Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@:10]2([CH3:21])[CH2:15][C@@H:14]([C:16]([F:19])([F:18])[F:17])[O:13][C:12]([NH2:20])=[N:11]2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([NH2:31])=[O:30])=[N:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.O1CCOCC1>[NH2:20][C:12]1[O:13][C@H:14]([C:16]([F:19])([F:18])[F:17])[CH2:15][C@:10]([C:4]2[CH:3]=[C:2]([NH:31][C:29](=[O:30])[C:26]3[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][N:27]=3)[CH:7]=[N:6][C:5]=2[O:8][CH3:9])([CH3:21])[N:11]=1
Reactant: COc1ncc(Br)cc1[C@]1(C)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: NC(=O)c1ccc(Cl)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ncc(NC(=O)c2ccc(Cl)cn2)cc1[C@]1(C)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 120 °C
Yield: 23.9 %

Procedure:
A microwave vial was charged with (4S,6S)-4-(5-bromo-2-methoxypyridin-3-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.100 g, 0.272 mmol), 5-chloropicolinamide (0.064 g, 0.407 mmol), copper(I) iodide (10.35 mg, 0.054 mmol) and potassium carbonate powder (0.113 g, 0.815 mmol). The vial was purged with nitrogen followed by the addition of 1,4-dioxane 1 mL and (1R,2R)-(−)-N,N″-dimethylcyclohexane-1,2-diamine (0.043 ml, 0.272 mmol). The vial was sealed and heated at 120° C. overnight. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc three times. The organic layers were combined, washed with brine and dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography using a gradient of 15-85% EtOAc/hexane to give N-(5-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-6-methoxypyridin-3-yl)-5-chloropicolinamide (0.029 g, 0.065 mmol, 24.06% yield). MS m/z=443.9 [M+H]+. Calculated for C18H17ClF3N5O3: 443.8
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:30]([NH:32][CH3:33])=[O:31])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:20])=[O:16])[C:10](=[O:34])[CH:9]1[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[OH:42][C:39]1[CH:38]=[CH:37][C:36]([CH2:35][CH:9]2[NH:8][CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:30]([NH:32][CH3:33])=[O:31])[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:20])=[O:16])[C:10]2=[O:34])=[CH:41][CH:40]=1
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CN1CCN(C(=O)OC(C)(C)C)C(Cc2ccc(O)cc2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CN1CCNC(Cc2ccc(O)cc2)C1=O

Procedure:
Piperazinone acetyl-gly-phe-NHCH3 11a (0.58 g, 1.0×10-3 mole) and trifluoroacetic acid are stirred at room temperature for 1/2 hour. The solvent is then evaporated and the residue dissolved in CH2Cl2. The CH2Cl2 solution is washed in turn with saturated aqueous NaHCO3 and saturated aqueous NaCl before being dried over Na2SO4. Filtration of the drying agent and evaporation of the filtrate give 12a which is purified by chromatography and the structure corroborated by NMR. NMR (Acetone-d6) δ (d, 3, methyl amide), 3.0-4.3 (m, 14, methylenes and phenolic-OH), 4.53 (m, 1, phenylalanine methine), 6.88 (8, 4, aromatic), 7.25 (s, 5, aromatic), 7.6-8.0 (m, 3, amide NH's).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)=[O:16])=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][C:15]([N:17]4[CH2:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH2:18]4)=[O:16])=[CH:6][CH:7]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)N1Cc2ccccc2C1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(=O)N4Cc5ccccc5C4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-1-(1,3-dihydro-isoindol-2-yl)-ethanone and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.Cl[C:9]1[CH:10]=[C:11]([N:28]([CH:38]2[CH2:40][CH2:39]2)[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:12]2[N:13]([C:15]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=3)=[O:19])=[CH:16][N:17]=2)[N:14]=1>CN1C(=O)CCC1.CO>[Cl:27][C:23]1[CH:22]=[C:21]([NH:20][C:18]([C:15]2[N:13]3[N:14]=[C:9]([NH:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH:10]=[C:11]([N:28]([CH:38]4[CH2:39][CH2:40]4)[CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[C:12]3=[N:17][CH:16]=2)=[O:19])[CH:26]=[CH:25][N:24]=1
Reactant: NC1CCOCC1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Solvent: CO
Solvent: CN1CCCC1=O
Product: COc1ccc(CN(c2cc(NC3CCOCC3)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.4 %

