Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18]Br.[I-].[K+].N12CCCN=C1CCCCC2.[NH4+].[Cl-]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[N:7]([CH2:18][CH:17]([O:20][CH3:21])[O:16][CH3:15])[N:6]=[CH:5]2
Reactant: COC(CBr)OC
Reactant: COC(=O)c1cc(Cl)cc2cn[nH]c12
Agent: [Cl-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: COC(=O)c1cc(Cl)cc2cnn(CC(OC)OC)c12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Methyl 5-chloro-1H-indazole-7-carboxylate (2.65 g, 12.6 mmol; 1 eq) from Step A above was stirred in DMSO (25 mL) at room temperature while bromoacetaldehyde dimethyl acetal (3 mL, 25.2 mmol) pre-mixed with potassium iodide (209 mg, 1.3 mmol) was added. 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 2 mL, 12.6 mmol) was then added dropwise. The reaction mixture was stirred at 80° C. (external temperature) overnight. The reaction mixture was neutralized with sat. NH4Cl then partitioned between H2O and ethyl acetate. The ethyl acetate layers were combined, dried (Na2SO4), filtered, concentrated and purified by column chromatography (silica gel, 1:1 ethyl acetate/hexanes) to afford methyl 5-chloro-1-(2,2-dimethoxyethyl)-1H-indazole-7-carboxylate as a light yellow oil (404 mg, 11%, regioisomer confirmed by NOE): 1H NMR (300 MHz, CDCl3) δ 8.04 (s, 1H), 8.84 (s, 2H), 4.93 (d, J=5.1 Hz, 2H), 4.50 (t, J=5.1 Hz, 1H), 3.99 (s, 3H), 3.27 (s, 6H). [1.29 g starting material recovered; 846 mg, 22% undesired regioisomer methyl 5-chloro-2-(dimethoxymethyl)-2H-indazole-7-carboxylate collected as side product, dark yellow solid]
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[C:19]=3[NH:24][C:25]([O:27][C@@H:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[F:36])[CH3:29])=[O:26])=[CH:14][C:13]=2[CH3:37])=[CH:8][CH:7]=1)C.[OH-].[Li+]>CO.O>[F:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C@H:28]([O:27][C:25]([NH:24][C:19]1[C:20]([CH3:23])=[N:21][O:22][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C:4]([OH:38])=[O:3])=[CH:11][CH:10]=2)=[C:13]([CH3:37])[CH:14]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3F)cc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(-c2onc(C)c2NC(=O)O[C@H](C)c2ccccc2F)ccc1-c1ccc(CC(=O)O)cc1

Procedure:
(4′-{4-[(R)-1-(2-Fluoro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-2′-methyl-biphenyl-4-yl)-acetic acid ethyl ester (0.282 g, 0.53 mmol) was hydrolyzed with lithium hydroxide in methanol and water, and the crude material was purified by preparative HPLC to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[NH2:17].O.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:17][C:3]1[CH:4]=[C:5]([N:8]([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])[CH:6]=[CH:7][CH:2]=1
Reactant: Nc1cc(N(C(F)(F)F)C(F)(F)F)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1cccc(N(C(F)(F)F)C(F)(F)F)c1
Yield: 44.4 %

