Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8]1([CH2:34][CH2:35][O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[S:12][C:11]2[CH:13]=[C:14]3[S:18][C:17]([CH2:26][CH2:27][O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH2:19][CH2:20][O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:16][C:15]3=[CH:33][C:10]=2[S:9]1)([CH3:4])([CH3:3])[CH3:2].[I:41]I.S(=O)(O)[O-].[Na+]>>[C:29]([O:28][CH2:27][CH2:26][C:17]1([CH2:19][CH2:20][O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:18][C:14]2[C:13]([I:41])=[C:11]3[S:12][C:8]([CH2:34][CH2:35][O:36][C:37]([CH3:40])([CH3:39])[CH3:38])([CH2:7][CH2:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[S:9][C:10]3=[CH:33][C:15]=2[S:16]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OCCC1(CCOC(C)(C)C)Sc2cc3c(cc2S1)SC(CCOC(C)(C)C)(CCOC(C)(C)C)S3
Reactant: II
Agent: O=S([O-])O
Agent: [Na+]
Product: CC(C)(C)OCCC1(CCOC(C)(C)C)Sc2cc3c(c(I)c2S1)SC(CCOC(C)(C)C)(CCOC(C)(C)C)S3
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
A dry flask under argon was charged with 2,2,6,6-tetra(t-butoxyethyl)benzo[1,2-d:4,5-d']bis(1,3)dithiole (60.0 g, 95.08 mmol) and dry tetrahydroturan (2000 ml). The mixture was cooled to -20° C. and n-Butyl lithium (76 ml of a 2.5 M solution in hexane, 0.19 mol) was added over 3 minutes. The mixture was stirred for 20 minutes at -20° C. and then a solution of iodine (120 g, 0.475 mol) in tetrahydroturan (500 ml) was added. The reaction mixture was poured into an aqueous sodium bisulphite solution and extracted with diethyl ether. The organic phase was washed once with an aqueous solution of sodium bisulphite and once with brine, dried (MgSO4) and evaporated.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[C:4]#[N:5].O=[C:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19]([C:18]1[C:17]([CH3:24])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[C:6]([O:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=[CH:8][CH:9]=2)=[O:20])[CH3:23]
Reactant: CC(C)(C)COc1cccc(N)c1C#N
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(neopentyloxy)benzonitrile (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl 3-oxobutanoate as a white solid (64%). 1H NMR (400 MHz, DMSO-d6) δ 1.06 (s, 9H), 1.32 (t, J=6.8 Hz, 3H), 2.54 (s, 3H), 3.86 (s, 2H), 4.31 (q, J=6.8 Hz, 2H). 6.88-6.91 (m, 1H), 7.22-7.25 (m, 1H), 7.50 (t, J=8.0 Hz, 1H), 8.06 (s, 2H). MS 317 (MH+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:11]2[C:16]([CH3:17])=[CH:15][S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[C:11]3[C:16]([CH3:17])=[CH:15][S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: COc1ccc(CNc2nc(Cl)nc3scc(C)c23)cc1OC
Reactant: Cc1ncc[nH]1
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3scc(C)c23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[N:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[CH:42]=2)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1.O>[CH:24]([N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:5]3[C:6]4[N:7]([N:8]=[CH:9][N:10]=4)[C:2]([C:41]4[CH:46]=[CH:45][N:44]=[C:43]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[CH:42]=4)=[CH:3][N:4]=3)=[CH:13][CH:14]=2)[CH2:19][CH2:20]1)([CH3:26])[CH3:25]
Reactant: CC(C)N1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cc2)CC1
Reactant: CC(=O)OCc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)OCc1cc(-c2cnc(Nc3ccc(N4CCN(C(C)C)CC4)cc3)c3ncnn23)ccn1
Temperature: 25 °C