Procedure:
A solution of tetrahydro-2H-pyran-4-amine (105 mg, 1.034 mmol) and 6-chloro-N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (50 mg, 0.103 mmol) in NMP (1 mL) was heated to 140° C. The reaction was stirred for 16 hours until starting material was consumed and then cooled to room temperature. The crude reaction product was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 40 min gradient, monitored at 220 nm). The product (retention time=47.580 minutes) was isolated and lyophilized to dryness. to afford N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)-6-(tetrahydro-2H-pyran-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (7 mg, 11.57%). HPLC Rt=4.595 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). [M+H+]=548.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]2[C:18]#[N:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2].S(Cl)([Cl:23])(=O)=O>ClC(Cl)(Cl)Cl>[Cl:23][C:15]1[CH:14]=[C:13]([C:18]#[N:19])[N:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[C:16]=1[CH3:17]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)c1ccc(-n2c(C)ccc2C#N)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(-n2c(C#N)cc(Cl)c2C)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a suspension of 1-(4-ethoxycarbonylphenyl)-5-methylpyrrole-2-carbonitrile (1.76 g) and silica gel (8.0 g, Mallinckrodt) in tetrachloromethane (26 ml) was added dropwise sulfuryl chloride (760 μl) at 5° C. under nitrogen atmosphere. The suspension was stirred at 5° C. for one hour and then at ambient temperature for half an hour. The mixture was filtered off and washed with a little amount of tetrachloromethane. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (elution by ethyl acetate/n-hexane=1/7) to yield 4-chloro-1-(4-ethoxycarbonylphenyl)-5-methylpyrrole-2-carbonitrile (1.36 g).
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(N[C:42]1[CH:47]=[CH:46][C:45]([C:48](=[O:53])NCCC)=[CH:44][CH:43]=1)=O)C2>>[C:48]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:28]3)=[O:19])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)(=[O:53])[C:45]1[CH:46]=[CH:47][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccccc2C1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CC(=O)Cl
Product: O=C(Nc1ccc(C2=CCN(C(=O)c3ccccc3)CC2)cc1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting benzoyl chloride for acetyl chloride and N-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-1,3-dihydro-2H-isoindole-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (s, 1H), 7.56-7.59 (m, 2H), 7.44-7.49 (m, 5H), 7.34-7.40 (m, 4H), 7.29-7.34 (m, 2H), 5.91-6.27 (m, 1H), 4.76-4.77 (bs, 4H), 4.02-4.26 (m, 2H), 3.36-3.59 (m, 2H), 2.51-2.61 (m, 2H); MS (ESI(+)) m/e 424 (M+H)+.
Reaction SMILES: [OH:1]O.[C:3]1([S:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N>C(O)(=O)C>[C:3]1([S:9]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OO
Reactant: c1ccc(Sc2cccnc2)cc1
Agent: N
Solvent: CC(=O)O
Product: O=S(c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
23.6 g. 35% perhydrol is added dropwise to a solution of 44 g. 3-phenylthiopryidine in 200 ml. glacial acetic acid. The reaction mixture is stirred for 24 hours at ambient temperature and then poured into ice water. The mixture is rendered alkaline by adding aqueous ammonia, while cooling, and then extracted with dichloromethane. The extract is dried and evaporated and the residue is recrystallised from diisopropyl ether/ethyl acetate. There is obtained 3-(phenyl-sulphinyl)-pyridine in a yield of 83% of theory; m.p. 56° C.
Reaction SMILES: [C:1]([N:5]([C:20](=[O:29])[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1)[NH:6][C:7](=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[CH2:16][S:17][CH3:18])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:38])C=1>C(Cl)Cl>[C:1]([N:5]([C:20](=[O:29])[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1)[NH:6][C:7](=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[CH2:16][S:17]([CH3:18])=[O:38])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cccc(C(=O)NN(C(=O)c2cc(C)cc(C)c2)C(C)(C)C)c1CSC
Solvent: ClCCl
Product: COc1cccc(C(=O)NN(C(=O)c2cc(C)cc(C)c2)C(C)(C)C)c1CS(C)=O
Reaction time: 0.08 h

