Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:9][CH2:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[F:21])[N:17]=[CH:16][CH:15]=[CH:14]3)[C:5]([NH2:8])=[N:6][CH:7]=1.[N:22]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[N:3]=[C:4]2[N:9]([CH2:10][C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][C:20]=3[F:21])[N:17]=[CH:16][CH:15]=[CH:14]4)[N:22]=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)nc1NCc1cc2cccnc2cc1F
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Fc1cc2ncccc2cc1Cn1nnc2ncc(Br)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of 5-bromo-N*3*-(7-fluoro-quinolin-6-ylmethyl)-pyrazine-2,3-diamine (90 mg, 0.26 mmol) in acetic acid (4 mL) was added a solution of sodium nitrite (11.4 mg, 0.26 mmol) in water (1 mL). After stirring at rt for 3 h, the solvent was removed in vacuo. The residue was diluted with NaHCO3 (aq.), extracted with DCM. The organic layer was separated and washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography with DCM:MeOH=50:1 to give the title compound as a yellow solid (57.0 mg, 61%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.03 (s, 1H), 8.94 (d, 1H), 8.40 (d, 1H), 8.08 (d, 1H), 7.84 (d, 1H), 7.55 (dd, 1H), 7.53 (dd, 1H), 6.21 (s, 2H). LCMS (method A): [MH]+=359/361, tR=2.23 min.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[CH:5][N:4]=1.O.[NH2:16][NH2:17]>C(O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[N:6]=[CH:5][N:4]=[C:3]([NH:16][NH2:17])[N:8]=1
Reactant: CSc1ncnc(-c2ccccn2)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1ncnc(-c2ccccn2)n1

Procedure:
A stirred solution of the product of step 2 (0.763 g, 3.74 mmol) and hydrazine hydrate (0.22 mL, 3.9 mmol) in ethanol (8 mL) was heated at reflux for 30 minutes. The reaction was cooled in an ice bath and the precipitate was filtered off. Vacuum oven drying afforded crude product as light brown solid. This material was used without further purification in the next step.
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:59])[C@H:41]([CH:56]([CH3:58])[CH3:57])[NH:42][C:43]([N:45]([CH2:47][C:48]1[N:49]=[C:50]([CH:53]([CH3:55])[CH3:54])[S:51][CH:52]=1)[CH3:46])=[O:44])[CH2:9][C@H:10]([O:29][CH:30](SCCCC)[CH2:31][CH2:32][CH3:33])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:60](=[O:64])([OH:63])([OH:62])[OH:61].IN1C(=O)CCC1=O.C([O-])([O-])=O.[Na+:77].[Na+]>CN(C=O)C.CO>[CH2:1]([C@H:8]([NH:39][C:40](=[O:59])[C@H:41]([CH:56]([CH3:58])[CH3:57])[NH:42][C:43]([N:45]([CH2:47][C:48]1[N:49]=[C:50]([CH:53]([CH3:54])[CH3:55])[S:51][CH:52]=1)[CH3:46])=[O:44])[CH2:9][C@H:10]([O:29][CH:30]([O:64][P:60]([O-:63])([O-:62])=[O:61])[CH2:31][CH2:32][CH3:33])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:77].[Na+:77]
Reactant: CCCCSC(CCC)O[C@@H](C[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reactant: O=P(O)(O)O
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1I
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCC(O[C@@H](C[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1)OP(=O)([O-])[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution containing the product from Example 12A (1.2 g, 1.4 mmol), molecular sieves (4 Å, 6.0 g), and phosphoric acid (0.85 g) in DMF (28 mL) at 0° C. was added N-iodosuccinimide (0.406 g), and the mixture was stirred at 0° C. for 1 hour. To the cold reaction was added 10% Na2CO3 to adjust the pH to 9, and the mixture was diluted with methanol and filtered. The filtrate was treated with 1 M Na2S2O3 until it was clear, diluted with methanol and filtered again. The solvent was evaporated, and the crude product was purified by HPLC on a C18 column, eluting with a gradient starting with water and ending with methanol to give the title compound (0.605 g, 47% yield).
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH3:26])[CH:20]=3)[CH2:13][CH2:12]2)=[N:3]1.[CH3:27][C:28]([CH3:33])=[CH:29][C:30](Cl)=[O:31]>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:30](=[O:31])[CH:29]=[C:28]([CH3:33])[CH3:27])=[C:21]([CH3:26])[CH:20]=3)[CH2:15][CH2:16]2)=[N:3]1
Reactant: Cc1cc(CCN2CCN(c3nsc4ccccc34)CC2)ccc1N
Reactant: CC(C)=CC(=O)Cl
Agent: Cl
Product: CC(C)=CC(=O)Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1C
Yield: 74.1 %