Procedure:
A suspension of (5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-[4-(4-isopropyl-piperazin-1-yl)phenyl]amine (300 mg, 0.723 mmol) and Pd(dppf)Cl2 (59 mg, 10 mol %) in 4/1 dioxane/water (5 mL) is stirred at rt and potassium carbonate (200 mg, 1.45 mmol, 2.0 equiv.) and acetic acid 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-ylmethyl ester (300 mg, 1.08 mmol, 1.5 equiv.) are added. The resulting mixture is heated at 85° C. overnight. The resulting solution is partitioned between dichloromethane and water, and the organic layer is concentrated onto silica and purified by column chromatography (98/2 DCM/MeOH) to afford the title compound as a yellow solid. LCMS: Rt=0.78 min (100%), m/z 445 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[C:22]([C:24]1[CH:25]=[C:26]([CH3:33])[C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1)#[N:23]>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:15])[F:16])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30](=[O:31])[C:27]3[C:26]([CH3:33])=[CH:25][C:24]([C:22]#[N:23])=[CH:29][N:28]=3)[CH:3]=[CH:4][C:5]=2[F:21])([CH2:19][F:20])[N:9]=1
Reactant: Cc1cc(C#N)cnc1C(=O)O
Reactant: NC1=N[C@](CF)(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)O1
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-2) and 5-cyano-3-methylpicolinic acid [S. Badiger et al. WO2011009943 (2011)] following General Procedure G yielded the title compound as a light yellow solid. MS: m/z=454.4 [M+H]+.
Reaction SMILES: COC1C=C(CNCCC2(C3C=CC(F)=CC=3)CCOC(C)(C)C2)C=CC=1OC.[C:30]([CH:32]([C:37]1([C:48]2[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=2)[CH2:42][C:41]2([CH2:47][CH2:46][CH2:45]C[CH2:43]2)[O:40][CH2:39][CH2:38]1)C(OC)=O)#[N:31].C(C(C1(C2C=CC(F)=CC=2)CC2(CCCC2)OCC1)C(OC)=O)#N.FC1C=CC(C2(CC#N)CC3(CCCCC3)OCC2)=CC=1>>[F:54][C:51]1[CH:50]=[CH:49][C:48]([C@@:37]2([CH2:32][C:30]#[N:31])[CH2:42][C:41]3([CH2:43][CH2:45][CH2:46][CH2:47]3)[O:40][CH2:39][CH2:38]2)=[CH:53][CH:52]=1
Reactant: COC(=O)C(C#N)C1(c2ccc(F)cc2)CCOC2(CCCCC2)C1
Agent: COC(=O)C(C#N)C1(c2ccc(F)cc2)CCOC2(CCCC2)C1
Agent: COc1ccc(CNCCC2(c3ccc(F)cc3)CCOC(C)(C)C2)cc1OC
Agent: N#CCC1(c2ccc(F)cc2)CCOC2(CCCCC2)C1
Product: N#CC[C@@]1(c2ccc(F)cc2)CCOC2(CCCC2)C1

Procedure:
By the procedure described in the preparation of intermediate 10 substituting methyl 2-cyano-2-[4-(4-fluorophenyl)-1-oxaspiro[5.5]undecan-4-yl]acetate for methyl 2-cyano-2-[9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]acetate, 2-[4-(4-fluorophenyl)-1-oxaspiro[5.5]undecan-4-yl]acetonitrile was prepared (m/z 287.2 [M+H]+ observed).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]([N:15]2[N:19]=[CH:18][C:17]3([CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:16]2)SC)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:24].[CH2:25]([NH2:27])[CH3:26].O>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]([N:15]2[N:19]=[CH:18][C:17]3([CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:16]2)[NH:27][CH2:25][CH3:26])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:24]
Reactant: CSC(=NS(=O)(=O)c1ccc(N)c(F)c1)N1CC2(C=N1)CCCC2
Reactant: CCN
Solvent: O
Solvent: CO
Product: CCNC(=NS(=O)(=O)c1ccc(N)c(F)c1)N1CC2(C=N1)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a solution of 840 mg 4-amino-N-[(2,3-diaza-spiro[4.4]non-3-en-2-yl)-methylsulfanyl-methylene]-3-fluoro-benzenesulfonamide (crude) in 25 mL MeOH was added 3.43 mL of a 70% aqueous solution of ethylamine. The mixture was stirred for 1 h. at room temperature, water was added, and the mixture was extracted with DCM. The combined organic layers were dried over MgSO4 and evaporated to dryness. The residue was purified by flash chromatography (EA/PA 3:1) to give 260 mg (33% over 2 steps) of 4-amino-N-[(2,3-diaza-spiro[4.4]non-3-en-2-yl)-ethylamino-methylene]-3-fluoro-benzenesulfonamide as a brown oil. 1H NMR (400 MHz, CDCl3) δ 1.16 (t, J=7.2 Hz, 3H), 1.57-1.87 (m, 7H), 3.43-3.53 (m, 2H), 3.82 (s, 2H), 4.02-4.07 (m, 2H), 6.77 (t, J=8.4 Hz, 1H), 6.80 (s, 1H), 7.50-7.58 (m, 2H) [NH2 invisible].
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-])=O.C([O-])([O-])=O.[K+].[K+].[C:21]([O:25][CH3:26])(=[O:24])[CH2:22][SH:23]>CN(C=O)C>[CH3:26][O:25][C:21]([C:22]1[S:23][C:4]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=2[CH:6]=1)=[O:24]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc([N+](=O)[O-])cc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2,4-dinitrobenzaldehyde (6.45 g, 32.9 mmol) and K2CO3 (5.45 g, 39.4 mmol) in DMF (60 mL) was slowly added methyl thioglycolate (3.0 mL, 32.9 mmol). The mixture was stirred at RT for 1 h, then at 50° C. for 2 h. The resultant mixture was poured into H2O/ice and stirred until a precipitate formed. The solid was filtered and triturated with hot MeOH. The pale brown solid was filtered. 1H NMR (DMSO-d6) δ 9.13 (s, 1H), 8.33 (s, 1H), 8.30-8.17 (m, 2H), 3.89 (s, 3H). MS (EI): cal'd (MH+) 238.01, exp (MH+) 238.10.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:24][CH2:25][CH3:26])[C:15]2[C:20]([N+:21]([O-])=O)=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+]>[Cl-].[Ti+3].[Cl-].[Cl-]>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:24][CH2:25][CH3:26])[C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN(c1ncccc1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1
Agent: [Ti+3]
Agent: [Cl-]
Agent: [NH4+]
Product: CCCN(c1ncccc1N)C1CCN(Cc2ccccc2)CC1
Reaction time: 18 h