Procedure:
3-Methoxy-2-methylsulfanylmethyl-benzoic acid N′-tert-butyl-N′-(3,5-dimethyl-benzoyl)-hydrazide in CH2Cl2 was stirred at room temperature with 1.0 eq of m-chloroperbenzoic acid. The reaction was complete within 5 min as indicated by TLC. The reaction mixture was washed with saturated NaHCO3 and the organic layer was stripped under vacuum. The residue was mixed with 1-2 mL of 1:1 ether:hexane and the solution was removed with a pipette, leaving the product which was then dried under vacuum.
Reaction SMILES: COC([N:5]1[CH2:10][C@@H:9]([CH2:11][C@@H:12]([CH2:16][CH3:17])[CH2:13][CH2:14][CH3:15])[C:8](=[O:18])N(C)[C@@H]1C(C)(C)C)=O.Cl.[O:25]1CCOCC1>>[NH2:5][CH2:10][C@@H:9]([CH2:11][C@@H:12]([CH2:16][CH3:17])[CH2:13][CH2:14][CH3:15])[C:8]([OH:18])=[O:25]
Reactant: C1COCCO1
Reactant: CCC[C@H](CC)C[C@@H]1CN(C(=O)OC)[C@@H](C(C)(C)C)N(C)C1=O
Agent: Cl
Product: CCC[C@H](CC)C[C@H](CN)C(=O)O
Temperature: 105 °C
Yield: 57 %

Procedure:
A stirred solution of (2S,5R)-2-tert-butyl-5-((S)-2-ethyl-pentyl)-3-methyl-4-oxo-tetrahydro-pyrimidine-1-carboxylic acid methyl ester (0.185 g, 0.567 mmol) in a 1:1 mixture of 6N HCl/dioxane (8 mL) was heated at 105° C. for 6 days. The reaction was cooled to room temperature and concentrated under reduced pressure. The product was dissolved in 1:1 MeOH/H2O and loaded onto an ion exchange chromatography column (Varian SCX-Prepacked 10 g, 60 mL) and eluted with 1:1 MeOH/H2O (95%)+NH4OH. The fractions containing product were collected and concentrated under reduced pressure to yield 0.06 g (57%) of product: 1H NMR (400 MHz, CD3OD) δ ppm 0.9 (m, 6 H), 1.3 (m, 5 H), 1.4 (m, 3 H) 1.7 (m, 1 H), 2.5 (m, 1 H), 2.9 (d, J=6.6 Hz, 2 H). MS: M+1 (188).
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:8][CH:9]=1)[CH3:3].[H][H]>C(O)C.[Pd]>[CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:1]
Reactant: [H][H]
Reactant: C=C(C)c1ccc(C(=O)OCC)nc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(C(C)C)cn1
Yield: 99 %

Procedure:
10% palladium-activated carbon (5.8 g) was added to a solution of ethyl 5-(prop-1-en-2-yl)pyridine-2-carboxylate (10 g) in ethanol (100 mL), and the mixture was stirred in a hydrogen gas stream at room temperature overnight. The reaction solution was filtered through celite, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→0:1) to give ethyl 5-isopropylpyridine-2-carboxylate as a colorless oil (10 g, 95%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[O:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:26][C:27](=[CH2:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>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>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[O:19][C:18]([CH3:24])([CH3:25])[CH2:17]2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:26]=[C:27](\[CH3:35])/[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)O1
Reactant: C=C(C)C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C/C(=C\c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)cc2)cc1)C(=O)OC(C)(C)C

