Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.C([O:5][C:6]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][Cl:14])[N:12]=1)=O)C.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[Cl:14][CH2:13][C:11]1[N:12]=[C:8]([CH2:6][OH:5])[S:9][CH:10]=1
Reactant: CCOC(=O)c1nc(CCl)cs1
Agent: CC(C)C[AlH]CC(C)C
Agent: N#N
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Solvent: C1CCOC1
Product: OCc1nc(CCl)cs1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-chloromethyl-thiazole-2-carboxylic acid ethyl ester (2.47 g, 12.03 mmol) in THF (120.0 mL) was treated at −78° C. with DiBAL (36.09 mL of a 1M sol in THF, 36.09 mmol) and the reaction mixture was stirred for 1 h at −78° C. and then allowed to warm to rt over 1 h. The reaction mixture was poured into a sat. aq. Rochelle's salt sol. and stirred for 1 h at rt. The aq. layer was extracted with EtOAc (2×150 mL) and the combined org. layer was washed with brine (200 mL). The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a light yellow oil. TLC: rf (1:1 hept-EA)=0.30. LC-MS-conditions 02: tR=0.59 min, [M+H]+=164.07.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:14]([CH2:22][CH:23]=[CH:24][Cl:25])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].CCCC[SnH](CCCC)CCCC.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[Cl:25][CH2:24][CH:23]1[C:2]2[C:11]3[CH:10]=[C:9]([C:12]#[N:13])[CH:8]=[CH:7][C:6]=3[CH:5]=[CH:4][C:3]=2[N:14]([C:15]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:21])[CH2:22]1
Reactant: CC(C)(C)OC(=O)N(CC=CCl)c1ccc2ccc(C#N)cc2c1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CC(CCl)c2c1ccc1ccc(C#N)cc21
Yield: 91.6 %

Procedure:
A mixture of 195 (3.00 g, 7.13 mmol), Bu3SnH (2.49 g, 8.55 mmol) and AIBN (120 mg, 0.71 mmol) in benzene (20 mL) was heated under reflux for 1.5 h. The benzene was removed under reduced pressure and the residue was triturated with pentane (×4) and recrystallised (MeOH) to give tert-butyl 1-(chloromethyl)-8-cyano-1,2-dihydro-3H-benzo[e]indole-3-carboxylate (196) (2.24 g, 92%) as colorless needles: mp 138-140° C.; 1H NMR (CDCl3) δ 8.35 (br s, 1H), 8.09 (s, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.48 (dd, J=8.5, 1.5 Hz, 1H), 430 (br d, J=11.2 Hz, 1H), 4.18 (dd, J=11.8, 8.7 Hz, 1H), 4.50 (tt, J=9.3, 3.0 Hz, 1H), 3.87 (dd, J=−11.3, 3.3 Hz, 1H), 3.53 (dd, J=11.2, 9.6 Hz, 1H), 1.61 (s, 9 M); 13C NMR δ 152.3, 142.9, 131.2, 130.2, 130.0, 128.9, 128.2, 124.2, 123.3, 119.2, 118.8, 110.5, 81.8, 52.8, 462, 41.5, 28.4. Anal. (C19H19ClN2O2) C, H, N.
Reaction SMILES: [C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C@@H:16]([OH:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2].C.N([CH2:29]NC(N)=O)=O.[H+].[B-](F)(F)(F)F>C(Cl)Cl>[C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C@@H:16]([O:23][CH3:29])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]1CC2
Reactant: NC(=O)NCN=O
Agent: C
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Product: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)[C@@H](OC)CC[C@H]3[C@@H]1CC2