Procedure:
Starting with 4-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-2-methyl-phenylamine hydrochloride (0.60 g, 1.702 mmol) and 3,3-dimethyl-acryloyl chloride (0.189 mL, 1.702 mmol) and following the procedure outlined in Example 512, 3-methyl-but-2-enoic acid{4-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-2-methyl-phenyl]amide (0.553 g, 1.261 mmol) was obtained. Yield=75%. 100% purity at 254 nM; LCMS (APCI): 435.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.00 (d, J=8.42 Hz, 2H), 7.50 (t, J=7.47 Hz, 1H), 7.38 (t, J=7.47 Hz, 1H), 7.26 (d, J=7.47 Hz, 1H), 7.02 (s, 1H), 6.97 (d, J=7.47 Hz, 1H), 5.90 (s, 1H), 3.44–3.36 (m, 4H), 3.30 (s, H2O), 2.71–2.58 (m, 6H), 2.57–2.49 (m, 2H), 2.45 (p, DMSO), 2.11 (s, 3H), 2.07 (s, 3H), 1.80 (s, 3H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[Mg].Cl[Si@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:9][CH2:8]1>O1CCCC1>[CH2:3]([Si@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[CH2:9][CH2:8]1)[CH2:2][CH3:1]
Reactant: Fc1ccc(-c2ccc(CC[C@H]3CC[Si@H](Cl)CC3)cc2)cc1
Reactant: CCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](CCc2ccc(-c3ccc(F)cc3)cc2)CC1

Procedure:
2.5 g (20 mmol) of n-propyl bromide was dripped into a mixture of 0.5 g (21 mmol) of magnesium and 50 ml of tetrahydrofuran (hereafter abbreviated as "THF") to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 6.7 g (20 mmol) of 4-[2-(trans-4-chloro-4-silacyclohexyl)ethyl]-4'-fluorobiphenyl to obtain 4-[2-(trans-4-n-propyl-4-silacyclohexyl) ethyl]-4'-fluorobiphenyl. The silacyclohexane rings of this product were a mixture of trans isomers and cis isomers. After a conventional after treatment, they were separated by means of chromatography to obtain 6.1 g of the trans isomers (yield 90%).
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8])C.[C:12](#[N:14])[CH3:13]>C1CCCCC1.O>[CH3:10][C:7]([CH3:8])([CH3:9])[C:6](=[O:11])[CH2:13][C:12]#[N:14]
Reactant: CC#N
Reactant: CCOC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCCCC1
Product: CC(C)(C)C(=O)CC#N
Temperature: 80 °C

Procedure:
To a refluxed solution of sodium hydride (33.18 g, 553.03 mmol) in 275 mL of cyclohexane is added a mixture of 2,2-dimethyl-propionic acid ethyl ester (30 g, 230.43 mmol) in 79 mL acetonitrile (553.03 mmol) in 25 mL of cyclohexane. The mixture is maintained at 80° C. overnight. The mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organics are washed with water, dried over sodium sulfate, filtered and concentrated to afford title compound which was used crude in subsequent reaction. ESI m/z 124=MH−
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.Br[CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19]
Reactant: N#Cc1cccc(CBr)c1
Reactant: COCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCNCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.9 %

