Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:11]=3[F:20])=[N:7][C:6]=2[CH:21]=1.Cl.[CH:23]([C:26]1[N:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[O:28][N:27]=1)([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+].C(CC(=O)C)(=O)C>CN1C(=O)CCC1.Cl[Cu]>[F:20][C:11]1[CH:12]=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=[CH:15][C:10]=1[C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([N:34]3[CH2:33][CH2:32][CH:31]([C:29]4[O:28][N:27]=[C:26]([CH:23]([CH3:25])[CH3:24])[N:30]=4)[CH2:36][CH2:35]3)=[CH:21][C:6]=2[N:7]=1
Reactant: CC(C)c1noc(C2CCNCC2)n1
Reactant: CS(=O)(=O)c1ccc(-c2nc3cc(Br)ccc3o2)c(F)c1
Agent: Cl[Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: CC(=O)CC(C)=O
Product: CC(C)c1noc(C2CCN(c3ccc4oc(-c5ccc(S(C)(=O)=O)cc5F)nc4c3)CC2)n1
Temperature: 130 °C
Reaction time: 16 h
Yield: 12.6 %

Procedure:
Intermediate 28 (150 mg, 0.41 mmol), 3-isopropyl-5-(piperidin-4-yl)-1,2,4-oxadiazole hydrochloride (96 mg, 0.5 mmol), K2CO3 (59 mg, 0.43 mmol), CuCl (2 mg, 0.02 mmol), acetyl acetone (5 mg, 0.05 mmol) were dissolved in NMP (1 ml). This reaction mixture was stirred at 130° C. for 16 h under N2 atmosphere. Work up (EtOAc/H2O) followed by purification on combiflash using a gradient mixture of EtOAc and Petether (30:70) as eluent afforded the titled compound (25 mg) as a pale-yellow solid. M. P.: 206-209° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.26 (d, J 8.2, 1H), 7.97 (d, J 1.4, 1H), 7.69 (d, J 1.4, 1H), 7.63 (dd, J 1.5, 8.2, 1H), 7.56-7.48 (m, 2H), 3.49-3.39 (m, 2H), 3.15-3.04 (m, 5H), 3.03-2.93 (m, 2H), 2.25-2.16 (m, 4h), 1.36 (d, J 7, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:45])[C@H:12]([CH2:34][CH2:35][CH2:36][NH:37]C(OC(C)(C)C)=O)[N:13]([C:15](=[O:33])[C@H:16]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][CH:27]=2)[NH:17]C(OC(C)(C)C)=O)[CH3:14])=[CH:4][CH:3]=1.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>>[OH:50][C:48]([C:47]([F:52])([F:51])[F:46])=[O:49].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:45])[C@H:12]([CH2:34][CH2:35][CH2:36][NH2:37])[N:13]([C:15](=[O:33])[C@H:16]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([I:32])=[CH:30][CH:31]=2)[NH2:17])[CH3:14])=[CH:6][CH:7]=1
Reactant: CN(C(=O)[C@H](Cc1ccc(I)cc1)NC(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)[C@@H](N)Cc1ccc(I)cc1)[C@@H](CCCN)C(=O)NCCc1ccc(F)cc1

Procedure:
Boc-4-iodophenylalanyl-Nδ-Boc-Nα-methylornithine 2-(4-fluorophenyl)ethylamide was deprotected with trifluoroacetic acid (Procedure E) to afford a white solid: 1H NMR (400 MHz, D2O) δ1.50 (m, 1H), 1.60 (m, 1H), 1.71 (m, 1H), 1.83 (m, 1H), 2.73 (s, 2H), 2.92 (m, 2H), 3.03 (m, 3H), 3.12 (m, 1H), 3.59 (m, 2H), 4.74 (m, 1H), 4.91 (m, 1H), 7.04 (d, J=8.0 Hz, 1H), 7.11 (t, J=10.9 Hz, 2H), 7.35 (m, 2H), and 7.79 (d, J=8.5 Hz, 2H).
Reaction SMILES: C=CC=C.O.C(=O)=[O:7].[CH2:9](O)[CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16]>CN(C)C=O>[CH2:9]=[CH:10][CH:11]([OH:7])[CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16]
Reactant: C=CCCCC=CCO
Reactant: O=C=O
Agent: C=CC=C
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCCC(O)C=C
Yield: 10.1 %

