Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:23])=[C:19]([CH:21]=[CH2:22])[CH:20]=1)(OC(C)(C)C)=O.C=O.[OH-].[Na+]>C(O)=O>[Cl:23][C:18]1[N:17]=[CH:16][C:15]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH3:1])=[CH:20][C:19]=1[CH:21]=[CH2:22]
Reactant: C=Cc1cc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)cnc1Cl
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: C=Cc1cc(OC[C@H]2CCCN2C)cnc1Cl
Temperature: 70 °C
Yield: 53 %

Procedure:
To the product from 167a (328 mg, 0.97 mmol) was added formic acid (88%, 3 mL) and formaldehyde (37%, 6 mL). The mixture was stirred and heated at 70° C. for 6 h. After cooling to room temperature, the mixture was basified with aqueous 10% NaOH. The solution was then extracted with CH2Cl2 (3X), the combined organic layers were dried (MgSO4), concentrated and chromatographed (silica gel; CH2Cl2, 10:0.3 to 10:1) to afford an oil (130 mg, 53%): 1H NMR (CDCl3, 300 MHz) δ 1.70-1.90 (m, 3H), 2.02 (m, 1H), 2.32 (m, 1H), 2.48 (s, 3H), 2.66 (m, 1H), 3.12 (m, 1H), 3.98 (m, 2H), 5.48 (d, 1H, J=10.5 Hz), 5.76 (d, 1H, J=17.5 Hz), 6.98 (dd, 1H, J=11.0, 17.5 Hz), 7.40 (d, 1H, J=3.0 Hz), 8.00 (d, 1H, J=3.0 Hz); MS (CI/NH3) m/z 253 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][C:43]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[F:55])([OH:47])[CH2:42]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:55][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=1[CH2:48][C:43]1([OH:47])[CH2:44][CH2:45][CH2:46][CH:41]([NH:40][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:18])[CH2:42]1
Reactant: NC1CCCC(O)(Cc2ccccc2F)C1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(O)(Cc5ccccc5F)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.05 mmol, 24.8 mg), HCl salt of 3-amino-1-(2-fluorobenzyl)cyclohexanol (0.05 mmol, 11 mg), HATU (0.05 mmol, 19 mg) and DIEA (80 μL) in DMA (300 μL) was stirred at room temperature for overnight. The product, N-(3-(2-fluorobenzyl)-3-hydroxycyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, was obtained after evaporation of solvent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30]([O:32]CC)=O)[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:36][NH2:37]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30]([NH:37][CH3:36])=[O:32])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O
Product: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxo-1-piperidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and methylamine using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.65-1.81 (m, 6 H), 2.19 (t, J=6.21 Hz, 2 H), 2.91 (d, J=4.84 Hz, 3 H), 3.20 (t, J=5.79 Hz, 2 H), 3.38 (q, J=7.09 Hz, 2 H), 4.16-4.25 (m, 4 H), 7.11-7.18 (m, 2 H), 7.37-7.44 (m, 2 H), 8.01 (s, 1 H), 8.55 (d, J=1.68 Hz, 1 H), 10.14 (d, J=4.63 Hz, 1 H), 17.23 (s, 1 H); ES+ MS: 467 (M+H+).
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[NH2:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:17]1>N1C=CC=CC=1.C1C=CC=CC=1.C(Cl)(Cl)Cl>[NH:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:15][N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:17]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: Nn1cc(-c2ccccc2)c2ccccc21
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nn2cc(-c3ccccc3)c3ccccc32)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
11.7 G (0.05 mol) of p-acetaminobenzene sulphonyl chloride were added in portions and with stirring to a solution of 15.6 g (0.075 mol) of 1-amino-3-phenyl-indole in 100 ml of pyridine. The temperature of the mixture rose to about 45° C. The mixture was then heated to 60° C. and stirred for 3 hours at this temperature. The red solution obtained was then concentrated by evaporation under vacuum. The viscous, oily residue which was obtained was taken up in a mixture of benzene and chloroform (1:1 by volume) and chromatographically purified through a column of 300 ml Alox Woelm neutral Akt. II. The resulting oily product was crystallised from a little ethanol and was recrystallised from ethanol/water. The crystals of 1-(p-acetaminobenzene sulphonylamino)-3-phenyl-indole melted at 190°-193° C. and were obtained in a yield of 16.5 g (55% of the theoretical).
Reaction SMILES: [CH:1]1([NH:5][S:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[CH:1]1([NH:5][S:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)NC2CCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)NC2CCC2)cc1
Yield: 75.3 %

