]=2)=[C:12]([O:35][CH3:36])[CH:11]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[CH:27]=[N:28][N:29]5[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=45)[CH:23]=[CH:22][N:21]=3)=[C:12]([O:35][CH3:36])[CH:11]=2)[CH2:4]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Temperature: 140 °C
Yield: 79.2 %

Procedure:
(3R)—N,N-Dimethylpyrrolidin-3-amine (64 mg, 0.56 mmol), N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 127, 267 mg, 0.53 mmol) and DIPEA (0.186 mL, 1.07 mmol) were suspended in DMA (2 mL), sealed into a microwave tube and then heated to 140° C. for 1 h in a microwave reactor. After cooling to r.t. the mixture was part-purified by ion exchange chromatography, using an SCX column. The column was first washed with CH3OH and then eluted with 0.7M methanolic ammonia. Clean fractions were concentrated in vacuo to give crude material as an orange gum. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (201 mg, 79%) as a orange gum; 1H NMR (CDCl3): 1.89-1.98 (3H, m), 2.05-2.12 (2H, m), 2.16-2.23 (1H, m), 2.30 (6H, s), 2.78-2.87 (1H, m), 3.14-3.37 (5H, m), 3.54 (1H, td), 3.96 (3H, s), 4.20 (2H, t), 6.34 (1H, s), 6.85 (1H, d), 7.33 (1H, s), 7.95 (1H, s), 8.30 (1H, d), 8.95 (1H, s); m/z: ES+ MH+ 479.60.
Reaction SMILES: C([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5](CO)[C:4]=1[OH:13])O.C(O)(=O)C(O)=O.[C:20]1([C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[OH:23])[OH:21]>O>[CH3:10][O:9][C:7]1[CH:8]=[CH:3][C:4]([OH:13])=[CH:5][CH:6]=1.[C:20]1([C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[OH:23])[OH:21]
Reactant: COc1cc(CO)c(O)c(CO)c1
Agent: O=C(O)C(=O)O
Agent: Oc1ccccc1O
Solvent: O
Product: COc1ccc(O)cc1
Temperature: 70 °C

Procedure:
To a 1 liter, 3 necked round bottomed flask equipped with a paddle stirrer, condenser, thermometer and heating source, were added 150 g (0.81 mole) of the 2,6-dimethylol-4-methoxyphenol, followed by 9 g (0.1 moles) of oxalic acid and 180 g (1.63 moles) of catechol. To this were added 400 g of water. The reaction mixture was stirred and heated to 70° C. Solution occurred when the temperature reached approximately 60° C. Then, the reaction mixture was heated to reflux and held at reflux for 4 hours. After 1 hour at reflux, the product began to separate.
Reaction SMILES: C(C1C=CC(OC2C(OC)=NN(CC(O)=O)C=2CC)=CC=1)#N.[C:23]([C:25]1[C:49]([CH3:50])=[CH:48][C:28]([O:29][C:30]2[C:31]([CH:45]3[CH2:47][CH2:46]3)=[N:32][N:33]([C:35]([CH3:44])([CH3:43])[C:36]([O:38]C(C)(C)C)=[O:37])[CH:34]=2)=[CH:27][C:26]=1[CH3:51])#[N:24]>>[C:23]([C:25]1[C:26]([CH3:51])=[CH:27][C:28]([O:29][C:30]2[C:31]([CH:45]3[CH2:47][CH2:46]3)=[N:32][N:33]([C:35]([CH3:44])([CH3:43])[C:36]([OH:38])=[O:37])[CH:34]=2)=[CH:48][C:49]=1[CH3:50])#[N:24]
Reactant: Cc1cc(Oc2cn(C(C)(C)C(=O)OC(C)(C)C)nc2C2CC2)cc(C)c1C#N
Agent: CCc1c(Oc2ccc(C#N)cc2)c(OC)nn1CC(=O)O
Product: Cc1cc(Oc2cn(C(C)(C)C(=O)O)nc2C2CC2)cc(C)c1C#N
Yield: 66 %

Procedure:
The title compound (287 mg, 66%) was prepared by a similar method to that described for the acid of step (b) of Example 80 using the ester of step (a) from above as starting material.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:29]([CH2:30][CH:31]=[CH2:32])[C:28]3[C:27](=[O:33])[NH:26][C:25](=[O:34])[N:24]([CH3:35])[C:23]=3[N:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH2:30]([N:29]1[C:28]2[C:27](=[O:33])[NH:26][C:25](=[O:34])[N:24]([CH3:35])[C:23]=2[N:22]=[C:21]1[N:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1)[CH:31]=[CH2:32]
Reactant: C=CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCn1c(N2CCNCC2)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
Trifluoroacetic acid (294 μl) was added dropwise to a solution of 4-(7-allyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperazine-1-carboxylic acid tert-butyl ester (150 mg) in methylene chloride (2 ml), and the reaction mixture was stirred at room temperature for 1 hour and 30 minutes. The solvent was removed by distillation at reduced pressure from the reaction mixture. The residue was subjected to azeotropic distillation with toluene, and then was purified by silica gel column chromatography to give 85 mg of the title compound from a fraction eluted with methanol-ethyl acetate (1:10).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:7]2=[N:6][C:5]=1[CH3:17].[H][H]>CO.[Pd]>[OH:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH:14]([O:15][CH3:16])[C:7]2=[N:6][C:5]=1[CH3:17]
Reactant: COc1cccn2c(=O)c(CCO)c(C)nc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC1CCCn2c1nc(C)c(CCO)c2=O
Yield: 70.2 %