Procedure:
The thus deposited and separated palladium complex was placed again in the autoclave, to which 0.5 mol of 1,3-butadiene, 1 mol of water, 0.6 mol of carbon dioxide, and 63 ml of dimethyl formamide were fed afresh. Then, the reaction was conducted under the same conditions as mentioned above, with the consequence that 0.158 mol of 2,7-octadien-1-ol, and 0.016 mol of 1,7-octadien 3-ol were produced.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1>[Pd].C(O)C>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[O:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1
Reactant: COc1c(C)c(C)c(OC)c(Oc2ccc([N+](=O)[O-])cc2)c1C
Agent: [Pd]
Solvent: CCO
Product: COc1c(C)c(C)c(OC)c(Oc2ccc(N)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
A mixture of 4.8 g of 2,5-dimethoxy-3,4,6-trimethyl-1-(4-nitrophenoxy)benzene [prepared as described in step (b) above], 1.0 g of 10% w/w palladium-on-charcoal and 100 ml of ethanol was stirred under a hydrogen atmosphere at room temperature for 3 hours. At the end of this time, the catalyst was filtered off, and the filtrate was concentrated by evaporation under reduced pressure, to give 3.9 g of the title compound. p Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH2:21])=[CH:15][CH:14]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C.O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: NCCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Cl)cc1)NCCc1ccc(Cl)cc1
Yield: 88.6 %

Procedure:
To a mixture of 4-chlorophenylacetic acid (500 mg, 3.0 mmol) and 2-(4-chlorophenyl)ethylamine (456 mg, 3.0 mmol) in DMF (50 ml) were added WSC.HCl (592 mg, 3.1 mmol), HOBt.H2O (474 mg, 3.1 mmol) and triethylamine (0.43 ml, 3.1 mmol), and the mixture was stirred at RT for 18 h. After adding water, the mixture was extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, and filtered. Concentrating under vacuum gave N-[2-(4-chlorophenyl)ethyl]-(4-chlorophenyl)acetamide (819 mg, 89%) which was used in the next step without further purification.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[CH3:6][C:7]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]2[C:8]=1[CH:9]=[CH:10][CH2:11]2.O>CCCCCC.C1COCC1.CCCCCC>[CH3:5][C:4]1[CH:11]=[CH:12][C:13]([CH3:16])=[C:2]2[C:3]=1[CH:2]=[CH:3][CH:4]2[C:5]1[CH:14]=[CH:15][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[C:12]2[C:8](=[C:7]([CH3:6])[CH:15]=[CH:14][C:13]=2[CH3:16])[CH:9]=[CH:10]1
Reactant: Cc1ccc(C)c2c1C=CC2
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1ccc(C)c2c1C=CC2Cc1ccccc1C1C=Cc2c(C)ccc(C)c21
Temperature: -70 °C
Reaction time: 1 h

Procedure:
4.12 ml (10.3 mmoles) of n-BuLi 2.5 M in hexane are added to a solution of 1.48 g of 4,7-dimethyl indene (XVIII) (10.3 mmoles; obtained as described above) in 55 ml of a mixture of THF-hexane 2/1. At the end of the addition, the mixture is left under stirring for 1 hour. It is then cooled to −70° C. and a solution of 2.3 g of the brominated compound having formula (XX) (7.37 mmoles) in THF/hexane are added dropwise. The mixture is left to rise to room temperature and is left to rest for 6 hours. It is then poured into water and is extracted with ethyl ether. The organic phase is washed until neutrality and dehydrated on sodium sulfate. The residue obtained by evaporation of the solvent is purified by silica gel chromatography eluating with petroleum ether. After evaporation of the eluant 2.0 g of the bis-indenyl ligand having formula (XXI) and indicated below, are obtained (72% yield).
Reaction SMILES: O[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2ncccc12
Product: Clc1ncnc2ncccc12
Yield: 32 %

