Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:18])=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>CC(C)=O>[CH3:36][O:35][C:33](=[O:34])[CH2:32][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[C:4]([CH3:18])=[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:2]3[CH3:1])=[CH:12][CH:13]=1
Reactant: COC(=O)CBr
Reactant: Cc1c(-c2ccccc2)n(C)c2cccc(-c3ccc(O)cc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(-c2cccc3c2c(C)c(-c2ccccc2)n3C)cc1

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 4. Thus, 4-(1,3-dimethyl-2-phenyl-1H-indol-4-yl)-phenol (0.300 g, 0.957 mmol) was reacted with K2CO3 (0.172 g, 1.244 mmol) and methyl bromoacetate (0.190 g, 1.244 mmol) in acetone (5 ml) to give the product (0.287 g, 0.745 mmol, 78%) as a white solid, mp 110-112° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl:32][C:33]1[S:37][C:36]([C:38]2[CH:39]=[N:40][N:41]([CH3:46])[C:42]=2[C:43]([OH:45])=O)=[N:35][C:34]=1[CH:47]([F:49])[F:48].[C:50]1([C:56]2[N:57]=[C:58]3[CH:63]=[C:62]([NH2:64])[CH:61]=[CH:60][N:59]3[CH:65]=2)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C)C=O>[Cl:32][C:33]1[S:37][C:36]([C:38]2[CH:39]=[N:40][N:41]([CH3:46])[C:42]=2[C:43]([NH:64][C:62]2[CH:61]=[CH:60][N:59]3[CH:65]=[C:56]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[N:57]=[C:58]3[CH:63]=2)=[O:45])=[N:35][C:34]=1[CH:47]([F:49])[F:48]
Reactant: Nc1ccn2cc(-c3ccccc3)nc2c1
Reactant: Cn1ncc(-c2nc(C(F)F)c(Cl)s2)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(-c2nc(C(F)F)c(Cl)s2)c1C(=O)Nc1ccn2cc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.4 %

Procedure:
Diisopropylethylamine (0.30 ml) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (276 mg) were added to an N,N-dimethylformamide (0.72 ml) solution of the 4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (42 mg) obtained in (Example 1.7) <Step 2>. The obtained mixture was stirred in a nitrogen atmosphere at room temperature for 30 minutes. Thereafter, 2-phenylimidazo[1,2-a]pyridin-7-amine (30 mg) was added to the reaction solution, and the obtained mixture was then stirred at 60° C. for 1 hour. Thereafter, the reaction solution was fractionated and purified by LC/MS to obtain the title compound (1 mg) in the form of a light brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([Cl:15])[N:12]=[C:11](Cl)[C:7]=3[NH:8][C:9]=2[CH:10]=1.[CH3:17][CH2:18][O-:19].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([Cl:15])[N:12]=[C:11]([O:19][CH2:18][CH3:17])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: Clc1nc(Cl)c2[nH]c3cc(Br)ccc3c2n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(Cl)nc2c1[nH]c1cc(Br)ccc12
Temperature: 25 °C
Yield: 98.8 %

Procedure:
5 g (15.8 mmol) 7-bromo-2,4-dichloro-5H-pyrimido[5,4-b]indole was suspended in 20 ml ethanol and mixed with 15.8 ml (31.5 mmol) 2M sodium ethylate solution (EtOH). The mixture was refluxed for 9.5 h. Having cooled down to room temperature, the solvent was concentrated and water was added. The resulting precipitate was sucked off and washed with water. 5.1 g (99%) 7-bromo-2-chloro-4-ethoxy-5H-pyrimido[5,4-b]indole was obtained. ESI-MS [m/z]: 324, 326 [M−H]−
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.F[C:22]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>>[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:22]2[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])=[CH:16][CH:15]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1cc(F)c(F)cc1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(F)c(F)cc1Nc1ccc(F)cc1
Yield: 88.1 %