Procedure:
A mixture of intermediate 10 (14 g) in methanol (250 ml) was hydrogenated at 50° C. with palladium on activated carbon (10%) (2 g) as a catalyst. After uptake of hydrogen (2 eq.), the catalyst was filtered off. The filtrate was evaporated and the residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent was evaporated, yielding 10 g (71%) of (±)-6,7,8,9-tetrahydro-3-(2-hydroxyethyl)-9-methoxy-2-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one (intermediate 11).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH3:12])=[O:10])=[CH:4][C:3]=1I.[CH3:14][Si:15]([C:18]#[C:19][Si](C)(C)C)([CH3:17])[CH3:16].C([O-])(O)=O.[Na+]>CC#N>[CH3:12][NH:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][C:18]([Si:15]([CH3:17])([CH3:16])[CH3:14])=[CH:19]2
Reactant: CNC(=O)Cc1ccc(N)c(I)c1
Reactant: C[Si](C)(C)C#C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CNC(=O)Cc1ccc2[nH]c([Si](C)(C)C)cc2c1
Yield: 38.7 %

Procedure:
4-Amino-3-iodo-N-methyl-benzeneacetamide (7) (7.26 g, 0.025 mol), bis(trimethylsilyl) acetylene (8.52 g, 0.05 mol) and tetrakistriphenylphosphine Pd(O) (2.89 g, 0.0025 mol) were dissolved in CH3CN (400 mL) followed by the addition of saturated aqueous NaHCO3 (30 mL). The mixture was heated at reflux for 24 h. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The organic phase was extracted with brine, dried over MgSO4, filtered and concentrated in vacuo. Silica gel chromatography (50-100% EtOAc gradient in hexane) of the concentrate afforded the product (8) (2.52 g, 38.8%) as a yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[O:9][CH2:8][C:7](=O)[C:6]=2[CH:11]=1>C(O)C.[Pt]=O>[Cl:1][C:2]1[C:3]([N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:11]=1
Reactant: O=C1COc2cc(N3CCCCC3)c(Cl)cc21
Agent: O=[Pt]
Solvent: CCO
Product: Clc1cc2c(cc1N1CCCCC1)OCC2

Procedure:
200 mg of platinum oxide are added to a solution of 1.38 g (5.5 mmole) of 5-chloro-6-(piperidin-1-yl)-benzofuran-3(2H)-one in 20 ml of ethanol and the whole is hydrogenated at 3 atmospheres. The catalyst is filtered off and the filtrate is concentrated in a vacuum rotary evaporator. The residue is chromatographed over silica gel using methylene chloride as eluant. Recrystallisation from petroleum ether yields 5-chloro-6-(piperidin-1-yl)-2,3-dihydrobenzofuran having a melting point of 38°-40°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[Cl:18])C(OC)=O.[Cl-].[Na+].CS(C)=O.O>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[Cl:18]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc([N+](=O)[O-])cc1Cl
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 60.4 %

Procedure:
2-(2-Chloro-4-nitro-phenyl)-malonic acid dimethyl ester (6.0 g, 20.9 mmol) and sodium chloride (2.2 g, 37.6 mmol) were added to a mixture of DMSO (100 mL) and water (0.38 mL, 20.9 mmol) and the reaction mixture was heated for 8 hours at 110° C. The reaction mixture was cooled to RT and poured into water (500 mL). EtOAc (200 mL) was added to the mixture which was then stirred for 15 minutes. The separated aqueous phase was extracted with EtOAc (100 mL). The combined organic extracts were washed with brine (100 mL), dried (Na2SO4) and the solvents removed under reduced pressure. The residue was purified by column chromatography on neutral silica gel using 3-6% EtOAc in hexane to give the title compound (2.9 g, 60%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([NH:11][C:12]2[CH:13]=[N:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=2)[N:5]=[CH:4][N:3]=1.Cl.[CH:23]([C:26]1[N:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[O:28][N:27]=1)([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:23]([C:26]1[N:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([C:2]3[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([NH:11][C:12]4[CH:13]=[N:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=4)[N:5]=[CH:4][N:3]=3)[CH2:33][CH2:32]2)[O:28][N:27]=1)([CH3:25])[CH3:24]
Reactant: CC(=O)c1c(Cl)ncnc1Nc1ccc(S(C)(=O)=O)nc1
Reactant: CC(C)c1noc(C2CCNCC2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1c(Nc2ccc(S(C)(=O)=O)nc2)ncnc1N1CCC(c2nc(C(C)C)no2)CC1
Yield: 30.4 %