Procedure:
A mixture of 1-benzyl-4-[N-propyl-N-(3-nitro-2-pyridinyl)amino]piperidine (EXAMPLE 113, 2.61 g) in aqueous titanium (III) chloride (30 ml, 19 wt % in 20% aqueous hydrochloric acid) is stirred under reduced pressure for 18 hrs and then added to concentrated aqueous ammonium hydroxide (250 ml), and the resulting mixture is extracted with methylene chloride (4×100 ml). The combined organic phase is washed with saline (50 ml), dried over sodium sulfate, and concentrated under reduced pressure to give the crude product which is then chromatographed (silica gel, 230-400 mesh, 150 g; eluting with a gradient of methanol/methylene chloride (2.5/97.5-5/95)) to give the title compound, mp=73°-74°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[CH2:8][C:7]=1[C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=1.[CH3:13][N:14]([CH2:18][CH2:19]Cl)[CH2:15][CH2:16]Cl.Cl.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:7]12[CH2:8][C:4](=[CH:3][C:2]=1[N:1]1[CH2:19][CH2:18][N:14]([CH3:13])[CH2:15][CH2:16]1)[C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]2=1
Reactant: CN(CCCl)CCCl
Reactant: NC1=C2CC(=C1)c1ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN1CCN(C2=C3CC(=C2)c2ccccc23)CC1

Procedure:
2-Aminobenzobicyclo[2.2.1]heptene (1.1 g) was combined with mechlorethamine hydrochloride (1.4 g), potassium carbonate (1.5 g), and acetonitrile (25 ml) and heated to reflux for 24 hours. Water (50 ml) was added to the mixture and the resulting mixture was extracted with ether (3×50 ml). The combined ether solutions were dried over magnesium sulfate and the ether was removed on a rotary evaporator. The residue was combined with concentrated hydrochloric acid (5 ml) and 2-propanol (25 ml) and the solvent was removed on a rotary evaporator. The residue was suspended in 2-propanol and the solvent was removed on a rotary evaporator. This latter step was repeated. The residue was recrystallized from 2-propanol to provide the product as a tan solid. Analytical data are reported in Table I.
Reaction SMILES: Br[C:2]1[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3C2CCCCO2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].CC1(C)C(C)(C)OB([C:38]2[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH:43]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[Cl:9][C:6]1[C:7]([F:8])=[C:2]([C:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH:39]=2)[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][NH:17]3)[CH3:11])[CH:5]=1
Reactant: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(F)c1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(F)c1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Yield: 55 %