Procedure:
1-Acetoxy-3-methoxyestra-1,3,5(10)-trien-17β-ol (1.0 g) is etherified with CH2H2, generated from N-nitrosomethylurea and catalyzed with a drop of 48% HBF4 in methylene chloride. The resulting polymethylene polymer is filtered and the methylene chloride filtrate is washed with 10% sodium bicarbonate solution, water and then dried over sodium sulfate. Evaporation in vacuo gives an oil which is crystallized from ethanol to give 1-acetoxy-3,17β-dimethoxy-1,3,5(10)-estratriene as a white solid, yield 0.78 g (75%); m.p. 81°-83° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:19][NH:20][C:21]([NH:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[C:26]([N+:34]([O-:36])=[O:35])[CH:25]=3)=[S:22])[CH3:18])[C:12]=2[OH:37])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:19][NH:20][C:21]([NH:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[C:26]([N+:34]([O-:36])=[O:35])[CH:25]=3)=[S:22])[CH3:18])[C:12]=2[OH:37])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(NC(=S)NN=C(C)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)c([N+](=O)[O-])c1)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
Methyl 4-{[(2-{1-[5-(4-t-butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)-carbonothioyl]amino}-2-nitrobenzoate (100 mg, 0.19 mmol) synthesized in Synthetic Example 102 was dissolved in methanol (6.7 ml), and 1 M sodium hydroxide aqueous solution (0.96 ml, 0.96 mmol) was added thereto, following by stirring overnight at room temperature. After, completion of the stirring, the reaction solution was washed with ethyl acetate, and to the aqueous layer, 1 M hydrochloric acid was added. The precipitated solid was filtered to obtain 27 mg of the desired product as a pale yellow solid (yield 28%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][C:12](O)=[O:13])=[CH:4][CH:3]=1.CSC.B>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])=[CH:6][CH:7]=1
Reactant: O=C(O)COCCc1ccc(Br)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OCCOCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
To a solution of [2-(4-bromophenyl)ethoxy]acetic acid (14 g, 0.054 mol; see step (ii) above) in dry THF (150 mL), borane methyl sulphide (6.16 g, 0.082 mol) was added, dropwise at from 0 to 5° C. The resulting mixture was stirred at room temperature for 3 h. After cooling the reaction mixture to between 0 and 5° C., 1.5 NHCl (80 mL) was added, dropwise, and the resulting mixture was refluxed for 30 minutes. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water and brine and concentrated to give the sub-title compound (yield: 10.8 g, 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:19])[CH3:18])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])[CH:7]=1.[Br:20][C:21]1[CH:26]=[CH:25][C:24](F)=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1.[F-].[K+]>CN(C=O)C>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([NH:1][C:2]2[CH:3]=[C:4]([NH:16][C:17](=[O:19])[CH3:18])[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=3[F:15])[CH:7]=2)=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(=O)Nc1cc(N)cc(-c2ccc(F)cc2F)c1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Nc2ccc(Br)cc2[N+](=O)[O-])cc(-c2ccc(F)cc2F)c1
Yield: 45 %