Procedure:
26.5 g of 4-chloro-3-amino-N,N-bistrifluoromethyl-aminobenzene were dissolved in 50 g of toluene and reacted at 350° C. The reaction products were introduced into 150 ml of water. The two-phase mixture obtained was made alkaline with 20% strength by weight aqueous sodium hydroxide solution, and the toluene phase was separated off, to give 10.3 g of 3-amino-N,N-bistrifluoromethyl-aminobenzene of boiling point 76° to 78° C. at 20 mbar by distillation.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:14]([NH:16][C@@H:17]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:18]([OH:47])[CH2:19][C@@H:20]([NH:34][C:35]([C@@H:37]([NH:42][C:43](=[O:46])[O:44][CH3:45])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=2)=[O:15])[C:9]1=[O:59])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:60]([O:64][C:65]([NH:67][C@H:68]([C:70](O)=[O:71])[CH3:69])=[O:66])([CH3:63])([CH3:62])[CH3:61].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:60]([O:64][C:65]([NH:67][C@H:68]([C:70]([O:47][C@H:18]([C@@H:17]([NH:16][C:14](=[O:15])[C@@H:13]([N:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:19][C@@H:20]([NH:34][C:35](=[O:36])[C@H:37]([C:38]([CH3:41])([CH3:40])[CH3:39])[NH:42][C:43]([O:44][CH3:45])=[O:46])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:24][CH:23]=1)=[O:71])[CH3:69])=[O:66])([CH3:62])([CH3:63])[CH3:61]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](OC(=O)[C@H](C)NC(=O)OC(C)(C)C)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a solution containing the compound of Example 111 (0.100 g, 0.124 mmol), N-(tert-butoxycarbonyl) L-alanine (0.028 g, 0.147 mmol)), and 4(dimethylamino)pyridine (0.018 g, 0.147 mmol) in N,N-dimethylformamide (1.0 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (0.029 g, 0.151 mmol) and the mixture was stirred at room temperature for 2 hours. Two subsequent additions of N-(tert-butoxycarbonyl) L-alanine (0.028 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (0.029 g) were made at two hour intervals. The solvent was evaporated and the reaction mixture was partitioned between ethyl acetate and aqueous NaHCO3. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient starting with chloroform and ending with 66% ethyl acetate in chloroform, to give the title compound (0.100 g, 82%).
Reaction SMILES: [SH:1]CCC(OC)=O.[H-].[Na+].[Cl:10][C:11]1[C:12]([C:27]([NH2:29])=[O:28])=[C:13]2[N:18]([C:19]=1[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:17][CH2:16][C:15](Cl)=[CH:14]2.Cl>CN(C)C=O.O>[Cl:10][C:11]1[C:12]([C:27]([NH2:29])=[O:28])=[C:13]2[N:18]([C:19]=1[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:17][CH2:16][C:15]([SH:1])=[CH:14]2
Reactant: COC(=O)CCS
Reactant: NC(=O)c1c(Cl)c(-c2cccnc2)n2c1C=C(Cl)CC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1c(Cl)c(-c2cccnc2)n2c1C=C(S)CC2
Temperature: 68 °C
Yield: 36 %

Procedure:
2.4 g of methyl 3-mercaptopropionate are dissolved in 100 cm3 of dimethylformamide. 0.8 g of sodium hydride is added in small fractions, and then 3.08 g of 2,7-dichloro-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxamide in 80 cm3 of dimethylformamide are poured in. The mixture is heated at 68° C. for 2 hours 30 minutes, and then poured into 25 cm3 of hydrochloric acid (4 N). The mixture is concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 60° C. The yellow residue obtained is taken up in 280 cm3 of water and 10 cm3 of hydrochloric acid (2 N), and then filtered and washed with twice 5 cm3 of water. 1.1 g of 2-chloro-3-pyridin-3-yl-7-mercapto-5,6-dihydroindolizine-1-carboxamide are thus obtained in the form of a yellow powder melting at 232° C.
Reaction SMILES: [C:1]([CH:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][C:9]#[N:10])([O:3]CC)=O.[CH3:16][O:17][C:18]1[CH:29]=[C:28]2[C:21]([NH:22][CH:23]=[C:24]2[CH2:25][CH2:26]N)=[CH:20][CH:19]=1>C(O)(=O)C.[Pd]>[CH3:16][O:17][C:18]1[CH:29]=[C:28]2[C:21](=[CH:20][CH:19]=1)[NH:22][C:23]1[CH:9]3[CH2:8][CH2:7][CH:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:1](=[O:3])[N:10]3[CH2:26][CH2:25][C:24]2=1
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Reactant: CCOC(=O)C(CCC#N)C(=O)OCC
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)C1CCC2c3[nH]c4ccc(OC)cc4c3CCN2C1=O
Reaction time: 48 h
Yield: 35 %