Procedure:
The solution of 4-hydroxypyrido[2,3-d]pyrimidine (2.00 g, 13.6 mmol) in POCl3 (40 mL) was refluxed for 2 hours. After cooling, the excess POCl3 was removed under vacuum. The residue was quenched with saturated NaHCO3 and extracted with ethyl acetate (3×100 mL). The organic phase was dried and concentrated. The residue was subject to column chromatography, eluted by hexane/ethyl acetate (1:1) to give 4-chloropyrido[2,3-d]pyrimidine (0.72 g, 32%). 1H NMR (CDCl3, 400 MHz) δ 9.35 (m, 1H), 9.30 (s, 1H), 8.66 (m, 1H), 7.73 (m, 1H). MS (APCI+) [M+H]+166.
Reaction SMILES: C(I)I.[Zn]([CH2:7][CH3:8])CC.[Br:9][C:10]1[CH:15]=[C:14]2[NH:16][C:17](=[O:36])[C:18]3([CH:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[CH2:22][C:21](=[O:31])[NH:20][CH:19]3[C:32](=C)[CH2:33][CH3:34])[C:13]2=[CH:12][CH:11]=1.[CH3:37][O:38][CH:39]([Si:41]([CH3:44])([CH3:43])[CH3:42])[CH3:40]>C1(C)C=CC=CC=1>[Br:9][C:10]1[CH:15]=[C:14]2[NH:16][C:17](=[O:36])[C:18]3([CH:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[CH2:22][C:21](=[O:31])[NH:20][CH:19]3[C:32]3([CH2:7][CH3:8])[CH2:34][CH2:33]3)[C:13]2=[CH:12][CH:11]=1.[CH3:37][O:38][CH:39]([Si:41]([CH3:44])([CH3:43])[CH3:42])[CH3:40]
Reactant: CC[Zn]CC
Reactant: C=C(CC)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Agent: COC(C)[Si](C)(C)C
Solvent: ICI
Solvent: Cc1ccccc1
Product: CCC1(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Br)ccc23)CC1
Reaction time: 0.17 h

Procedure:
CH2I2 (1.2 g, 4.6 mmol) was dissolved in dry toluene (5 mL) at 0° C. After stirred for 10 min under Argon, Et2Zn (1 M in THF, 3.3 mL, 3.67 mmol) was added. After stirred for 15 min, a solution of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (270 mg, 0.46 mmol) prepared in example 161b in dry toluene (10 mL) was added. After stirred at room temperature for 3 h, the reaction was quenched with saturated NH4Cl (20 mL). The aqueous layer was extracted with EtOAc. The combined organic layer was dried over Na2SO4, concentrated, the residue, was used for next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]([F:29])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=4)[OH:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:28]=1.[CH3:30][C:31]([OH:35])([CH3:34])[C:32]#[CH:33]>>[F:27][C:22]1[CH:21]=[C:20]([CH:18]([OH:19])[C:12]2[N:8]3[CH2:9][CH2:10][O:11][C:5]4[CH:4]=[C:3]([F:29])[C:2]([C:33]#[C:32][C:31]([OH:35])([CH3:34])[CH3:30])=[CH:28][C:6]=4[C:7]3=[N:14][C:13]=2[C:15]([NH2:17])=[O:16])[CH:25]=[C:24]([F:26])[CH:23]=1
Reactant: C#CC(C)(C)O
Reactant: NC(=O)c1nc2n(c1C(O)c1cc(F)cc(F)c1)CCOc1cc(F)c(Br)cc1-2
Product: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(O)c1cc(F)cc(F)c1
Yield: 45 %