Procedure:
A solution of N-(5-amino-2′,4′-difluorobiphenyl-3-yl)acetamide (3.0 g, 11.44 mmol), 4-bromo-1-fluoro-2-nitrobenzene (2.52 g, 11.44 mmol, 1.0 eq.) and potassium fluoride (0.663 g, 11.44 mmol, 1.0 eq.) in DMF was heated at 130° C. for 5 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off under reduced pressure and the crude residue was purified by column chromatography (60-120 silica gel, 40% ethyl acetate in hexane) to afford the product in 45% yield (2.4 g).
Reaction SMILES: CN(C)C=[N:4][C:5]1[N:10]([CH2:11][CH3:12])[C:9](=[O:13])[N:8]([CH2:14][CH2:15][CH3:16])[C:7](=[O:17])[CH:6]=1>CO.N>[NH2:4][C:5]1[N:10]([CH2:11][CH3:12])[C:9](=[O:13])[N:8]([CH2:14][CH2:15][CH3:16])[C:7](=[O:17])[CH:6]=1
Reactant: CCCn1c(=O)cc(N=CN(C)C)n(CC)c1=O
Agent: N
Solvent: CO
Product: CCCn1c(=O)cc(N)n(CC)c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 6-[2-(dimethylamino)-1-azavinyl]-1-ethyl-3-propyl-1,3-dihydropyrimidine-2,4-dione (2.1 g) was dissolved in a mixture of methanol (10 ml) and 28% aqueous ammonia solution (20 ml), and stirred for 72 hours at room temperature. Solvent was then removed under reduced pressure, and the residue purified by chromatography on a silica gel column, eluting with a mixture of dichloromethane/methanol (15/1), to provide 6-amino-1-ethyl-3-propyl-1,3-dihydropyrimidine-2,4-dione, a compound of formula (8).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23](F)=[CH:22][C:21]=2[O:27][CH2:28][CH2:29][S:30][CH3:31])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[CH3:33][N:34]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(N)(=O)C1C=CC=CC=1>CS(C)=O.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([N:37]3[CH2:38][CH2:39][CH2:40][N:34]([CH3:33])[CH2:35][CH2:36]3)=[CH:22][C:21]=2[O:27][CH2:28][CH2:29][S:30][CH3:31])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: CN1CCCNCC1
Reactant: CSCCOc1cc(F)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Agent: NC(=O)c1ccccc1
Solvent: CS(C)=O
Solvent: ClCCl
Product: CSCCOc1cc(N2CCCN(C)CC2)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Temperature: 100 °C
Yield: 117.4 %

Procedure:
In a 4 mL screw-cap vial were dissolved 5-fluoro-2-[4-fluoro-2-(2-methylthioethoxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (131 mg, 274 μmol) and 1-methylhexahydro-1,4-diazepine (157 mg, 1.37 mmol, 5 eq) in 250 μL DMSO to give a light yellow solution. The solution was heated to 100° C. for 36 hours in a heatblock, then allowed to cool to room temperature. The resulting brown solution was diluted with 1 mL dichloromethane, washed four times with water, once with brine, then dried over sodium sulfate and concentrated. The residue was combined with that from a separate, smaller scale run (100 μmol of starting benzamide) and purified via radial chromatography with 95:5, then 9:1 dichloromethane:methanol to produce 184 mg (86%) of the title compound as a yellow oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C:18]1([OH:42])[CH2:23][CH2:22][N:21]([CH2:24][CH:25]([OH:41])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])=[CH:29][CH:28]=2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.[NH4+].[Cl-]>C(Cl)Cl>[CH2:11]([C:18]1([OH:42])[CH2:19][CH2:20][N:21]([CH2:24][C:25](=[O:41])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][Si:34]([C:37]([CH3:38])([CH3:39])[CH3:40])([CH3:35])[CH3:36])=[CH:29][CH:28]=2)[CH2:22][CH2:23]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(O)CN2CCC(O)(Cc3ccccc3)CC2)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)CN2CCC(O)(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
To a solution of oxalylchloride (0.28 ml, 3.3 mmol) in CH2Cl2 (4 ml) at -78° C. was added dropwise dimethyl sulfoxide (DMSO) (0.47 ml, 6.6 mmol). After 30 min., a solution of (RS)-4-Benzyl-1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-hydroxy-propyl}-piperidin-4-ol (0.75 g, 1.65 mmol) in CH2Cl2 (4 ml) was added. After another hour at -78° C., triethylamine (1.8 ml, 13.2 mmol) was added and reaction mixture was allowed to warm up slowly to room temperature. After 1 hour, 20% NH4Cl (15 ml) was added, the resulting aqueous phase was extracted with CH2Cl2 (3×30 ml). Combined organic phases were dried over Na2SO4 and concentrated. The residue was chromatographed over silica gel (hexane-ethylacetate 1:1 then ethyl acetate) to provide 1-(4-Benzyl-4-hydroxy-piperidin-1-yl)-3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propan-2-one (0.4 g, 54%) as a yellow oil, and MS: m/e=454.5 (M+H+).
Reaction SMILES: BrC1C=NC(I)=NC=1.FC1C=C(OCCCCCCCC)C=CC=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[F:34][C:35]1[C:40](F)=[C:39]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:38]=[CH:37][C:36]=1[C:51]1[N:56]=[CH:55][C:54]([Br:57])=[CH:53][N:52]=1>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.COCCOC>[F:34][C:35]1[CH:40]=[C:39]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:38]=[CH:37][C:36]=1[C:51]1[N:52]=[CH:53][C:54]([Br:57])=[CH:55][N:56]=1
Reactant: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)c(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Brc1cnc(I)nc1
Agent: CCCCCCCCOc1ccc(B(O)O)c(F)c1
Solvent: COCCOC
Product: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)c(F)c1
Yield: 69 %