Procedure:
4,4-Dicarbethoxybutyronitrile (1.2 g)and palladium-on-charcoal (0.6 g) are successively added to 5-methoxytryptamine (693 mg) dissolved in acetic acid. The mixture is stirred under a hydrogen atmosphere for 48 h. The medium is then filtered and the palladium is washed with a chloroform/methanol mixture. After evaporation of the solvent, the crude product obtained, dissolved in toluene, is refluxed overnight. The ethyl 9-methoxy-4-oxo-1,2,3,4,6,7,12,12b-octahydropyrido[2,1 -a]-(3-carboline-3-carboxylate precipitates and is recovered by simple filtration (35% yield).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:12]3=[N:11][N:10]=2)=[CH:5][CH:4]=1.Cl[CH2:20][C:21]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)[O:23][N:22]=1.[NH4+].[Cl-]>CN(C=O)C>[Cl:32][C:28]1[CH:27]=[C:26]([C:24]2[O:23][N:22]=[C:21]([CH2:20][N:18]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]4[C:9]([C:6]5[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=5)=[N:10][N:11]=[C:12]34)[N:25]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: ClCc1noc(-c2cccc(Cl)c2)n1
Reactant: c1cc(-c2nnc3n2CCCCN3)ccn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Clc1cccc(-c2nc(CN3CCCCn4c(-c5ccncc5)nnc43)no2)c1
Yield: 54.9 %

Procedure:
NaH (65 mg, 0.28 mmol) was added to a solution of 3-pyridin-4-yl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a][1,3]diazepine (54 mg, 0.25 mmol) in DMF (5 ml). After 10 min 3-(chloromethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (65 mg, 0.28 mmol) was added at r.t. Stirring was continued o.n. and NH4Cl solution, sat., was added and the mixture was extracted with EA. The organic phase was dried and concentrated. Flash chromatography (DCM/MeOH 20:1) yielded 56 mg (54%) of the title compound. 1H NMR: 1.89-2.01 (m, 4H), 3.33-3.42 (m, 2H), 3.90-3.98 (m, 2H), 4.88 (s, 2H), 7.42-7.49 (m, 3H), 7.53 (m, 1H), 7.98 (m, 1H), 8.09 (m, 1H), 8.71 (d, 2H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]2[C:16]3=[C:17]([CH2:19][S:20][CH2:21][CH2:22][N:15]3[C@H:14]3[CH2:23][CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][C@@H:13]23)[CH:18]=1>>[CH2:1]([NH:9][C:10]1[CH:11]=[C:12]2[C:16]3=[C:17]([CH2:19][S:20][CH2:21][CH2:22][N:15]3[C@H:14]3[CH2:23][CH2:24][NH:25][CH2:26][C@@H:13]23)[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Reactant: O=Cc1ccccc1
Product: c1ccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)cc1

Procedure:
Using benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 171. 1H NMR (CDCl3) δ: 7.42-7.25 (m, 5H), 6.37 (d, 1H, J=1.8 Hz), 6.26 (d, 1H, J=2.2 Hz), 4.27 (s, 2H), 3.69 (ABq, 2H, JAB=15.2 Hz), 3.60-3.50 (m, 1H), 3.37-3.30 (m, 1H), 3.28-3.20 (m, 1H), 3.10-2.85 (m, 6H), 2.62 (dd, 1H, J=12.8, 9.1 Hz), 1.89-1.80 (m, 2H). LRMS (ES)+: 352.4 (M+H)+.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][N:16]([C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])=[O:22])[CH2:15][CH2:14]2)=[O:10]>CO.Cl>[CH3:28][O:27][CH2:26][CH2:25][CH2:24][O:23][C:21]([N:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:9](=[O:10])[NH:8][OH:7])[CH:12]=2)[CH2:17]1)=[O:22]
Reactant: COCCCOC(=O)N1CCc2cc(C(=O)NOC3CCCCO3)ccc2C1
Agent: Cl
Solvent: CO
Product: COCCCOC(=O)N1CCc2cc(C(=O)NO)ccc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101 %