Procedure:
3-((3,5-difluorophenyl)(hydroxy)methyl)-9-fluoro-10-(3-hydroxy-3-methylbut-1-yn-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was prepared similarly according to General Procedure G with slight modifications. 10-bromo-3-((3,5-difluorophenyl)(hydroxy)methyl)-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 3-methyl-1-butyne-3-ol to afford 25.7 mg of the titled compound (45% yield). M+1=472.1. 1H NMR (400 MHz, DMSO) δ 8.57 (d, J=8.4 Hz, 1H), 7.94 (br s, 1H), 7.47 (br s, 1H), 7.18-7.06 (m, 2H), 7.05-7.00 (m, 2H), 6.98 (d, J=10.6 Hz, 1H), 6.91-6.85 (m, 1H), 5.54 (s, 1H), 4.58-4.49 (m, 1H), 4.48-4.36 (m, 2H), 4.11-3.92 (m, 1H), 1.49 (s, 6H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH:32]=[N:31][CH:30]=[N:29]1>>[N:29]1[N:28]([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH:38]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:36][CH:35]=2)[CH:32]=[N:31][CH:30]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Nc1ccc(Cn2cncn2)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(Cn2cncn2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(1,2,4-triazol-1-yl-methyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=10:1) C26H21N5O3
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1.Br[C:27]1[CH:39]=[CH:38][CH:37]=[CH:36][C:28]=1[O:29][C:30]1[N:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:27]2[CH:39]=[CH:38][CH:37]=[CH:36][C:28]=2[O:29][C:30]2[N:31]=[CH:32][CH:33]=[CH:34][N:35]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1
Reactant: Brc1ccccc1Oc1ncccn1
Reactant: CC1(C)OB(c2ccc(-c3cnc4[nH]ccc4c3)c(F)c2)OC1(C)C
Product: Fc1cc(-c2ccccc2Oc2ncccn2)ccc1-c1cnc2[nH]ccc2c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine and 2-(2-bromophenoxy)pyrimidine. MS (ESI): mass calcd. for C23H15FN4O, 382.12; m/z found, 383.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 8.51-8.42 (m, 3H), 8.14-8.05 (m, 1H), 7.57-7.28 (m, 8H), 6.99-6.89 (m, 1H), 6.55 (dd, J=3.6, 1.8, 1H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5].[C:14](#[N:17])[CH:15]=[CH2:16]>CO>[CH3:1][N:2]([CH2:16][CH2:15][C:14]#[N:17])[CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5]
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: C=CC#N
Solvent: CO
Product: CN(CCC#N)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 63 °C

Procedure:
607 g (3.1 mol) of N-methylglucamine (NMG) are suspended in 729 g of methanol in a 2 l four-necked flask with a stirrer, dropping funnel, reflux condenser and thermometer. The reaction mixture is heated to 63° C., while stirring. 163 g (3.1 mol) of acrylonitrile are added dropwise in the course of 30 minutes. When the addition has ended, the clear solution is stirred at 63° C. for a further 3 hours. According to analysis by gas chromatography, the conversion in the reaction is complete, so that the reaction product can be employed directly for the hydrogenation (second process stage).
Reaction SMILES: [CH3:1][C:2](=[O:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[C-:8]#[N:9].[K+].C#N>C(OC)(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[OH:7][C@@:2]([CH3:1])([C:3]([CH3:6])([CH3:5])[CH3:4])[C:8]#[N:9]
Reactant: CC(=O)C(C)(C)C
Reactant: [C-]#N
Agent: C#N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: COC(C)(C)C
Product: CC(C)(C)[C@](C)(O)C#N
Temperature: 2.5 °C
Yield: 74.7 %

Procedure:
10 mmol of pinacolone (1.25 g) were dissolved in 30 ml of methyl t-butyl ether, treated with 5 ml of enzyme solution (1000 IU/ml) and cooled to 0-5° C. with stirring. Parallel to this, 20 mmol of potassium cyanide were dissolved in 250 ml of 0.1 M aqueous citric acid with ice-cooling. The hydrocyanic acid solution prepared in this way was added to the reaction mixture and the reaction vessel was sealed pressure-tight. After a reaction time of 2.5 h, the mixture was diluted with 50 ml of methyl t-butyl ether and the reaction solution was extracted. The aqueous phase was separated off, extracted by shaking again with 80 ml of methyl t-butyl ether and then discarded. The combined organic phases were dried using anhydrous sodium sulfate and the solvent was removed under reduced pressure. After column chromatography, 0.95 g of (S)-2-hydroxy-2,3,3-trimethylbutanenitrile (75%) was obtained as a white solid (m.p. 98-99° C.).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[CH:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:2]1
Reactant: OCCC=C1CCOCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: OCCCC1CCOCC1
Yield: 89.3 %