Procedure:
--Quantities: 5-bromo-2-iodopyrimidine 2 (4.05 g, 14.2 mmol), 2-fluoro-4-octyloxyphenylboronic acid 5 (4.57 g, 17.0 mmol), tetrakis(triphenylphosphine)palladium (328 mg, 0.28 mmol), 2M sodium carbonate (50 ml), DME (50 ml). The experimental procedure was as described for compound 4 to yield the monofluorophenylpyrimidine 6 (3.68 g, 69%) (from MeOH), m.p. 7.16° C.; νmax /cm-1 (KBr) 2920, 2850, 1610, 1410, 1270, 1125 and 830; δ0.90 (3H, t, Me), 1.20-1.55 (10H, m), 1.82 (2H, quint, OCH2CH2), 4.00 (2H, t, OCH2), 6.75 (2H, m, 3'- and 4'-H), 8.06 (1H, t, 6'-H) and 8.85 (2H, s, 4- and 6-H); m/z 382 (M+), 380 (M+), 270 (M+ -C8H16), 268 (M+ -C8H16) and 137.
Reaction SMILES: Br[CH:2](C)[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]3[C:18]([NH2:33])=[N:19][CH:20]=[C:21]([C:23]4[CH:24]=[N:25][N:26]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:27]=4)[CH:22]=3)=[N:15][N:14]=[N:13]2)=[C:8]([F:34])[C:7]=1[F:35].[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.O.O1CCN(CCCCOC2C=CC(N3C(C4C(N)=NC=C(C5C=NN(CCC(C)C)C=5)C=4)=NN=N3)=C(F)C=2F)CC1>C1COCC1>[N:37]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[C:16]([C:17]4[C:18]([NH2:33])=[N:19][CH:20]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:27]=5)[CH:22]=4)=[N:15][N:14]=[N:13]3)=[C:8]([F:34])[C:7]=2[F:35])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: C1CCNCC1
Reactant: CC(C)CCn1cc(-c2cnc(N)c(-c3nnnn3-c3ccc(OCCC(C)Br)c(F)c3F)c2)cn1
Agent: CC(C)CCn1cc(-c2cnc(N)c(-c3nnnn3-c3ccc(OCCCCN4CCOCC4)c(F)c3F)c2)cn1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCn1cc(-c2cnc(N)c(-c3nnnn3-c3ccc(OCCCN4CCCCC4)c(F)c3F)c2)cn1
Temperature: 0 °C
Reaction time: 16 h
Yield: 62.5 %