Procedure:
A mixture of 90 mg 3-methoxypropyl 6-[(tetrahydro-2H-pyran-2-yloxy)carbamoyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate in 1 ml methanol and 1.5 ml aqueous HCl (0.1 N) is stirred for 3 h at ambient temperature. The reaction mixture is lyophilized. 71.4 mg of a colorless solid are obtained. MH+=309.0
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[F:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:2]([O:15][C:13]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([F:6])[CH:14]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCBr
Reactant: N#Cc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1ccc(C#N)c(F)c1

Procedure:
A solution of 1-bromobutane (18.0 g, 0.13 mol) in acetone (30 ml) was added dropwise to a stirred refluxing mixture of 2-fluoro-4-hydroxybenzonitrile (15.0 g, 0.11 mol) and potassium carbonate (46.0 g, 0.33 mol) in acetone (300 ml). The stirred mixture was heated under reflux for 21 h (glc analysis revealed absence of starting material). The product was extracted into ether (twice), and the combined ethereal extracts were washed with water, 5% sodium hydroxide, water and dried (MgSO4). The solvent and the excess of 1-bromobutane were removed in vacuo to yield a pale-orange solid.
Reaction SMILES: O[C:2]1([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15](=[O:17])[NH:14][C:13]=3[CH:18]=2)[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[O:8]=[C:5]1[CH2:6][CH2:7][C:2]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15](=[O:17])[NH:14][C:13]=3[CH:18]=2)=[CH:3][CH2:4]1
Reactant: O=C1CCC(O)(c2ccc3oc(=O)[nH]c3c2)CC1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: O=C1CC=C(c2ccc3oc(=O)[nH]c3c2)CC1
Reaction time: 8 h

Procedure:
A solution of 5-(1-hydroxy-4-oxo-cyclohexyl)-3H-benzooxazol-2-one (230 mg, 0.93 mmol) in THF (10 mL) was treated with Burgess' reagent (Aldrich, 334 mg, 1.40 mmol) at room temperature. The reaction was stirred overnight. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated and then purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:7]([F:17])[CH:6]=1)[C:3]#[N:4].[S]>C1(OC2C=CC=CC=2)C=CC=CC=1.CC(C)=O>[CH3:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([F:17])[CH:6]=1)[C:3]#[N:4]
Reactant: CC(C#N)c1ccc(C2CCCCC2)c(F)c1
Agent: [S]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CC(C)=O
Product: CC(C#N)c1ccc(-c2ccccc2)c(F)c1
Temperature: 250 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
A mixture of 6.93 g of α-methyl-4-cyclohexyl-3-fluorophenylacetonitrile (nD20 1.5182) and 3.46 g of sulphur in 15 ml of diphenyl ether was subjected to heating with stirring at 250° C. for 4 hours. The resulting reaction liquid was diluted with acetone, and the insoluble substances therein were removed by filtration. The filtrate was concentrated and then distilled to obtain 5.06 g of α-methyl-(2-fluoro-4-biphenylyl)acetonitrile.
Reaction SMILES: Cl[CH2:2][S:3][C:4]1[N:8]=[CH:7][N:6]([CH3:9])[N:5]=1.[I-:10].[Na+]>CC(C)=O.O>[I:10][CH2:2][S:3][C:4]1[N:8]=[CH:7][N:6]([CH3:9])[N:5]=1
Reactant: Cn1cnc(SCCl)n1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cn1cnc(SCI)n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution of 3-chloromethylthio-1-methyl-1,2,4-triazole (981 mg: 6.0 mMol.) in acetone (10 ml) is added sodium iodide (1.78 g: 12 mMol.), and the mixture is stirred at 50° C. for 3 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, and concentrated to give 3-iodomethylthio-1-methyl-1,2,4-triazole (1.50 g) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].[NH:15]1[CH2:19][C@@H:18]([OH:20])[C@H:17]([OH:21])[CH2:16]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:15]3[CH2:19][C@@H:18]([OH:20])[C@H:17]([OH:21])[CH2:16]3)=[O:13])[S:10][C:3]=12
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: O[C@@H]1CNC[C@H]1O
Agent: [Li+]
Product: O=C(c1cc2nccc(Cl)c2s1)N1C[C@@H](O)[C@H](O)C1