Procedure:
To a stirred solution of 2-methoxyethylamine (5.73 mL, 0.0612 mol) and triethylamine (4.05 mL, 0.0306 mol) in dry DCM (100 mL), was added 3-(bromomethyl)benzonitrile (6 g, 0.0306 mol) in portions over a period of 10 min at 0° C. After being stirred at RT for 5 h, the reaction mixture washed with water (2×100 mL), dried using sodium sulphate and concentrated under reduced pressure. The obtained crude was purified using column chromatography on silica gel (chloroform/methanol) to afford the title compound as a pale yellow liquid (5 g, 86%). 1H NMR (DMSO-d6, 400 MHz) δ 7.75 (s, 1H), 7.64-7.68 (m, 2H), 7.48-7.52 (m, 1H), 3.73 (s, 2H), 3.35-3.38 (m, 2H), 3.21 (s, 3H), 2.59-2.61 (m, 2H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.C(OP([CH2:21][C:22]([OH:24])=[O:23])(OCC)=O)C.[NH2:25][C:26]1[C:27]2[C:34]([C:35]3[CH:40]=[CH:39][C:38]([O:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[CH:37][CH:36]=3)=[CH:33][N:32]([CH:48]3[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]3)[C:28]=2[N:29]=[CH:30][N:31]=1>O1CCCC1>[NH2:25][C:26]1[C:27]2[C:34]([C:35]3[CH:36]=[CH:37][C:38]([O:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[CH:39][CH:40]=3)=[CH:33][N:32]([CH:48]3[CH2:53][CH2:52][C:51](=[CH:21][C:22]([OH:24])=[O:23])[CH2:50][CH2:49]3)[C:28]=2[N:29]=[CH:30][N:31]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(=O)CC1
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(=CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.7 %

Procedure:
A solution of diisopropylamine (1.40 g, 13.82 mmol) in tetrahydrofuran (60 mL) was added into a solution of 2.2 M n-BuLi (6.29 mL, 13.82 mmol) in tetrahydrofuran (20 mL) at −78° C. A solution of diethylphosphonoacetic acid (1.29 g, 6.59 mmol) in tetrahydrofuran (60 mL) was added at −78° C. under the atmosphere of nitrogen. The mixture was kept at −78° C. for 20 minutes and allowed to warm up to ambient temperature. The mixture was then transferred into a suspension of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone (2.50 g, 6.28 mmol) in tetrahydrofuran (150 mL) at −78° C. quickly. The resulting mixture was allowed to warm up to ambient temperature overnight and the solvent was removed under reduced pressure. The residue was taken in water and adjusted PH to be 3-4 with 1M aqueous acetic acid followed by extraction with ethyl acetate three times. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 2-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyliden}acetic acid (1.96 g, 4.44 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 11.98(br, 1H), 7.45(d, 2H), 7.41(s, 1H), 7.40(d, 2H), 7.16(t, 1H), 7.08(m, 4H), 6.10(br, 2H), 5.70(s, 1H), 4.80(m, 1H), 2.50-1.90(m, 8H); RP-HPLC (Hypersil C18, 5 μm, 100 A, 250×4.6 mm; 25%-100% acetonitrile-0.05M ammonium acetate over 10 min, 1 mL/min) Rt 9.70 min. MS: MH+ 441.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2>>[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:7][C:6]1[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]([O:2][CH3:1])=[CH:10][CH:9]=1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: COc1ccc(C=O)cc1-c1ccccc1
Product: COc1ccc(C=C2C(=O)Nc3ccc(Br)cc32)cc1-c1ccccc1

Procedure:
4-Methoxy-3-phenylbenzaldehyde was condensed with 5-bromo-2-oxindole to give 0.3 g of 5-Bromo-3-(6-methoxybiphenyl-3-ylmethylene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([C:13]([NH:15][CH2:16][C@@H:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C@H:18]2[OH:30])=[O:14])=[CH:4][C:3]=1[Cl:31]>Cl.CC(O)C.CO>[NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:11])([CH3:12])[O:10][C:6]=2[C:5]([C:13]([NH:15][CH2:16][C@@H:17]2[CH2:22][CH2:21][NH:20][CH2:19][C@H:18]2[OH:30])=[O:14])=[CH:4][C:3]=1[Cl:31]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CNC(=O)c2cc(Cl)c(N)c3c2OC(C)(C)C3)[C@H](O)C1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: CC1(C)Cc2c(N)c(Cl)cc(C(=O)NC[C@@H]3CCNC[C@H]3O)c2O1
Yield: 73 %

