Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[Cl:19][C:20]1[CH:36]=[CH:35][C:23]([CH2:24][N:25]2[C@H:29]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:33])[NH:27][C:26]2=[O:34])=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][N:25]2[C@H:29]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:33])[N:27]([CH2:2][C:3]3[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]4[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=4[CH:4]=3)[C:26]2=[O:34])=[CH:35][CH:36]=1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Reactant: CC(C)[C@@H]1C(=O)NC(=O)N1Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[C@@H]1C(=O)N(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)C(=O)N1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.1 %

Procedure:
To a solution of 0.5 g (1.63 mmoles) of 6-bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in DMF (5 ml) are added 0.653 g of (2.45 mmoles) of (R)-1-(4-chloro-benzyl)-5-isopropyl-imidazolidine-2,4-dione and 0.293 g (2.12 mmoles) of K2CO3 at ambient temperature under N2 atmosphere. The mixture is stirred at ambient temperature for 15 hours. The mixture is diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated. The crude product is purified by silica gel column chromatography to give 0.644 g of desired 6-[(R)-3-(4-chloro-benzyl)-4-isopropyl-2,5-dioxo-imidazolidin-1-ylmethyl]-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 78% yield.
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][C:6]([OH:8])=[O:7])[CH3:3].C(N(CC)CC)C.[N+:16]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Cl)([O-:18])=[O:17]>C(O)C>[N+:16]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][CH2:3][CH2:2][NH:4][CH2:5][C:6]([OH:8])=[O:7])([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccccc1CCl
Reactant: CCNCC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(O)CNCCCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a suspension of 55.9 g. (4.0 × 10-1 moles) of ethyl glycine hydrochloride in 300 ml. of absolute ethyl alcohol was slowly added (~5 minutes) under a nitrogen atmosphere a solution of 70 ml. (5.0 × 10-1 moles) of triethylamine in 200 ml. of absolute ethyl alcohol. The mixture was heated to reflux and a solution of 17.2 g. (1.0 × 10-1 moles)o-nitrobenzylchloride in 200 ml. of absolute ethyl alcohol was added over a 1.5 hour period. Upon complete addition, the mixture was allowed to reflux for 18 hours, cooled to room temperature and the solvent removed in vacuo. To the solid residue was added 500 ml. of water and enough 10% hydrochloric acid to make the solution acidic (pH~3). The acidic solution was washed with methylene chloride (2 × 150 ml.), made neutral (pH~7) by the addition of saturated sodium bicarbonate and the insoluble oil extracted with methylene chloride (2 × 250 ml). The methylene chloride extracts were combined, washed with water (250 ml.), dried (K2CO3) and the solvent removed in vacuo resulting in a yellow oil. Owing to the instability of the oil toward distillation, the compound was used as such in subsequent reaction.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([OH:14])[CH:12]=[CH2:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19]>>[CH2:19]([O:14][CH:11]([CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH:12]=[CH2:13])[CH:18]=[CH2:17]
Reactant: C=CC(O)C1CCC2(CC1)OCCO2
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Product: C=CCOC(C=C)C1CCC2(CC1)OCCO2
Reaction time: 1 h

Procedure:
A solution of 1-(1,4-dioxaspiro[4.5]decan-8-yl)prop-2-en-1-ol (414 mg, 2.09 mmol), prepared in the previous step, was added to a suspension of sodium hydride (104 mg, 4.12 mmol, 95%) dropwise at 0° C. under argon. After the complete addition, the reaction mixture was allowed to reach room temperature and stirred for 1 hour. Allyl bromide (0.35 mL, 4.05 mmol) was added dropwise and the mixture stirred overnight at room temperature. It was poured onto ice cooled saturated NaHCO3 solution. After extraction with ether, the organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, DCM) to afford the product.
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:11][C:10]=1[F:28])=O)(C)(C)C.CS(C1[N:38]=[C:37]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[CH2:47][C:48]([O:50][CH3:51])=[O:49])[C:36]([C:52]([F:55])([F:54])[F:53])=[CH:35][N:34]=1)(=O)=O.C(O)(C(F)(F)F)=O>FC(F)(F)CO>[F:28][C:10]1[CH:11]=[C:12]([CH:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[CH:13]=[CH:14][C:9]=1[NH:8][C:6]1[N:38]=[C:37]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[CH2:47][C:48]([O:50][CH3:51])=[O:49])[C:36]([C:52]([F:53])([F:54])[F:55])=[CH:35][N:34]=1
Reactant: COC(=O)Cc1ccccc1CCc1nc(S(C)(=O)=O)ncc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: OCC(F)(F)F
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2F)ncc1C(F)(F)F
Temperature: 100 °C