Procedure:
Using General Method 1, the reaction of 2.5 M solution of n-BuLi in hexanes (14 mL, 35 mmol), diisopropylamine (4.8 mL, 34 mmol), 4-fluoro-aniline (1.1 mL, 11 mmol), and 2,4,5-trifluorobenzoic acid (2 g, 11 mmol) provided 2.59 g of the crude title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([O:17][CH3:18])=[O:16]>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:14]1[O:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccco1
Reactant: Cc1ccccc1CCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(Cc2ccccc2C)o1
Yield: 49.2 %

Procedure:
A mixture of 2-methylbenzyl chloride [prepared as described by Voronkov and Popova, Latv. P.S.R. Zinat. Akad. Vestis Kim. Sev. 1970(5), 595; 62 g.], methyl 2-furoate (114 g.) and anhydrous ferric chloride (1.4 g.) in dry carbon tetrachloride (120 ml.) was heated on a steam bath under relfux for 18 hours. The solution was then evapoated to dryness. The residue was dissolved in chloroform, washed with 2N hydrochloric acid and water, dried over magnesium sulphate and distilled to give methyl 5-(2-methylbenzyl)-2-furoate (50 g.) in the form of a yellow coloured oil, b.p. 140°-170° C./0.1-0.5 mm.Hg.
Reaction SMILES: C([Li])CCC.[Cl-].[CH3:7][O:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[CH:37]([CH3:46])[C:38]([C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)=O.O>O1CCCC1>[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[CH:37]([CH3:46])/[C:38](/[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)=[CH:7]\[O:8][CH3:9]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C(=O)c1cccnc1)c1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CO/C=C(/c1cccnc1)C(C)c1ccc(Cl)cc1Cl
Reaction time: 3 h

Procedure:
135 ml of n-butyllithium (1.6M in n-hexane) are added dropwise at 0° C. under argon to a suspension of 73.9 g (0.215 mol) of methoxymethyltriphenylphosphonium chloride in 500 ml of anhydrous tetrahydrofuran in such a manner that the temperature does not exceed 5° C. After stirring at 0° C. for 30 minutes a solution of 50 g (0.178 mol) of 2-(2,4-dichlorophenyl)-1-(3-pyridyl)-1-propanone in 100 ml of dry tetrahydrofuran is added dropwise at -75° C. within 30 minutes. The mixture is stirred at this temperature for 3 hours and 100 ml of water are then added dropwise at 0° C. The tetrahydrofuran is distilled off under reduced pressure and the residue is extracted with ethyl acetate. After distilling off the ethyl acetate the oily residue is chromatographed on silica gel with dichloromethane/ethyl acetate (95:5 vol%) as the eluent. There is thus obtained with the 1st fraction (E)- 3-(2,4-dichloro-α-methoxy methylene-β-methylphenethyl)-pyridine as beige crystals, m.p. 67-68° C., and with the 2nd fraction (Z)-3-(2,4-dichloro-α-methoxymethylene-β-methylphenethyl)-pyri dine as a yellowish oil in the ratio of about 1:1 in a total amount of 44.4 g.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]=2[CH:15]=1)[CH:2]([CH3:4])[CH3:3].[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:16][C:7]1[C:8]2[O:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=2[CH:15]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:6]=1
Reactant: [Br-]
Reactant: CC(C)Cc1ccc2c(c1)C(C)(C)CO2
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)Cc1cc(Br)c2c(c1)C(C)(C)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
To a solution of 5-isobutyl-3,3-dimethyl-2,3-dihydro-benzofuran (1.59 g, 7.78 mmol) in dichloromethane (40 mL) was added pyridinium tribromide (2.49 g, 7.78 mmol) and the reaction mixture stirred at room temperature overnight. The solution was washed with water and brine, dried (MgSO4), filtered and evaporated. The residue was purified on silica gel (0% to 2% ethyl acetate in hexane) to give 1.51 g of 7-bromo-5-isobutyl-3,3-dimethyl-2,3-dihydro-benzofuran (68%). 1H NMR (300 MHz; CDCl3): δ 0.90 (d, J=6.3 Hz, 6H), 1.33 (s, 6H), 1.77 (m, 1H), 2.39 (d, J=7.5 Hz, 2H), 4.30 (s, 2H), 6.80 (d, J=1.5 Hz, 1H), 7.05 (d, J=1.5 Hz, 1H).
Reaction SMILES: [C:1]([CH2:6][NH:7][C:8]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11])([O:3][CH2:4][CH3:5])=[O:2].CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[NH2:11][C:10]1[C:9]2[C:8](=[CH:15][C:14]([F:16])=[CH:13][CH:12]=2)[NH:7][C:6]=1[C:1]([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CNc1cc(F)ccc1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2cc(F)ccc2c1N
Reaction time: 1 h
Yield: 76.5 %