Procedure:
A mixture of intermediate (26) (0.011 mol) in a mixture of HCl in 2-propanol (12 ml) and methanol (100 ml) was stirred and refluxed for 30 minutes. The mixture was cooled and the solvent was evaporated. The residue was partitioned between water/NH3 and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 2.84 g (73%) of (−)-(trans)-4-amino-5-chloro-2,3-dihydro-N-[(3-hydroxy-4-piperidinyl)methyl]-2,2-dimethyl-7-benzofurancarboxamide (interm. 14). A sample (0.5 g) was crystallized from ACN with a drop of water, filtered off and dried, yielding 0.2 g of intermediate (14) [mp. 116° C.; [α]D20=−15.91° (c=25.14 mg/5 ml in CH3OH)].
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([NH2:10])=[N:2]1.Cl[CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([Cl:29])=[CH:23][C:22]=2[F:30])[CH2:17][CH:16]1[CH3:31])=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:10][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:1]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([Cl:29])=[CH:23][C:22]=3[F:30])[CH2:17][CH:16]2[CH3:31])=[O:14])[N:2]=1
Reactant: Nc1n[nH]c2ncccc12
Reactant: COc1cc(N2CCN(C(=O)CCl)C(C)C2)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(N)c4cccnc43)C(C)C2)c(F)cc1Cl
Temperature: 80 °C

Procedure:
1H-Pyrazolo[3,4-b]pyridin-3-ylamine (67 mg), 2-Chloro-1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-ethanone (167 mg) and K2CO3 (414 mg) were combined in DMF (1 mL) and heated at 80° C. for 2 hr, then cooled to room temperature. The resultant mixture was purified by preparative HPLC to provide 2-(3-Aminopyrazolo[3,4-b]pyridin-1-yl)-1-[4-(4-chloro-2-fluoro-5-methoxyphenyl)-2-methylpiperazin-1-yl]ethanone as a yellow powder. LCMS (ES) M+H 433.5, Rf 2.06 min (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C., 1 ml/min flow rate, a 2.5 min gradient of 20% to 100% B with a 1.1 min wash at 100% B; A=0.1% formic acid /5% acetonitrile /94.9% water, B=0.1% formic acid /5% water/94.9% acetonitrile).
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25](C=O)=[CH:24][CH:23]=4)[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH3:30][OH:31]>C(O)(=O)C>[ClH:1].[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20]([C:22]4[CH:23]=[CH:24][C:25]([CH2:7][N:2]5[CH2:3][CH2:4][O:31][CH2:30][CH2:9]5)=[CH:26][CH:27]=4)[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: CO
Reactant: O=Cc1ccc(-c2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(-c3ccc(CN4CCOCC4)cc3)cc2s1

Procedure:
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(4-formylphenyl)-1-benzothiophene-2-carboxamide hydrochloride (Example 23A) in 1.5 ml of a 6:1 mixture of methanol and acetic acid. 2 h at room temperature and 6 h at 80° C. are followed by purification by preparative HPLC. The product fractions are concentrated and, after addition of a 5:1 mixture of methanol and 1N hydrochloric acid, again concentrated. Drying under high vacuum results in 87.7 mg (88% of theory) of the title compound.
Reaction SMILES: COC1C=C([C@H]2OC(=O)N[C@@H]2C2C=CC=C(C#CC3C=CC=CC=3)C=2)C=CC=1.Br[C:30]1[N:35]=[C:34]([C@@H:36]2[C@@H:40]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=3)[O:39][C:38](=[O:49])[NH:37]2)[CH:33]=[CH:32][CH:31]=1.[C:50]([C:52]1[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=1)#[CH:51]>>[F:58][C:55]1[CH:56]=[CH:57][C:52]([C:50]#[C:51][C:30]2[N:35]=[C:34]([C@@H:36]3[C@@H:40]([C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=4)[O:39][C:38](=[O:49])[NH:37]3)[CH:33]=[CH:32][CH:31]=2)=[CH:53][CH:54]=1
Reactant: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(Br)n2)c1
Reactant: C#Cc1ccc(F)cc1
Agent: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(C#Cc3ccccc3)c2)c1
Product: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(C#Cc3ccc(F)cc3)n2)c1