Procedure:
To a solution of 3-(2H-pyran-4(3H, 5H, 6H)-ylidene)propan-1-ol (13 g, 0.0916 mol) in methanol (260 mL) was added Pd(OH)2/C (1.3 g). The reaction flask was evacuated and filled with H2. Stirring was continued until the starting material had disappeared. The mixture was filtered through celite, and the filter cake was washed with MeOH (2×10 mL). The combined organic extracts were dried over Na2SO4, and concentrated under vacuum to give the product (11.8 g, 90%), which was used for the next step without purification. 1H NMR (CD3OD) δ 1.1-1.3 (m, 4H), 1.4-1.6 (m, 5H), 2.1-2.3 (s, 1H), 3.3-3.4 (t, 2H), 3.5-3.6 (t, 2H), 3.8-3.9 (dd, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:21])=[O:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19]([NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][N:3]=3)(=[O:20])=[O:21])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: Nc1ccncn1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)ccnc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccncn1)c1ccc2c(Cl)ccnc2c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 67.6 %

Procedure:
A flask containing a solution of 4-aminopyrimidine (0.026 g, 0.268 mmol) and perfluorophenyl 4-chloroquinoline-7-sulfonate (from Step 2, Intermediate LLLL; 0.100 g, 0.244 mmol) in THF (1.220 ml) was cooled to −78° C. for 10 minutes, and then lithium bis(trimethylsilyl)amide, 1.0 m solution in tetrahydrofuran (0.488 ml, 0.488 mmol) was added dropwise. After 20 minutes, the reaction had gone to completion. The reaction mixture was quenched with aq ammonium chloride, and concentrated under a vacuum. A 2:1 mixture of DCM:H2O was added, the flask sonicated, and the solids filtered to yield 4-chloro-N-(pyrimidin-4-yl)quinoline-7-sulfonamide (0.053 g, 0.165 mmol, 67.7% yield) as a light brown solid (carried forward crude). m/z (ESI) 321.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:15](=O)[CH2:14][C:13]([CH3:18])([CH3:17])[CH:12]([C:19]#[N:20])[C:11]2=O)=[CH:4][CH:3]=1.B.O1CCCC1.Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13]([CH3:18])([CH3:17])[CH:12]([CH2:19][NH2:20])[CH2:11]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)N(CCc2ccc(F)cc2)C(=O)C1C#N
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)CCN(CCc2ccc(F)cc2)CC1CN
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.7 %