Procedure:
To a mixture of tert-butyl 4-(4-((tert-butoxycarbonyl)amino)-3-fluorophenyl)piperidine-1-carboxylate (I57) (0.376 g, 0.954 mmol) and methyl 2-(2-(2-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I15) (0.268 g, 0.667 mmol) in 2,2,2-trifluoroethanol (15 mL) was added TFA (0.8 mL). The resulting mixture was heated under microwave irradiation at 100° C. for 20 minutes then 15 minutes then concentrated under reduced pressure to give a crude sample of the title compound (I58) (0.344 g) which was used without purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C(O)C>[N+:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH:11]=[CH:10]2)([O-:14])=[O:13]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Solvent: CCO
Product: O=[N+]([O-])c1ccc2nc(N3CCCCC3)ccc2c1
Temperature: 25 °C

Procedure:
The product (208 mg, 1.0 mmol) from Step B and piperidine (0.5 mL, 5 mmol) were mixed in absolute ethanol (3 mL) and then heated at reflux for 4 h. The reaction mixture was cooled to r.t., and the solvent removed under vacuum. The solids were taken up in EtOAc (125 mL). The mixture was transferred to a separatory funnel and washed with water (3×15 mL). The organic layer was dried over sodium sulfate, filtered and the solvent removed under vacuum to afford the product as a yellow solid, MS: m/z 258 (MH+) which was used without further purification.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([NH2:51])[CH2:48][CH:49]=[CH2:50]>>[CH2:47]([NH:51][C:41](=[O:43])[CH2:40][CH:37]1[CH2:38][CH2:39][N:34]([C:32]([N:12]2[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][C:7]=2[O:44][CH2:45][CH3:46])=[O:33])[CH2:35][CH2:36]1)[CH2:48][CH:49]=[CH2:50]
Reactant: C=CCCN
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: C=CCCNC(=O)CC1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with n-but-3-enylamine (Alfa) to give the title compound. LC-MS (ES+) 718 [(M+H)+].
Reaction SMILES: C(N(CC)CC)C.C(O[C:12](=[O:14])[CH3:13])(=O)C.[NH:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]3[CH:29]=[N:30][N:31]4[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][C:32]=34)[N:23]=2)[CH2:16]1>CN(C)C1C=CN=CC=1.ClCCl>[C:12]([N:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]3[CH:29]=[N:30][N:31]4[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][C:32]=34)[N:23]=2)[CH2:16]1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccn2ncc(-c3nccc(N[C@@H]4CCCNC4)n3)c2c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC[C@@H](Nc2ccnc(-c3cnn4ccc(C#N)cc34)n2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 46.1 %

Procedure:
Triethylamine (44 μL, 0.32 mmol), acetic anhydride (8.2 μL, 0.09 mmol) and N,N-dimethylpyridin-4-amine (1.2 mg, 0.01 mmol) were added to a stirred solution of 3-{4-[(3R)-piperidin-3-ylamino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine-5-carbonitrile (Preparation 7b, 40 mg, 0.06 mmol) in dichloromethane (1.5 mL) and the mixture was stirred at ambient temperature for 20 hours before being partitioned between dichloromethane and 4% aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (100:1 to 20:1 chloroform/methanol) to give the title compound (10 mg, 44%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7](=[O:12])[NH:8][CH:9]=[CH:10][O:11][C:5]=2[CH:4]=1.[H-].[Na+].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>CN(C)C=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:8]1[C:7](=[O:12])[C:6]2[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:11][CH:10]=[CH:9]1
Reactant: COc1ccc2c(c1)OC=CNC2=O
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC=CN(CCCCCBr)C2=O
Reaction time: 0.5 h