Procedure:
Into a microwave vial was added N-[1-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (85 mg, 0.17 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (65 mg, 0.21 mmol, Aldrich #706531), sodium carbonate (420 μL, 0.44 mmol), 1,4-dioxane (1 mL) and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.010 mmol). The mixture was bubbled with nitrogen for 5 min and heated at 90° C. overnight. The mixture was diluted with water, extracted with EtOAc, dried over magnesium sulfate and concentrated. Purification on silica gel using 0-100% EtOAc in hexane gave the desired compound (47 mg, 46%). LCMS calculated for C29H37ClFN6O4 (M+H)+: m/z=586.3. found: 587.2.
Reaction SMILES: Cl.[F:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[N:12]([O-])=O.[Na+]>Cl.O>[F:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH:5][NH2:12]
Reactant: O=N[O-]
Reactant: COc1ccc(N)c(F)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(NN)c(F)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 38.1 %

Procedure:
To a vigorously stirred suspension of 2-fluoro-4-methoxyaniline hydrochloride (665 mg, 3.7 mmol) in conc. HCl (5.5 mL) cooled to 0° C. was added a cold solution of NaNO2 (312 mg, 4.5 mmol) in H2O (1 mL). The mixture was stirred at 0° C. for 90 min. A cold solution of SnCl2-2H2O (3.4 g, 15.0 mmol) in conc. HCl (5.5 mL) was then added slowly to the solution of diazonium salt. The reaction was allowed to warm to room temperature, stirred for 30 min and the reaction was filtered. The collected precipitate was washed on the filter with several large portions of ether and dried under vacuum. The solid was dissolved in DCM and washed saturated NaHCO3, extracted and dried using a phase separator. Evaporation gave (2-fluoro-4-methoxyphenyl)hydrazine (220 mg 38%), which was used in the next step without further purification. The procedure was adapted from J. Med. Chem. 2000, 43, 4701.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH:25]=[CH2:26])[C@@H:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[NH:10][CH:11]([CH:15]2[CH2:17][CH2:16]2)[CH:12]2[CH2:14][CH2:13]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36].C(OCC)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH:25]=[CH2:26])[C@H:9]([N:10]([CH:11]([CH:12]2[CH2:13][CH2:14]2)[CH:15]2[CH2:16][CH2:17]2)[C:34](=[O:37])[CH:35]=[CH2:36])[C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=C[C@H](c1cccc(Cl)c1)[C@H](NC(C1CC1)C1CC1)c1ccc(Cl)cc1
Reactant: C=CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)N(C(C1CC1)C1CC1)[C@H](c1ccc(Cl)cc1)[C@H](C=C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2.1 g (5.44 mmol) of (1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)-N-(dicyclopropylmethyl)but-3-en-1-amine (Example 115, Step F) and triethylamine (1.89 mL, 13.59 mmol) in THF (30.0 mL) was added acryloyl chloride (0.66 mL, 8.15 mmol) at 0° C. The resulting reaction mixture was stirred at rt for 2 h. When LCMS indicated completion of the reaction, 100 ml of ethyl acetate was added and the combined organics were washed consecutively with water (10 ml), citric acid (10 ml, 1M), NaHCO3 solution (10 ml) and sat. NaCl solution (30 ml), dried over MgSO4, filtered and the filtrate was concentrated. The crude product was purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate, 90/10 to 20/80) to give the title compound.
Reaction SMILES: [CH2:1]1[CH2:5]OC[CH2:2]1.Cl[C:7]1[N:12]=[C:11]([C:13]2[CH:30]=[CH:29][C:16]([CH2:17][N:18]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:28])=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=1.[F-].[Cs+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CN(C=O)C>[CH2:11]([N:12]([CH2:2][CH2:1][CH3:5])[CH2:7][CH2:8][CH2:9][C:7]1[N:12]=[C:11]([C:13]2[CH:30]=[CH:29][C:16]([CH2:17][N:18]3[C:19](=[O:28])[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]3=[O:27])=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=1)[CH2:13][CH3:14]
Reactant: C1CCOC1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(-c2cccc(Cl)n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCN(CCC)CCCc1cccc(-c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
An anhydrous THF solution (1.0 ml) containing 2-propenyl dipropylamine (158 mg) was cooled with ice and a 0.5 mol/l 9-borabicyclo-[3,3,1]-nonane(9-BBN)/THF solution (2.06 ml) was dropped thereto. The whole was gradually warmed to room temperature and stirred for 5 hours. After that, a 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (PdCl2 (dppf)) (210 mg) and the compound (300 mg) obtained in Example 36-3 were added thereto together with DMF (3.0 ml), and a 3 mol/l aqueous solution (0.86 ml) of cesium fluoride was added thereto. The whole was stirred at 80° C. for 23 hours and then heated to 100° C. and stirred for 2 hours. After the resultant was cooled to room temperature, a solid component was separated by filtration and the solvent was distilled off. The concentrate was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform, and dried with anhydrous magnesium sulfate, followed by distillating off the solvent. The resultant residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (44.0 mg) as a pale-brown liquid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[C:11]([NH:14][NH2:15])(=O)[CH3:12].CCOC(C)=O>O=P(Cl)(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[O:8][C:11]([CH3:12])=[N:14][N:15]=2)=[CH:9][CH:10]=1
Reactant: CC(=O)NN
Reactant: O=C(O)c1ccc(I)cc1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nnc(-c2ccc(I)cc2)o1
Temperature: 80 °C
Yield: 31.9 %