Procedure:
The general Heck reaction procedure, described for 15 was followed. 4-[(4-bromophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenol (211) (0.440 g, 1.096 mmol) was reacted with 1,1-dimethylethyl 2-methyl-2-propenoate in the presence of PdCl2(PPh3)2 to afford the title compound as a mixture of Z and E isomers. The pure E-isomer (212) was isolated by HPLC as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.58 (s, 1H), 7.34 (d, J=8.1 Hz, 2H), 7.19 (d, J=8.1 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 7.81 (d, J=8.4 Hz, 2H), 5.80 (br s, 1H), 2.30 (d, J=3.0 Hz, 4H), 2.10 (s, 3H), 1.56 (s, 9H), 1.27 (s, 12H). LCMS (ESI): m/z 461 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22]([OH:24])=O.[C:25]1([CH:31]([NH2:39])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([CH:31]([NH:39][C:22]([C@H:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:15]([CH2:14][CH2:13][C@:11]23[CH3:12])[C@:16]2([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]2)=[CH:4][CH2:5]4)=[O:24])[CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Reactant: NC(Cc1ccccc1)c1ccccc1
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)NC(Cc4ccccc4)c4ccccc4)[C@@]3(C)CC[C@@H]12
Yield: 78 %

Procedure:
The title compound was prepared in a yield of 78% in a similar manner to that described in Example 1 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and 1,2-diphenylethylamine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[I:8].C([Sn](CCCC)(CCCC)[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)CCC.C(OCC)C>O1CCCC1.[Cu]I.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>[I:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: Brc1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOCC
Product: Ic1ccccc1-c1cnccn1
Temperature: 90 °C
Reaction time: 22 h
Yield: 16.2 %

Procedure:
1-Bromo-2-iodobenzene (0.32 mL, 2.4 mmol), copper(I) iodide (50 mg, 0.26 mmol) and bis(triphenylphosphine)palladium(II) chloride (88 mg, 0.12 mmol) were added to a degassed solution of 2-tributylstannylpyrazine (1.0 g, 2.4 mmol) in tetrahydrofuran (10 mL) and stirred at 90° C. under nitrogen for 22 hours. Diethyl ether was added to the cooled mixture, filtered through ‘Hyflo’ silica and concentrated in vacuo. Purification by flash column chromatography eluting with a 10-100% diethyl ether/isohexane gradient gave a pale yellow oil of 2-(2-iodophenyl)pyrazine (0.11 g, 16%) which contained some 2-(2-bromophenyl)pyrazine. 1H NMR (500 MHz, CDCl3) δ 8.85 (1H, d, J=1.4 Hz), 8.71-8.65 (1H, m), 8.59 (1H, d, J=2.5 Hz), 8.00 (1H, d, J=7.9 Hz), 7.49-7.46 (2H, m), 7.19-7.11 (1H, m); m/z (ES+) 283 [MH+].
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][NH2:12]>C(O)C>[NH:11]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[NH2:12]
Reactant: NN
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCO
Product: NNc1ncccc1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
To a suspension of 14.3 g of 2-chloro-3-nitropyridine in 90 mL of anhydrous ethanol was slowly added over 2-3 min with swirling 18 mL of 95% hydrazine. A new solid took the place of the chloro compound as spontaneous warming occurs. After 20 min at room temperature, filtration and washing with ethanol gave 15 g of 2-hydrazino-3-nitropyridine as a straw-yellow solid. To 4 g of the crude hydrazine suspended in 24 mL of anhydrous ethanol was added 16 mL of 95% hydrazine, and the mixture was warmed on a hot plate until the solid dissolved to give a deep red-colored solution and a spontaneous reaction set in with bubbling. The mixture was removed from the source of heat and the reaction allowed to proceed. After 5 min, the mixture was again heated to the boiling point and removed from the hot plate for 5 min. The mixture was treated twice more in this manner after which the deeply-colored solution had become lighter in color (reddish yellow). The solution was evaporated in a warm bath with a water aspirator to a brown oily material which was dissolved in 12 mL of water and acidified (Congo Red) with conc. HCl. Recrystallization from water (Norite) gave 1.10 (31%) of the hydroxytriazole as yellow-colored crystals, mp 203°-211° dec.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[CH2:39][CH3:40])=[C:10](\[C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:28][CH:27]=1)/[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16](C1CCCCO1)[N:15]=[CH:14]2.Cl>>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[CH2:39][CH3:40])=[C:10](\[C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:28][CH:27]=1)/[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(F)cc2Cl)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Agent: Cl
Product: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(F)cc2Cl)c2ccc3[nH]ncc3c2)cc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 164.9 %