Procedure:
The title compound was prepared from lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate and (3R,4R)-pyrrolidine-3,4-diol by a procedure analogous to Example 1C. MS: 299.3/301.3 (MH+); HPLC Rf: 3.091 min.; HPLC purity: 99%.
Reaction SMILES: C([C:3]1[C:21]([C:22]([OH:24])=[O:23])=[C:6]2[N:7]=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:9]=[C:10]([CH:11]3[CH2:13][CH2:12]3)[N:5]2[N:4]=1)C.[OH-].[Na+]>CO.O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:8]2[CH:9]=[C:10]([CH:11]3[CH2:13][CH2:12]3)[N:5]3[N:4]=[CH:3][C:21]([C:22]([OH:24])=[O:23])=[C:6]3[N:7]=2)=[CH:15][CH:16]=1
Reactant: CCc1nn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc2c1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Temperature: 80 °C
Yield: 85.4 %

Procedure:
A mixture of ethyl 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.95 g, 2.8 mmol) and 2 N NaOH solution (5.6 mL) in MeOH (35 mL) was heated to 80° C. for 0.5 h. The mixture was cooled, diluted with water (150 mL) and washed with diethyl ether. The aqueous layer was acidified by the addition of 3N HCl to pH 2. The precipitate formed was isolated by filtration, washed with water, and dried to give the title compound (0.75 g, 86%). Off-white solid. MS (ISN) 312.3 [(M−H)−]; mp 256° C.
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([CH3:12])=[CH:6][C:5]=1[O:13][CH3:14])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][NH:3][C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1cc(C)cc(OC)c1NC=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1c(OC)cc(C)cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
6 g of N-formyl-2,6-dimethoxy-4-methylaniline are suspended in 100 ml of tetrahydrofuran and then 33 ml of a 1M solution of lithium aluminium hydride in tetrahydrofuran are added dropwise under an inert atmosphere. The reaction mixture become homogeneous. The reaction mixture is left at room temperature for 2 hours and then, after cooling to 0° C., 1 ml of water, then 1 ml of a 15% aqueous sodium hydroxide solution and then 3 ml of water are successively added dropwise to the reaction mixture. The whole mixture is diluted with 100 ml of ethyl acetate and the precipitate is filtered. The filtrate, evaporated to dryness, leaves an oily residue which is purified by flash chromatography on a column of silica gel, eluent: toluene/ethyl acetate 8/2 (v/v) in order to obtain N-methyl-2,6-dimethoxy-4-methylaniline in the form of an oil, Yield: 85%.
Reaction SMILES: [H-].[Na+].CN(C)[CH:5]=[O:6].[CH3:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([OH:15])[CH3:14]>O>[CH3:14][CH:13]([O:15][CH2:8][CH2:9][CH2:10][CH2:11][CH:5]1[O:6][CH2:12][CH2:13][O:15]1)[CH2:12][CH2:11][CH2:10][CH:9]([CH3:16])[CH3:8]
Reactant: CN(C)C=O
Reactant: CC(C)CCCC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)CCCC(C)OCCCCC1OCCO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 19 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.83 g, 20 mmol) and dimethylformamide (70 mL) were charged to a 250 mL three necked flask fitted with thermocouple, magnetic stirrer, condenser and dropping funnel. To the reaction mixture was added dropwise over 10 minutes 6-methylheptan-2-ol (2.77 g, 21 mmol). The reaction mixture was stirred at room temperature for 90 minutes then water (10 mL) was added. The reaction mixture was poured into water (100 mL), extracted with methyltert-butyl ether (2×100 mL), the combined organic phase dried over magnesium sulphate and the solvent removed in vacuo. The pale yellow oil was chromatographed over silica gel to yield 2-{4-[(1,5-dimethylhexyl) oxy]butyl}-1,3-dioxolane as a colourless oil (1.4 g, 73% pure by GC RPA, 3.9 mmol, chemical yield 19%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O.C(=O)(O)[O-].[Na+].O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([C:26]2[S:25][CH:29]=[CH:28][CH:27]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1c(C(=O)c2ccc(Br)cc2)[nH]c2cc(Cl)ccc12
Reactant: OB(O)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1c(C(=O)c2ccc(-c3cccs3)cc2)[nH]c2cc(Cl)ccc12
Yield: 82.2 %