Procedure:
As shown in step 5-iii of Scheme 5,3-(1-(4-(3-bromobutoxy)-2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(1-isopentyl-1H-pyrazol-4-yl)pyridin-2-amine (Compound 1021, 111 mg, 0.203 mmol) was dissolved in 5 mL of THF and cooled to 0° C. The mixture was treated with piperidine (0.06 mL, 0.61 mmol), warmed to 70° C., and stirred for 16 hours. The reaction was cooled to room temperature, treated with cold water, and extracted with CHCl3 (50 mL). The organics were washed with water, washed with brine, dried over sodium sulfate, filtered, and the volatiles removed under reduced pressure. The residue was purified by silica gel chromatography (5% MeOH/CHCl3) to provide 3-(1-(4-(3-(piperidin-1-yl)propoxy)-2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(1-isopentyl-1H-pyrazol-4-yl)pyridin-2-amine (Compound 150, 70 mg, 78% yield).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:8]([I:15])=[N:9][N:10]([CH:12]([CH3:14])[CH3:13])[CH:11]=1)=O.Cl.[NH2:18][C:19]([NH2:21])=[NH:20].[OH-].[Li+]>C(O)(CC)C>[I:15][C:8]1[C:7]([C:5]2[CH:4]=[CH:3][N:18]=[C:19]([NH2:21])[N:20]=2)=[CH:11][N:10]([CH:12]([CH3:14])[CH3:13])[N:9]=1
Reactant: N=C(N)N
Reactant: CC(C)n1cc(C(=O)C=CN(C)C)c(I)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCC(C)O
Product: CC(C)n1cc(-c2ccnc(N)n2)c(I)n1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
A mixture of crude Intermediate 3-(dimethylamino)-1-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)prop-2-en-1-one (4.0 g, 12.0 mmol), guanidine hydrochloride (2.63 g, 27.6 mmol), lithium hydroxide (635 mg, 27.6 mmol), and sec-butanol (50 ml) was heated with stirring in a sealed reaction vessel at 110° C. for 20 h. The cooled reaction mixture was concentrated, then water was added and the mixture was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered, and concentrated. Ethyl acetate was added to the solid residue, and the mixture was sonicated. The solid product was collected on a filter, rinsed with ethyl acetate, and dried to give the title compound as a tan solid. MS m/z 330.0 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)[CH3:2].[O:8]1CCC[CH2:9]1.C([Li])CCC.CCCCCC>CN(C)C=O>[CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH:9]=[O:8])[CH3:2]
Reactant: C1CCOC1
Reactant: CCn1ccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCn1ccnc1C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.2 %

Procedure:
Under nitrogen, a solution of 15.1 g (0.157 moles) N-ethylimidazole and 150 ml tetrahydrofuran was cooled to -40° C. Sixty-three ml 2.6M n-butyllithium in hexane (0.164 moles) was added via syringe. After fifteen minutes, 12.8 ml N,N-dimethylformamide was added and the reaction was allowed to warm to room temperature. After 18 hours the reaction was quenched with 5N hydrochloric acid. After stirring 15 minutes, the tetrahydrofuran was removed under reduced pressure. The remaining aqueous solution was basified with potassium carbonate solution and the product extracted into ethyl acetate (3×150 ml). After drying (anhydrous sodium sulfate) and concentration, 18.15 g (93.2%) of product was obtained as a pale tan oil, bp 90° C. at 12 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N(CC)CC)C.CS(ON1C2C=CC=CC=2N=N1)(=O)=O.[CH2:37]([N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[CH2:44][NH2:45])[CH3:38]>O1CCCC1>[CH2:37]([N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[CH2:44][NH:45][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:10]=[CH:11][C:3]=1[O:2][CH3:1])[CH3:38]
Reactant: CCN1CCCC1CN
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)O
Agent: CS(=O)(=O)On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)ccc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.8 %