Procedure:
A round-bottom flask equipped with a magnetic stir bar was charged with (E)-ethyl 3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate (255.9 g, 457.8 mmol) and a solution of HCl (732 mL, 1.25 M in ethyl alcohol). The reaction was heated at 80° C. for 2.5 h, allowed to cool to room temperature, and then concentrated to an orange gel. tert-Butyl methyl ether (2.3 L) was added. After stirring for 5 min, solids began to precipitate. The mixture was stirred at room temperature for 2 h and then filtered. The solids were washed with MTBE (700 mL) and dried to give the title compound (193 g) as an off-white solid. 1H NMR (DMSO-d6): δ 8.11 (s, 1H), 7.69 (s, 1H), 7.57-7.50 (m, 2H), 7.45-7.33 (m, 4H), 7.21-7.10 (m, 2H), 6.96 (d, 2H), 6.48 (d, 1H), 4.14 (q, 2H), 2.38 (q, 2H), 1.19 (t, 3H), 0.90 (t, 3H); LCMS: 475 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[C:7]([OH:9])=O.CCN(C(C)C)C(C)C.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])[NH2:23]>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:7]([C:6]2[S:5][N:4]=[N:3][C:2]=2[CH3:1])=[O:9])[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Cc1nnsc1C(=O)O
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnsc1C(=O)Nc1ccc(F)c(Cl)c1
Reaction time: 3 h
Yield: 60 %

Procedure:
4-Methyl-1,2,3-thiadiazole-5-carboxylic acid (39.6 mg, 0.275 mmol) was suspended in DCM (2.0 mL). Bromotris(pyrrolydino)phophonium hexafluorophosphate (128 mg, 0.27 mmol) and DIPEA (96 μL, 0.55 mmol) were added and premixed for 5 minutes. 3-Chloro-4-fluoroaniline (40 mg, 0.27 mmol) was added. The solution was stirred for 3 hrs, then purified by silica gel chromatography, (Hex/EA)—eluting at ˜60% EA in hexane to afford the desired product (44 mg). MF═C10H7ClFN3OS; LCMS calculated for C10H8ClFN3OS(M+H)+: m/z=272.0.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[N:16]([CH3:21])[N:17]=[C:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1>>[CH3:21][N:16]1[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[C:25]([F:24])=[N:26][CH:27]=[CH:28][CH:29]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])=[CH:19][C:18]([CH3:20])=[N:17]1
Reactant: OB(O)c1cccnc1F
Reactant: Cc1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)n(C)n1
Product: Cc1cc(-n2c(=O)n(C)c3cnc4ccc(-c5cccnc5F)cc4c32)n(C)n1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(2,5-dimethyl-2H-pyrazol-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate C, 50 mg, 0.135 mmol) and 2-fluoropyridine-3-boronic acid (Aldrich, Buchs, Switzerland, 25 mg, 0.179 mmol) to give the title compound as a red solid. (HPLC: tR 2.57 min (Method A); M+H=389 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.07 (s, 1H), 8.27-8.22 (m, 1H), 8.18-8.13 (m, 1H), 8.06-7.99 (m, 1H), 7.89-7.83 (m, 1H), 7.51-7.45 (m, 1H), 7.24-7.20 (m, 1H), 6.45 (s, 1H), 3.60 (s, 3H), 3.55 (s, 3H), 2.24 (s, 3H))
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:18]#[N:19])=[CH:13][CH:12]=2.[C:20](#[N:22])C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[NH:10][C:11]2[C:16]([C:17]=1[C:20]#[N:22])=[CH:15][C:14]([C:18]#[N:19])=[CH:13][CH:12]=2
Reactant: COc1ccncc1-c1cc2cc(C#N)ccc2[nH]1
Reactant: CC#N
Product: COc1ccncc1-c1[nH]c2ccc(C#N)cc2c1C#N

Procedure:
2-(4-Methoxy-pyridin-3-yl)-1H-indole-5-carbonitrile (Example 128) is processed according to the method described in Example 140, using acetonitrile instead of dichloromethane, to give 2-(4-methoxy-pyridin-3-yl)-1H-indole-3,5-dicarbonitrile. MS (ESI) m/z 275.08 (M+H)+.