Procedure:
A mixture of methyl[6-chloro-2-(4-bromobenzoyl)-1H-indol-3-yl]acetate (Example 206, 0.40 g, 0.98 mmol), thiophene-2-boronic acid (0.14 g, 1.08 mmol), saturated aqueous sodium bicarbonate (4 ml), and dichlorobis(triphenylphosphine)palladium(II) (70 mg, 0.098 mmol) in DME (15 ml) was refluxed for 3 h. The mixture was poured into water (30 ml), and extracted with ethyl acetate (50 ml×2). The combined extracts were washed with brine (50 ml), dried (MgSO4), and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate-hexane (1:6) to afford 0.33 g (83%) of the title compound as yellow solids.
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:12][C:13]1[CH:14]=[C:15]([N:19]2[C:23](=[O:24])[CH2:22][C:21]([CH3:25])=[N:20]2)[CH:16]=[CH:17][CH:18]=1.[OH-].[Na+]>O>[Cl:12][C:13]1[CH:14]=[C:15]([N:19]2[C:23](=[O:24])[CH:22]=[C:21]([CH3:25])[N:20]2[CH3:1])[CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1=NN(c2cccc(Cl)c2)C(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(=O)n(-c2cccc(Cl)c2)n1C
Temperature: 150 °C
Reaction time: 2.5 h
Yield: 52.7 %

Procedure:
90 g of p-toluenesulfonic acid was added to 50 g of 1-(3-chlorophenyl)-3-methyl-2-pyrazolin-5-one [Chemical Abstracts Registry Number (90-31-3)], and the resulting mixture was stirred on an oil bath at 150° C. for 2.5 hours. The reaction mixture was allowed to cool down to 100° C. or less. A solution prepared from 25 g of sodium hydroxide and 150 ml of water was added dropwise thereto. After adding thereto 350 ml of water, the mixture was extracted with chloroform. The chloroform phase was separated and then dried over anhydrous potassium carbonate. After insoluble materials were filtered off, the filtrate was concentrated to dryness to obtain 28.1 g of 1-(3-chlorophenyl)-2,3-dimethyl-3-pyrazolin-5-one. When recrystallization was carried out from ethyl acetate, crystals having a melting point of 98° to 100° C. were obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[C:9]([C:21]([O:23]C)=[O:22])=[N:10][C:11]([O:18][CH2:19][CH3:20])=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[OH-].[Na+]>C1COCC1>[CH3:7][C:4]1[N:3]([C:8]2[C:9]([C:21]([OH:23])=[O:22])=[N:10][C:11]([O:18][CH2:19][CH3:20])=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: CCOc1nc(C(=O)OC)c(-n2c(C)ccc2C)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1nc(C(=O)O)c(-n2c(C)ccc2C)cc1C(F)(F)F

Procedure:
Methyl 3-(2,5-dimethyl-1H-pyrrol-1-yl)-6-ethoxy-5-(trifluoromethyl)picolinate (140 mg, 0.409 mmol) was dissolved in THF (2.045 ml). NaOH (0.613 ml, 1.226 mmol) was added and heated at reflux for 6 hours. The solvent was removed in vacuo and the resulting mixture was diluted with EtOAc (25 ml) was acidified to pH 1 using HCl (5M). The organic portion washed with brine, dried using a phase separator and concentrated in vacuo to afford the title compound as a yellow oil.