Procedure:
Dissolve 2-(Carbethoxy)methylamino-4-fluorobenzonitrile (220 mg, 1 mmol) intetrahydrofuran (3 mL) and add dropwise with stirring to a solution of potassium tert-butoxide (1 mL of a 1M solution in 1 mL tetrahydrofuran) under a nitrogen atmosphere. After 1 hour, dilute with ethyl acetate, rinse with water, dry the organic phase and concentrate in vacuo to yield the title compound (170 mg, 77%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1.[C:17]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH:17]1([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])[CH2:2]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(OCc1ccccc1)C1CCCNC1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)C1CCCN(C2CCCC2)C1
Reaction time: 48 h

Procedure:
The crude amine from the above step was dissolved in 1,2-dichloroethane (15 mL) and cyclopentanone (1.0 mL) was added via syringe. The reaction was allowed to stir for 5 min before the addition of HOAc (0.6 mL) and NaBH(OAc)3 (2.3 g, 10.9 mmol) in one portion. The reaction was allowed to stir for 48 h and then quenched with Na2CO3 (10%, 20 mL) and the reaction was allowed to stir for 1 h before being extracted with DCM (3×50 mL). The combined organics were washed with brine (sat, 200 mL), dried with sodium sulfate, filtered, concentrated to provide 1.3 g of crude oil that was purified by a 120 g Isco normal phase column (100% EtOAc) to give benzyl 1-cyclopentylpiperidine-3-carboxylate as a colorless oil. MS m/z: 288 (M+1).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[N:33]1([C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:8][CH:7]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:29])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2cc(C(=O)N3CCOCC3)cnc2c1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 50.4 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with morpholine (11 mg, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane and allowed to react overnight. The reaction mixture was concentrated, the residue was suspended in water, and the solid was collected by vacuum filtration. This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 28 mg of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:13].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:14][CH2:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[N:2]([CH3:1])[C:3](=[O:13])[CH:4]=[CH:5]2
Reactant: Cc1ccc2c(ccc(=O)n2C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1c(=O)ccc2cc(CBr)ccc21
Yield: 32.5 %

Procedure:
A stirred solution of 28b (22 g, 0.127 mol) and N-bromosuccinimide (23 g, 0.13 mol) in CCl4 (400 mls) was irradiated for 2.5 hours with a 275 watt heat lamp after an addition of AIBN (50 mg) to initiate the free radical reaction. During this time, the reaction achieved reflux. After cooling, the mixture was concentrated to a small volume and ethyl acetate (400 mls) and water (150 mls) were added and the layers separated. The organic phase was dried (MgSO4) and evaporated. The crude material was purified by chromatography on silica gel using 35% ethyl acetate/toluene to give the product 28c (10.4 g, 33%) as a solid, mp 99°-100° C. The structural assignment was supported by the 1H-NMR spectrum. Analysis calculated for C11H10NOBr: C, 52.41; H, 4.00; N, 5.56; Br, 31.69. Found: C, 52.11; H, 3.91; N, 5.40; Br, 31.40.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:55]1([CH2:58][NH:59][CH2:60][C@@H:61]2[CH2:65][CH2:64][CH2:63][NH:62]2)[CH2:57][CH2:56]1>CN(C=O)C>[CH:55]1([CH2:58][NH:59][CH2:60][C@@H:61]2[CH2:65][CH2:64][CH2:63][N:62]2[C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:32])[CH2:56][CH2:57]1
Reactant: C1CN[C@H](CNCC2CC2)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCC[C@H]1CNCC1CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol), EDAC (76 mg), HOBt (27 mg) in DMF (4 mL) was added cyclopropylmethyl-(S)-1-pyrrolidin-2-ylmethyl-amine (0.05 mL) and TEA (0.08 mL). The mixture was stirred at rt for 2 days. The reaction was concentrated and the residue was purified on a silica gel column to give the titled compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C@H:11]2[O:12][C@H:10]2[C:9]2[CH:8]=[C:7]([CH2:13][C:14]([NH:16][CH:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19][CH2:18]3)=[O:15])[CH:6]=[CH:5][C:4]=2[O:3]1.[NH3:28]>>[NH2:28][C@@H:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][C:14]([NH:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19][CH2:18]3)=[O:15])[CH:8]=2)[O:3][C:2]([CH3:27])([CH3:1])[C@H:11]1[OH:12]
Reactant: N
Reactant: CC1(C)Oc2ccc(CC(=O)NC3CCCc4ccccc43)cc2[C@@H]2O[C@@H]21
Product: CC1(C)Oc2ccc(CC(=O)N[C@@H]3CCCc4ccccc43)cc2[C@@H](N)[C@@H]1O