Procedure:
Prepared according to the same procedure as (+)-(4R,5R)-5-(3-methoxyphenyl)-4-(3-(phenylethynyl)phenyl)oxazolidin-2-one, starting with optically-enriched (4R,5R)-4-(6-bromopyridin-2-yl)-5-(3-methoxyphenyl)oxazolidin-2-one and 1-ethynyl-4-fluorobenzene. 1H-NMR (CDCl3, 500 MHz) δ 7.79 (dd, J=7.9, 7.6, 1H), 7.61 (m, 2H), 7.54 (d, J=7.6, 1H), 7.36 (m, 2H), 7.10 (m, 2H), 7.04 (m, 2H), 6.94 (m, 1H), 6.40 (bs, 1H), 5.62 (d, J=5.8, 1H), 4.98 (d, J=5.8, 1H), 3.85 (s, 3H). 13C-NMR (CDCl3, 126 MHz) δ 163.2 (d, J=251), 160.1, 158.9, 143.7, 139.8, 137.7, 134.2 (d, J=7.7), 130.2, 127.2, 120.0, 117.9, 116.0 (d, J=23), 114.8, 111.2, 89.1, 88.1, 83.7, 64.9, 55.5. Mass spec.: 389.17 (MH)+.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:17]1([CH2:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.CCCCCC>[C:1]([N:5]([C:24](=[O:25])[CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
N'-t-butyl-N-benzoylhydrazine (2 g) was stirred in toluene (35 ml) and 50% aqueous sodium hydroxide (1 g) at 5° C. Phenylacetylchloride (1.5 g) was added slowly, dropwise to the reaction mixture, warmed to room temperature and stirred 1 hour. The reaction mixture was diluted with hexane (50 ml) and filtered off to yield a solid product. The filter cake was washed with hexane and water and allowed to air dry. The white solid product obtained in 90% yield melted at 167°-169° C.
Reaction SMILES: C(OP([CH:9]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)[O:10][CH3:11])(=O)OCC)C.[H-].[Na+].[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[N:27]1[CH:32]2[CH2:33][CH2:34][CH:28]1[CH2:29][C:30](=O)[CH2:31]2>COCCOC>[Br:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]([O:10][CH3:11])=[C:30]2[CH2:31][CH:32]3[N:27]([C:22]4[N:21]=[CH:26][CH:25]=[CH:24][N:23]=4)[CH:28]([CH2:34][CH2:33]3)[CH2:29]2)=[CH:17][CH:16]=1
Reactant: O=C1CC2CCC(C1)N2c1ncccn1
Reactant: CCOP(=O)(OCC)C(OC)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=C1CC2CCC(C1)N2c1ncccn1)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 15.8 %

Procedure:
To a solution of [(4-bromo-phenyl)-methoxy-methyl]-phosphonic acid diethyl ester (4.58 g, 13.5 mmol) in 1,2-dimethoxy-ethane (60 ml), was added NaH (540 mg, 13.5 mmol, 60% in mineral oil) in one portion. The mixture was stirred at 50° C. for 1.5 hrs before it was added by 8-pyrimidin-2-yl-8-aza-bicyclo[3.2.1]octan-3-one (2.0 g, 9.85 mmol) in 1,2-dimethoxy-ethane (5 ml). The mixture was stirred at 50° C. over the weekend. The resulting mixture was concentrated down and purified by ISCO to afford 3-[(4-bromo-phenyl)-methoxy-methylene]-8-pyrimidin-2-yl-8-aza-bicyclo[3.2.1]octane (600 mg, 30%). The white solid product was used as it was. MS (M+1)=386.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:11][OH:12].[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[N:11][OH:12]
Reactant: NO
Reactant: O=Cc1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a suspension of 2-fluorobenzaldehyde (63.3 g, 495 mmol) and hydroxylamine hydrochloride (38.2 g, 544 mmol) in ethanol (36 mL) and water (69 mL) was added ice (205 g). Then an aqueous solution of sodium hydroxide (32%, 115 mL, 1.24 mol) was added dropwise within a 10 min period (temperature rises from −8° C. to +7° C.) whereupon most of the solid dissolves. After 1 h stirring at room temperature the resulting mixture was then acidified with HCl (5 N). The mixture was then extracted with dichloromethane to afford the title compound (66.8 g, 97%) which was obtained as a light yellow solid. MS m/e (EI): 139.0 [M].
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-:16].[Na+]>Cl>[CH3:15][S:14][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:16])[CH:7]=2)[CH:13]=[CH:12][N:11]=1
Reactant: CSc1nccc(-c2ccnc(F)c2)n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CSc1nccc(-c2cc[nH]c(=O)c2)n1
Temperature: 25 °C
Yield: 49 %