Procedure:
To a solution of 1-[4-chloro-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-5-yl]-ethanone (0.21 mmol, 70 mg) and 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine hydrochloride (0.21 mmol, 49 mg) in N,N-dimethyl formamide (500 uL) was added potassium carbonate (0.21 mmol, 29 mg). The mixture was microwaved at 100° C. for 150 seconds. Its progress was monitored by thin layer chromatography and LCMS. The reaction was treated with water and the desired compound was extracted in ethyl acetate. Organic layer was evaporated in vacuo. Purification by HPLC provided Compound B139 as a white solid (31 mg, 31%). 1H-NMR (400 MHz, CDCl3) δ(ppm): 10.9 (s, 1H); 8.90 (d, 1H); 8.58 (d, 1H); 8.32 (s, 1H); 8.05 (d, 1H); 4.09 (m, 2H); 3.41 (m, 2H); 3.29 (h, 1H); 3.23 (s, 3H); 3.09 (h, 1H); 2.48 (s, 3H), 2.18 (m, 2H), 2.02 (m, 2H), 1.35 (d, 6H) LCMS (ESI), m/z 486.3 (M+H+, 100%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[N+:6]=1[O-:12])(=[O:3])[CH3:2].[SH-:13].[Na+].Cl>C(O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([SH:13])[N+:6]=1[O-:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(Br)[n+]1[O-]
Reactant: [SH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1cccc(S)[n+]1[O-]
Yield: 79 %

Procedure:
2 gms (0.0087 mole) of 2-acetamido-6-bromopyridine-1-oxide was suspended in 35 ml (0.035 mole) of 1M aqueous sodium hydrosulfide and 30 ml of ethanol and agitated at 60° C for 5 hours and at room temperature one night. Concentrated hydrochloric acid was added dropwise to the cold yellow solution and the precipitated solid filtered, giving a 79% yield of 2-acetamido-6-mercaptopyridine-1-oxide. This impure product was purified by recrystallization from 2-propanol and hot filtration to remove a small amount of contaminating sulfur to give pale yellow crystals, m.p.=172.8°-173.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([CH2:9][CH:10]1[CH2:19][C:18](=[O:20])[C:17]2[C:12](=[CH:13][C:14]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:15][CH:16]=2)[O:11]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:30])[N:7]([CH2:9][CH:10]1[CH2:19][CH:18]([OH:20])[C:17]2[C:12](=[CH:13][C:14]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:15][CH:16]=2)[O:11]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CC1CC(=O)c2ccc(S(=O)(=O)c3ccccc3)cc2O1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CN(CC1CC(O)c2ccc(S(=O)(=O)c3ccccc3)cc2O1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a solution of (7-benzenesulfonyl-4-oxo-chroman-2-ylmethyl)-methyl-carbamic acid tert-butyl ester (216 mg, 0.5 mmol) in MeOH (40 mL) was added Pd/C (10%, 20 mg) and the mixture was stirred under balloon pressure of H2 overnight. The reaction was filtered through a celite pad and the filtrate was concentrated in vacuo. The residue was purified via flash chromatography (DCM/MeOH, 99/1) to give (7-benzenesulfonyl-4-hydroxy-chroman-2-ylmethyl)-methyl-carbamic acid tert-butyl ester (159 mg, 74% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:12][C:13]([N:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:22][CH:23]=2)[C@H:18]([NH:29]C(OC(C)(C)C)=O)[CH2:17][C@@H:16]1[CH:37]1[CH2:39][CH2:38]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[OH-].[Na+]>ClCCl>[C:8]([O:12][C:13]([N:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([F:27])([F:26])[F:28])=[CH:22][CH:23]=2)[C@H:18]([NH2:29])[CH2:17][C@@H:16]1[CH:37]1[CH2:38][CH2:39]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C2CC2)N(C(=O)OC(C)(C)C)c2ccc(C(F)(F)F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](N)C[C@@H]1C1CC1
Yield: 37.9 %

Procedure:
Trifluoroacetic acid (3.4 g) was added in portions to a solution of cis-4-tert-butoxycarbonylamino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (Example 107B) (3.4 g; 7.4 mmol) in 150 ml dichloromethane, and the reaction was stirred until no starting material was observed by thin-layer chromatography. A small amount of 1N NaOH was added and the reaction mixture was dried (MgSO4), filtered and concentrated. Chromatography on silica gel (50% ethyl acetate:hexane through 5% MeOH:dichloromethane) afforded the title product (1.0 g). 1H NMR (CDCl3) δ 1.5 (s, 9H), 1.7 (m, 1H), 2.5 (m, 1H), 4.1 (q, 1H), 7.6 (m, 3H).