Procedure:
2-Methoxy-5-sulfamoylbenzoic acid (2.3 g) and triethylamine (1.4 ml) are dissolved in anhydrous tetrahydrofuran (20 ml), and therto is added 1-methanesulfonyloxy-1,2,3-benzotriazole (2.2 g). After stirring at room temperature for 20 minutes, to the mixture is added 1-ethyl-2-aminomethylpyrrolidine (1.3 g) to precipitate oily products with exotherm. The mixture is stirred for 1 hour and then the solvent is distilled off. The resulting oily residue is dissolved in 1 N hydrochloric acid and the solution is washed twice with ethyl acetate. The aqueous layer is distilled under a reduced pressure to remove the remaining ethyl acetate and made alkaline with aqueous ammonia. The resulting precipitates are separated by filtration, washed with diluted aqueous ammonia and dried to give 1-ethyl-2-(2-methoxy-5-sulfamoylbenzamidomethyl)pyrrolidine (2.2 g), melting point: 175°-177° C.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[N:11][C:10]([NH:13][NH2:14])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](O)(=O)[CH2:16][OH:17].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:15]([CH2:16][OH:17])=[N:14][N:13]=3)[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNc1ccc(-c2ccccc2)nn1
Reactant: O=C(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1nnc2ccc(-c3ccccc3)nn12

Procedure:
A mixture of 1-(6-phenylpyridazin-3-yl)hydrazine (2.00 g, 10.7 mmol), glycolic acid (0.825 g, 10.8 mmol), p-TsOH.H2O (2.55 g, 13.4 mmol) in PhMe (50 mL) was refluxed for 14 h. PhMe was removed in vacuo. The resulting solids were diluted with water (30 mL). The mixture was brought to pH˜10 with 2N NaOH. The solids were isolated solid by filtration, washed with water and dried under vacuum to give an off white solid which was used without further purification. (ESI, pos. ion) m/z: 227.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:5].[S:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(O)(=O)C>[CH2:23]([O:22][C:19]1[CH:20]=[CH:21][C:2]([NH:1][CH:33]2[CH2:34][CH2:35][S:30][CH2:31][CH2:32]2)=[C:3]([CH:18]=1)[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:5])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1CCSCC1
Reactant: COc1ccc(CNC(=O)c2cc(OCc3ccccc3)ccc2N)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(CNC(=O)c2cc(OCc3ccccc3)ccc2NC2CCSCC2)cc1OC
Yield: 67.8 %

Procedure:
A mixture of 0.235 g of 2-amino-5-(benzyloxy)-N-(3,4-dimethoxybenzyl)benzamide, 0.090 g of tetrahydro-4H-thiopyran-4-one and 0.78 g of sodium triacetoxyborohydride in 0.5 ml of acetic acid is irradiated in a microwave field for 5 minutes at 130° C. 1N HCl is added and the mixture is extracted with EtOAc. The organic phase is dried over MgSO4 and filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a heptane/EtOAc mixture from (90/10, v/v) to (20/80, v/v) to give 0.2 g of the expected product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[F:16])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: Nc1ccccc1F
Product: Fc1ccccc1NC1CCCc2c1[nH]c1ccc(Br)cc21

Procedure:
6-Bromo-N-(2-fluorophenyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (200 mg, 0.76 mmol) and 2-fluoroaniline (168 mg, 1.51 mmol) in a similar manner as described above to give 37 mg (14%) of a white solid; 1H-NMR (DMSO-d6): δ 11.04 (s, 1H), 7.55 (d, 1H), 7.23 (d, 1H), 7.12 (dd, 1H), 7.05-6.85 (m, 3H), 6.59-6.54 (m, 1H), 5.53 (m, 1H), 4.87-4.82 (m, 1H), 2.68-2.57 (m, 2H), 2.04-1.92 (m, 2H), 1.87-1.72 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[H-]>>[Cl:1][C:2]1[CH:11]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][C:3]=1[O:12][CH2:13][C:14]([F:15])([F:16])[F:17]
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(Cl)c1
Agent: [H-]
Product: OCc1cnc(OCC(F)(F)F)c(Cl)c1
Yield: 78 %

Procedure:
The title compound is prepared in 78% yield (210 mg, white solid) from methyl 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinate (300 mg, 1.1 mmol, Step-1) and diisobutylalminium hydride (1.0 M in hexane, 2.4 mL, 2.4 mmol) instead of lithium aluminum hydride in a similar manner to Step-2 of Amine-3.