Procedure:
1-[2-(4-Fluorophenyl)-ethyl]-4,4-dimethyl-2,6-dioxopiperidine-3-carbonitrile (1.0 g, 3.47 mmol) was treated with 1.0 M borane in tetrahydrofuran (69.4 mL, 69.4 mmol) and stirred at room temperature for 18 hours. The solution was cooled on an ice bath and treated very slowly with 2.0 N hydrochloric acid. The mixture was concentrated under vacuum to remove the tetrahydrofuran, and the aqueous residue was heated at reflux for 60 minutes. The mixture was cooled to room temperature and treated with 50% aqueous sodium hydroxide to adjust the pH to about 11. The mixture was extracted with ethyl acetate, and the organic extracts were dried over sodium sulfate and concentrated. The residue was purified by flash chromatography, eluting with 10% methanol in dichloromethane, to provide an oil (300 mg, 33%). 1H NMR (300 MHz, CDCl3) δ7.15 (m, 2H), 6.96 (t, J=9 Hz, 2H), 3.66 (m, 1H), 3.11 (m, 2H), 2.97 (m, 1H), 2.9-2.7 (m, 3H), 2.60 (m, 2H), 2.39 (m, 1H), 2.24 (m, 1H), 2.00 (m, 1H), 1.7-1.3 (3H), 1.00 (s, 3H), 0.80 (s, 3H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]O)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[Br:42]Br>C(#N)C.C(OCC)C>[Br:42][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:10][CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCO)cc1
Reactant: BrBr
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCBr)cc1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
To a stirring solution of 2-(4-(tert-butyldimethylsilyloxy)phenyl)ethanol (1250 mg, 4.95 mmol) in acetonitrile (50 mL) and diethyl ether (25 mL) was sequentially added triphenylphosphine (3.44 mL, 14.8 mmol), 1H-imidazole (1011 mg, 14.8 μmol), and bromine (765 μl, 14.8 mmol). The clear solution was stirred at 23° C. for 18 h. The mixture was concentrated directly onto silica (20 g) under reduced pressure then purified on 120 grams of silica eluting with 0-5% EtOAc/Hexane. MS (ESI pos. ion) m/z (MH+): 315/317. Calc'd exact mass for C14H23BrOSi: 314. 1H NMR (400 MHz, Chloroform-d) δ ppm 0.19 (s, 6 H) 0.98 (s, 9 H) 3.08 (t, J=7.78 Hz, 2 H) 3.47-3.57 (m, 2 H) 6.78 (d, J=8.53 Hz, 2 H) 7.05 (d, J=8.53 Hz, 2 H).
Reaction SMILES: C(=O)C1C=CC=CC=1.[NH2:9][CH2:10][C@@H:11]([CH3:32])[O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([Cl:31])[CH:25]=1)=[N:16][CH:17]=[N:18]2.C(=O)([O-])[O-].[K+].[K+].Cl.[N:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46]Cl.O1CCOCCOCCOCCOCCOCC1>CN(C=O)C>[NH2:9][CH2:10][C@@H:11]([CH3:32])[O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:46][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][N:40]=3)=[C:26]([Cl:31])[CH:25]=1)=[N:16][CH:17]=[N:18]2
Reactant: C[C@H](CN)Oc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Reactant: ClCc1ccccn1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O=Cc1ccccc1
Solvent: CN(C)C=O
Product: C[C@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reaction time: 0.33 h
Yield: 99.8 %

Procedure:
Benzaldehyde (1.46 ml, 14.3 mmol) was added to a solution of 4-({5-[(1R)-2-amino-1-methylethoxy]quinazolin-4-yl}amino)-2-chlorophenol (obtained as described in Example 4.4, preparation of starting materials, 4.5 g, 13.08 mmol) in DMF (50 ml) and the mixture was stirred for 20 minutes. Potassium carbonate (7.23 g, 52.32 mmol), picolyl chloride hydrochloride (2.57 g, 15.70 mmol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6/catalytic amount) were added and the reaction mixture was stirred vigorously for 16 hours. The reaction mixture was concentrated, the residue was stirred in water (250 ml) and the precipitated solid was filtered off. The solid was dissolved in 1M HCl (150 ml) and the solution washed with ethyl acetate (3×50 ml). The aqueous phase was basified with 2M NaOH and the resultant precipitate was filtered off to give 5-[(1R)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (5.69 g, 100%); NMR spectrum (DMSO-d6) 1.39 (d, 3H), 2.88-3.05 (m, 2H), 4.74-4.86 (m, 1H), 5.28 (s, 2H), 7.14-7.25 (m, 2H), 7.30 (d, 1H), 7.33-7.40 (m, 1H), 7.57 (d, 1H), 7.65 (dd, 1H), 7.70 (dt, 1H), 7.87 (dt, 1H), 8.20 (d, 1H), 8.49 (s, 1H), 8.56-8.61 (m, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[CH3:16][S:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][C:19]=1[C:26]([F:29])([F:28])[F:27]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([S:15][CH2:22][C:21]4[CH:24]=[CH:25][C:18]([S:17][CH3:16])=[C:19]([C:26]([F:29])([F:27])[F:28])[CH:20]=4)=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: Sc1nnc(-c2ccc3c(c2)CCO3)o1
Reactant: CSc1ccc(CCl)cc1C(F)(F)F
Product: CSc1ccc(CSc2nnc(-c3ccc4c(c3)CCO4)o2)cc1C(F)(F)F
Yield: 89 %

Procedure:
In the same manner as in Example 7 and using 5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(1H-indazol-5-yl)-1,3,4-oxadiazole-2-thiol and 4-(methylthio)-3-(trifluoromethyl)benzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 89%) was obtained as colorless crystals.