Procedure:
40 g of the 2-[(1aS,7bS)-(2,2-dimethyl-1a,7b-dihydro-2H-oxireno[c]chromen-6-yl]-N-1,2,3,4-tetrahydronaphth-1-yl acetamide obtained above and 250 ml of a 25%-strength aqueous ammonia solution were reacted in a manner corresponding to the procedure of Example 1E). Chromatography of the crude product on silica gel (mobile phase: dichloromethane/methanol/25%-strength aqueous ammonia solution (75:50:2 v/v/v)) yielded 13.2 g 2-[(3S,4R)-4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl]-N-[(1R)-1,2,3,4-tetrahydronaphth-1-yl]acetamide as oil, which was used without further purification for the subsequent reaction.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([OH:16])[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1.C1C(=O)N([Br:24])C(=O)C1.[O-]S([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[Br:24][C:5]1[S:1][C:2]([C:6]2([OH:16])[CH2:7][CH2:8][C:9]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:14][CH2:15]2)=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OC1(c2nccs2)CCC2(CC1)OCCO2
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OC1(c2ncc(Br)s2)CCC2(CC1)OCCO2
Temperature: 45 °C
Yield: 95.5 %

Procedure:
To a solution of 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (15.0 g, 62.2 mmol) in DMF (75 mL) was added NBS (6.9 g, 55 mmol) and the solution warmed to 45° C. for 8 hours. The solution was treated with Na2SO3(3.9 g, 31 mmol) in H2O (150 mL) and the resulting slurry was filtered and washed with water (70 mL) to afford 8-(5-bromo-1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol as a white solid (16.8 g, 52.5 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[OH-].[Na+].[F:12][C:13]1[CH:22]=[CH:21][C:16]([CH2:17][CH2:18][CH:19]=[O:20])=[CH:15][CH:14]=1.S(=O)(=O)(O)O>CO>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:18]([CH:19]=[O:20])[CH2:17][C:16]1[CH:21]=[CH:22][C:13]([F:12])=[CH:14][CH:15]=1
Reactant: O=Cc1ccccc1Cl
Reactant: O=CCCc1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=CC(=Cc1ccccc1Cl)Cc1ccc(F)cc1
Reaction time: 1 h

Procedure:
71.7 g (0.51 mol) of 2-chlorobenzaldehyde are added to a solution of 4 g of 50% strength sodium hydroxide solution in 300 ml of methanol while cooling, at a rate such that the temperature does not exceed 20° C. 70.0 g (0.46 mol) of p-fluorodihydrocinnamaldehyde are then added dropwise at 25°-30° C. in the course of 4 hours. Stirring is continued for one hour at 30° C., the mixture is neutralized with dilute sulfuric acid and evaporated down and the residue is distilled.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:18]([CH3:23])([CH3:22])[C:19](F)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH3:28].O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:18]([CH3:22])([CH3:23])[C:19]([NH2:28])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: N
Reactant: CC(C)CC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(C)(C)C(=O)F
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(C)(C)C(N)=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhexanoyl fluoride (1.65 g, 4.23 mmol) in anhydrous THF (30 mL) at −78° C. was bubbled NH3 (g) for 10 minutes. The reaction mixture was sealed and stirred at −78° C. for 15 min and at rt for 1 hr. Water (100 mL) was added, the reaction mixture was extracted with ethyl acetate (100 mL), dried (Na2SO4), and concentrated to give 1.62 g (100% yield) of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhexanamide, the NMR spectrum of which was consistent with the desired structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=C)[N:13]=[CH:12][C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[O:30]CC1>CC(C)=O.O.O=[Os](=O)(=O)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([C:17](=[O:30])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: C=C(c1ccccc1)c1cc2c(cn1)C(C)(C)CN2C(=O)OC(C)(C)C
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(C(=O)c3ccccc3)cc21
Yield: 65 %