Procedure:
350 mg of 4,5-dihydro-8-methoxy1,4-benzoxazepin-5-one was dissolved in 5 ml of dimethylformamide, then 88 mg (1.2 equivalents) of 60% sodium hydride was added. This was agitated for 30 minutes, then 0.60 ml (2.4 equivalents) of 1,5-dibromopentane was added and the resultant mixture was agitated at room temperature for 6 hours.
Reaction SMILES: [C:1]1([NH:7]/[N:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:15]([O:22][CH2:23][C@@H:24]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][N:25]1[C:34]([C:36]1[CH:37]=[C:38]([CH:46]=[CH:47][C:48]=1[CH:49]=[C:50]([N+]([O-])=O)[CH2:51][CH2:52][CH2:53][CH3:54])[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:35])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[C:42]([O:41][C:39]([C:38]1[CH:46]=[CH:47][C:48]([C:49]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:50]=2[CH2:51][CH2:52][CH2:53][CH3:54])=[C:36]([C:34]([N:25]2[C@H:24]([CH2:23][O:22][Si:15]([C:18]([CH3:19])([CH3:21])[CH3:20])([CH3:16])[CH3:17])[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:35])[CH:37]=1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CCOC(=O)/C=N/Nc1ccccc1
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1Cc2ccccc2C[C@H]1CO[Si](C)(C)C(C)(C)C)[N+](=O)[O-]
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)c(C(=O)OCC)nn1-c1ccccc1
Yield: 64.6 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 223E, (E)-ethyl 2-(2-phenylhydrazono)acetate (133 mg, 0.690 mmol) and of (S)-tert-butyl 3-(3-((tert-butyldimethylsilyloxy)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-(2-nitrohex-1-enyl)benzoate (420 mg, 0.690 mmol) were converted to the title compound (335 mg, 65%). 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.15-8.06 (m, 2H), 7.51-7.39 (m, 5H), 7.22-6.80 (m, 5H), 5.02-4.98 (m, 1H), 4.39-4.04 (m, 3H), 3.82-3.28 (m, 2H), 3.04-3.00 (m, 1H), 2.90-2.78 (m, 1H), 2.61-2.24 (m, 2H), 1.61 (s, 9H), 1.32-0.90 (m, 7H), 0.77 (s, 9H), 0.59 (t, J=8 Hz, 1.5H), 0.55 (t, J=8 Hz, 1.5H), 0.00 (s, 9H); MS(ESI+) m/z 752.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH3:23][N:24]([CH3:45])[C:25]([CH:27]1[CH2:31][C:30]2[CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=[CH:35][C:29]=2[O:28]1)=[O:26].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:33]3[CH:34]=[CH:35][C:29]4[O:28][CH:27]([C:25]([N:24]([CH3:23])[CH3:45])=[O:26])[CH2:31][C:30]=4[CH:32]=3)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Reactant: CN(C)C(=O)C1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CC(C(=O)N(C)C)O5)n[nH]c3n2)c1F
Temperature: 115 °C
Reaction time: 5 h

Procedure:
A mixture of 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (16.7 mg, 0.0400 mmol), N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-carboxamide (19.0 mg, 0.0600 mmol) (Example 1, Step 2), tetrakis(triphenylphosphine)palladium(0) (2.77 mg, 0.00240 mmol) and sodium carbonate (12.7 mg, 0.120 mmol) in 1,4-dioxane (0.42 mL) and water (0.14 mL) in a reaction vial was sealed, and degassed and recharged with nitrogen for three times. The mixture was stirred at 115° C. for 5 h. After cooling, the mixture was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+=482.0.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:43])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38][N:37]=2)[CH:31]=1)=O)(C)(C)C>>[CH3:42][C:40]1[N:39]=[CH:38][N:37]=[C:36]([C:32]2[CH:31]=[C:30]([C:28]3[CH2:27][C:26](=[O:43])[NH:19][C:9]4[CH:10]=[C:11]([N:14]5[CH:18]=[CH:17][CH:16]=[CH:15]5)[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[CH:41]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Product: Cc1cc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)ncn1