Procedure:
A suspension of 4-(2-fluoropyridin-4-yl)-2-(methylthio)pyrimidine (6.83 g, 30.9 mmol) in 2N HCl (100 mL) was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and placed in an ice bath. The pH was adjusted to about 7 with 2N NaOH (about 100 mL). The resulting solids were collected by filtration, washed with water and dried to give 4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (5.07 g) as a solid. This material was placed in the thimble of a Soxhlet apparatus and was attached to a 1 L flask charged with ethyl acetate (500 mL). The material was continuously extracted for 3 days. The resulting white precipitate from the ethyl acetate layer was collected by filtration (3.3 grams, 49% yield). 1H NMR (400 MHz, (CD3)2SO) δ 11.85 (br, s, 1H), 8.75 (d, J=5.0 Hz, HA), 7.79 (d, J=5.0 Hz, 1H), 7.54 (d, J=7.0 Hz, 1H), 7.13 (s, 1H), 6.86 (d, J=7.0 Hz, 1H), 2.58 (s, 3H); m/z (APCI-pos) M+1=220.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:26])[C:5]2[CH:6]=[N:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]CC4C=CC=CC=4)=[C:13]([F:25])[CH:12]=3)[C:9]=2[CH:10]=1.B(Br)(Br)Br.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([OH:26])[C:5]2[CH:6]=[N:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:25])[CH:12]=3)[C:9]=2[CH:10]=1
Reactant: Oc1cc(Cl)cc2c1cnn2-c1ccc(OCc2ccccc2)c(F)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(-n2ncc3c(O)cc(Cl)cc32)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a suspension of 6-chloro-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-1H-indazol-4-ol (D11) (60 mg, 0.163 mmol) in dry DCM (2 mL) cooled to −78° C. was added BBr3 (1M in DCM, 0.326 mL, 0.326 mmol) dropwise. The resulting mixture was stirred at this temperature for 1 hour, then it was warmed to room temperature, treated with water and the pH adjusted to 7 by addition of saturated NaHCO3. The solution was extracted with EtOAc (2×) and the combined organics were dried over MgSO4. The crude material (49 mg) was then purified by flash chromatography with a gradient of 5-100% EtOAc in hexane to give a the title compound (E8) as a colourless solid (35 mg).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[CH2:17][C:18]([O:20]C)=[O:19].O.O[Li].O.Cl>C1COCC1>[F:23][C:2]([F:1])([F:22])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH:8]=[CH:7][C:6]=1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: COC(=O)Cc1ccc(N2CCOCC2)cc1OCC(F)(F)F
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(N2CCOCC2)cc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of methyl 2-(2,2,2-trifluoroethoxy)-4-(4-morpholinyl)phenylacetate (0.22 g, 0.67 mmol) from Step 2 above in THF (2 mL) and water (0.5 mL) was added LiOH.H2O (0.056 g, 1.3 mmol). The mixture was stirred at ambient temperature for 14 h. The solution was adjusted to pH 3 by the addition of 5 N aqueous HCl and the solvents were removed under reduced pressure and the residue was purified by pressurized silica gel column chromatography using a gradient elution of 0-50% MeOH:CH2Cl2 as eluant. 2-(2,2,2-Trifluoroethoxy)-4-(4-morpholinyl)phenylacetic acid was obtained as a gum (HPLC retention time=5.8 min (method A)).