Procedure:
A mixture of 4-iodobenzoic acid (1.0 g) and acethydrazide (329 mg) in POCl3 (4 ml) is stirred over night at 80° C., then another day at 100° C. AcOEt (50 ml) is added and the mixture is washed with H2O (50 ml), sat. aq. Na2CO3 sol. (50 ml) and H2O (50 ml). After drying over Na2SO4 the solvent is evaporated and the product is purified by flash chromatography (silica gel, CH2Cl2/MeOH/25% aq. NH4OH 90:9:1). 368 mg of 2-(4-iodo-phenyl)-5-methyl-[1,3,4]oxadiazole (19) are obtained as a yellowish solid, MS (ESI) 287.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10]I)[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:6]=1)=[O:4].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CO>[CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:6]=1)=[O:4]
Reactant: C1COCCN1
Reactant: COC(=O)c1nc(CI)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Solvent: CO
Product: COC(=O)c1nc(CN2CCOCC2)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Reaction time: 8 h

Procedure:
A mixture of 38.7 g (0.075 mole) of 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(iodomethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester and 13.1 g (0.150 mole) of morpholine in 750 ml of methanol is stirred for 8 hours at 40°. The reaction mixture is then concentrated in vacuo; water is added to the residue and extraction is performed twice with methylene chloride. The organic phase is washed three times with water and twice with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo. The residue is triturated with ether, whereupon the reaction product is obtained in crystalline form. After filtration with suction and drying in vacuum, there is obtained 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(morpholinomethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester, m.p. 141°-143°.
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:10]=[C:11]([C:15]3[N:23]4[C:18]([CH:19]=[N:20][C:21](O)=[N:22]4)=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH:26]=1>>[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:21]3[N:20]=[CH:19][C:18]4=[CH:17][CH:16]=[C:15]([C:11]5[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([N:1]6[CH2:5][CH2:4][CH2:3][CH2:2]6)(=[O:8])=[O:7])[CH:10]=5)[N:23]4[N:22]=3)=[CH:33][CH:32]=2)[CH:26]=1
Reactant: O=S(=O)(c1cccc(-c2ccc3cnc(O)nn23)c1)N1CCCC1
Reactant: Nc1ccc(-c2cccnc2)cc1
Product: O=S(=O)(c1cccc(-c2ccc3cnc(Nc4ccc(-c5cccnc5)cc4)nn23)c1)N1CCCC1

Procedure:
(4-Pyridin-3-yl-phenyl)-{7-[3-(pyrrolidine-1-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl}-amine was prepared from 7-[3-(pyrrolidine-1-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 4-pyridin-3-yl-phenylamine in an analogous manner to Example 1052a. Product isolated as a yellow solid (88 mg, 58%). m.p.=194-200° C.; LCMS (m/e) 497 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.87 (s, 1H), 8.78 (s, 1H), 8.56 (d, 1H, J=4.3 Hz), 8.53 (s, 1H), 8.43 (d, 1H, J=8.0 Hz), 7.91 (d, 1H, J=8.0 Hz), 7.84 (d, 1H, J=7.8 Hz), 7.74 (d, 1H, J=8.6 Hz), 7.71-7.61 (m, 3H), 7.35 (dd, 1H, J=4.9 and 7.7 Hz), 7.09 (d, 1H, J=4.8 Hz), 6.98 (s, 1H), 6.89 (d, 1H, J=4.8 Hz), 3.36-3.22 (m, 4H), 1.83-1.72 (m, 4H).