Procedure:
The title compound was prepared from (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert-butyl ester (Example J11) (137 mg, 0.5 mmol) and 3-[3-(6-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K41) (172 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (40 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1.[CH3:22]C(O)C>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14][CH:15]([CH3:22])[CH3:16])=[O:13])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)O
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Product: CC(C)OC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Yield: 10 %

Procedure:
Ethyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate (100 mg, 0.32 mmol) was added to propan-2-ol (1.0 ml, excess) and the reaction mixture was heated at 100 deg C for 14 h. After completion of the reaction (monitored by LCMS) reaction mixture was concentrated and basified with aqueous saturated sodium bicarbonate, extracted with ethyl acetate. The organic layer was concentrated to dryness and the crude obtained was purified by silica gel chromatography (Eluent: 10% MeOH in dichloromethane) to get 10 mg (yield: 10%) of isopropyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate. The free base product (10 mg, 0.03 mmol) was dissolved in THF (1.0 ml), oxalic acid (4 mg, 0.03 mmol) in THF (1.0 ml) was added slowly, the mixture was stirred at RT for 20 minutes and the solid obtained was filtered, washed with ether and dried to get 10 mg (yield: 83%) of isopropyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate as oxalate salt. 1H NMR (DMSO) OXALATE SALT 7.60 (s, 1H), 7.50 (d, 1H), 7.20 (d, 1H), 5.1 (s, 2H), 4.90 (m, 1H), 4.50 (m, 1H), 4.20 (m, 1H), 3.5 (m, 2H), 3.10 (bs, 2H), 3.0 (s, 3H), 1.10 (d, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.Cl[CH:11]([F:13])[F:12]>CC(O)C.[OH-].[K+].O>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH:11]([F:13])[F:12])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: FC(F)Cl
Reactant: Oc1cc(Br)cc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: FC(F)Oc1cc(Br)cc(Br)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a tared, sealed 350 mL round-bottomed pressure flask containing a solution of 3,5-dibromophenol (10.0 g, 39.7 mmol; see Example 27(ii) above) in 2-propanol (100 mL) and 30% KOH (80 mL) at −78° C. was added chlorodifluoromethane via bubbling for 15 min through the septum. The septum was replaced with a Teflon stopper and the flask was then sealed and allowed to warm to room temperature where the flask was weighed and determined to contain 12.0 g (138 mmol) of chlorodifluoromethane. The solution was refluxed overnight in an oil bath set at 80° C. The flask was cooled to room temperature, the pressure cautiously released and the contents diluted with H2O (200 mL). The aqueous layer was extracted with CHCl3 (2× 150 mL), then the combined organics were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by Kugelrohr distillation at 80° C. at 0.2 mm Hg to afford the sub-title compound (9.6 g, 80%) as clear liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[S:16][C:17]([CH2:20]Cl)=[CH:18][N:19]=2)([F:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:14])([C:15]2[S:16][C:17]([CH2:20][O:32][C:29]3[CH:28]=[CH:27][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:31][CH:30]=3)=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2ncc(CCl)s2)CC1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ncc(COc3ccc(S(C)(=O)=O)cc3)s2)CC1