Procedure:
To a solution of 3,3-dimethyl-6-(1-phenyl-vinyl)-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (914 mg, 2.6 mmol) in THF (10 mL), acetone (5 mL) and water (5 mL) was added NaIO4 (2.8 g, 13.05 mmol), then OsO4 (2 mL of 4% solution in water, 0.3 mmol) and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo, water (20 mL) was added and the product was extracted with EtOAc (2×20 mL). The organic phase was washed with brine, dried (MgSO4), filtered and the solvent evaporated. The crude product was purified by column chromatography on silica, eluted with petrol-EtOAc 0-40% to afford the title compound (654 mg, 65%). MS: [M+H]+=353.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1)#[CH:2].I[C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].C(N(CC)C(C)C)(C)C>C1COCC1.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.[Cu]I>[C:30]([O:29][C:28]([NH:27][C:19]1[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=1[C:2]#[C:1][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:6]=[CH:7][CH:8]=1)=[O:34])([CH3:33])([CH3:31])[CH3:32]
Reactant: C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc([N+](=O)[O-])cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cc([N+](=O)[O-])ccc2NC(=O)OC(C)(C)C)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
A solution of tert-butyl (3-ethynylphenyl)carbamate (12.7 g, 58.5 mmol), tert-butyl (2-iodo-4-nitrophenyl)carbamate (14.2 g, 39.0 mmol), bis(triphenylphosphine)palladium(II) chloride (1.37 g, 1.95 mmol), and copper(I) iodide (371 mg, 1.95 mmol) in THF (200 mL) was treated with N,N-diisopropylethylamine (7.47 mL, 42.9 mmol) dropwise and stirred at 20° C. overnight. The reaction mixture was concentrated and diluted with water (200 mL) and ethyl acetate (200 mL). The organic layer was separated, washed with brine, dried with sodium sulfate, filtered, and concentrated to give a yellow/brown solid which was washed with ethyl acetate to give the desired product as light yellow solid (15 g, 85%). LCMS calculated for C24H27N3O6Na (M+Na)+: m/z=476.2.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].CO[CH:11](OC)[CH2:12][NH2:13].[ClH:16]>CO>[ClH:16].[NH:2]1[CH:11]=[CH:12][N:13]=[C:1]1[C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: N#Cc1ncccn1
Reactant: COC(CN)OC
Agent: Cl
Solvent: CO
Product: c1cnc(-c2ncc[nH]2)nc1
Temperature: 100 °C
Reaction time: 30 h

Procedure:
A mixture of 2-Cyanopyrimidine (8.0 g, 76 mmol, prepared according to Liebigs Ann.Chem. 2, 1981, 333-341) and Aminoacetaldehyde dimethyl acetal (8 g, 76 mmol) is heated at 100° C. for 4 hours, cooled, and 100 mL of MeOH and 5 mL of concentrated HCl are added. The mixture is heated at reflux with stirring for 30 hours, cooled and evaporated to dryness in vacuo. 50 mL of i-PrOH is added to the residue and the mixture is heated at reflux with stirring for 30 minutes and cooled. The crystals are collected by filtration, washed with ether, and dried to give the title compound. 1H NMR (DMSO): δ 9.08 (d, 2H), 7.87 (s, 2H), 7.75 (t, 1H). LRMS calcd 146, found 147 (MH+).