Procedure:
A mixture of 4-(5-Chloromethyl-thiazol-2-yl)-4-fluoro-piperidine-1-carboxylic acid tert-butyl ester (1.42 g, 4.24 mmol), 4-methanesulfonyl-phenol (731 mg, 1.0 eq.) and K2CO3 (878 mg, 1.5 eq.) in acetone (30 mL) was heated to reflux overnight. After cooling, the solid was filtered off through a pad of celite. The filtrate was concentrated in vacuo. The crude product was purified on silica gel (EtOAc:hexanes=1:1) to afford the desired product as a white solid. 1H NMR (CDCl3): δ 7.86 (2H, d, J=9.2 Hz), 7.35 (1H, s), 7.10 (2 H, d, J=9.2 Hz), 5.22 (2H, s), 4.08 (2H, br), 3.19 (2H, br), 3.02 (3H, s), 2.05˜2.32 (4H, m), 1.46 (9H, s).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[OH:11])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[CH:20]([Si:23](OS(C(F)(F)F)(=O)=O)([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[O:11][Si:23]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:20]([CH3:22])[CH3:21])=[CH:4][CH:3]=1
Reactant: OC1CCc2ccc(Br)cc21
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)[Si](OC1CCc2ccc(Br)cc21)(C(C)C)C(C)C
Reaction time: 0.5 h

Procedure:
To 6-Bromo-2,3-dihydro-1H-inden-1-ol (300 mg, 1.41 mmol) in CH2Cl2 (4 mL) was added 2,6-lutidine (151 μL, 1.41 mmol) followed by triisopropylsilyltriflate (378 μL, 1.41 mmol) at room temperature. The reaction was stirred for 30 min then added to 1N HCl and extracted. The organic layer was washed with saturated sodium bicarbonate then brine and dried over MgSO4. The solvent was removed in vacuo and the crude material purified by column chromatography.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[NH:3][C:4]([N:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[OH:7])=[O:5].[OH-].[Na+].Cl[C:19](OCC)=[O:20]>>[C:8]1([N:6]2[C:4](=[O:5])[N:3]([C:2]([F:14])([F:15])[F:1])[C:19](=[O:20])[O:7]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)Cl
Reactant: O=C(NC(F)(F)F)N(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=c1on(-c2ccccc2)c(=O)n1C(F)(F)F
Reaction time: 0.5 h

Procedure:
1-Trifluoromethyl-3-phenyl-3-hydroxyurea (11 grams; 0.05 mol) is dissolved in a cooled (10°C) 2N aqueous sodium hydroxide solution (35 ml). Ethyl chloroformate (6 ml; 0.06 mol) is added dropwise at 10° to 15°C with stirring. Stirring is continued for a period of about 1/2 hour after the addition is completed resulting in the formation of a precipitate. The precipitate is recovered by filtration, washed with water and dried to yield 2-phenyl-4-trifluoromethyl-1,2,4-oxadiazolidine-3,5-dione.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].[Mn]([O-])(=O)(=O)=[O:16].[K+]>O>[N+:8]([C:7]1[C:2]2[C:1](=[O:16])[NH:14][S:11](=[O:13])(=[O:12])[C:3]=2[CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1c([N+](=O)[O-])cccc1S(N)(=O)=O
Agent: [K+]
Solvent: O
Product: O=C1NS(=O)(=O)c2cccc([N+](=O)[O-])c21

Procedure:
8.0 gm (37 mmols) of 2-methyl-3nitro-benzene sulfonamide were oxidized with potassium permanganate in water analogous to Example 8. After extraction with ether, evaporation and recrystallization from water 3.8 gm (45% of theory) of the nitro compound were obtained.
Reaction SMILES: O=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([C:18]([OH:20])=O)[O:3]1.[CH2:21]([NH2:24])[CH2:22][NH2:23]>>[O:20]=[C:18]1[C:4]2[N:24]([C:2](=[O:3])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:5]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:21][CH2:22][NH:23]1
Reactant: NCCN
Reactant: O=C(O)c1oc(=O)c2ccccc2c1-c1ccccc1
Product: O=C1NCCn2c1c(-c1ccccc1)c1ccccc1c2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acid (500 mg) and ethylenediamine (15 ml) was stirred at room temperature overnight. After evaporation of the solvent, concentrated hydrochloric acid (10 ml) and acetic acid (10 ml) were added to the residue. The mixture was heated under reflux for 48 hours. To the mixture was added water, and extracted with ethyl acetate. The extract was washed successively with water, aqueous sodium hydrogen carbonate and water, dried, and evaporated to yield the title compound as colorless crystals (115 mg).