Procedure:
4-(N-Cyclobutylsulphamoyl)nitrobenzene (Method 52; 11.79 g) was reduced by hydrogenation in ethanol (300 ml) over 10% palladium on carbon (1 g) at 3 bar pressure. The catalyst was removed by filtration and the volatiles evaporated to give the title compound (7.84 g). NMR: 1.50 (m, 2H), 1.75 (m, 2H), 1.93 (m, 2H), 3.60 (m, 1H), 5.90 (br s, 2H), 6.65 (d, 2H), 7.45 (d, 2H); m/z: 226.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:29])[NH:14][CH:15]1[CH2:19][C:18](=[O:20])[O:17][CH:16]1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:22]([O:21][CH:16]1[CH:15]([NH:14][C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:29])[CH2:19][C:18](=[O:20])[O:17]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(NC(=O)C2CCCN2)C(OCc2ccccc2)O1

Procedure:
A solution of 118 (405 mg, 1.0 mmol) was treated with TFA (2 mL) in CH2Cl2 (2 mL) for one hour. The reaction solution was evaporated in vacuo and azeotrapped with CH2Cl2 four times to give pyrrolidine-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl)-amide as a pale yellow solid. 1H-NMR (500 MHz, CDCl3): δ 1.87-2.15 (m, 4H), 2.30-2.70 (m, 2H), 2.80-3.08 (m, H), 3.45 (br, 2H), 4.35-4.98 (m, 3H), 5.30-5.56 (m, H), 7.10-7.60 (m, 5H); Analytical HPLC: 7.78/8.20 min.; LC-MS: m/e=305 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([O-:12])=[O:11])[CH:5]=[N:6][CH:7]=1.[BH4-].[Na+].[C:15](OCC)(=O)C>CO.[Cl-].[Na+].O.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:15][O:11][C:10](=[O:12])[CH2:9][CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CCOC(C)=O
Reactant: O=C([O-])C=Cc1cncc(Br)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: COC(=O)CCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(5-bromopyridin-3-yl)acrylate (180 mg, 0.744 mmol) and nickel chloride hexahydrate (17.6 mg, 0.074 mmol) in MeOH (3 ml) was added sodium borohydride (56.3 mg, 1.487 mmol) at 0° C. This mixture was stirred for 30 min at room temperature. Brine and ethyl acetate were added and the organic layer was separated and washed with brine twice. The combined organic layer was dried over Na2SO4, filtered and concentrated to give 155 mg of crude 3-(5-Bromo-pyridin-3-yl)-propionic acid methyl ester. ESI-MS m/z: 246[M+1]+.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[Cl:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=2)=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: Oc1cccc(Cl)c1
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Product: COC(=O)c1cc(Cl)ccc1COc1cccc(Cl)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 3-chlorophenol:
Reaction SMILES: N1C=CC=CC=1.C(N(C(C)C)C(C)C)C.[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:26][C:27]([NH:37][CH:38]([CH3:42])[C:39](=[O:41])[CH3:40])([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[CH:30]=1)[CH3:28]>ClCCl.O>[CH3:28][C:27]([N:37]([CH:38]([CH3:42])[C:39](=[O:41])[CH3:40])[C:23](=[O:24])[CH2:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[CH:30]=1)[CH3:26]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(=O)C(C)NC(C)(C)c1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)C(C)N(C(=O)Cc1ccccc1)C(C)(C)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
In 15 ml of dichloromethane containing 2.0 g of pyridine and 1.0 g of N-ethyl-N,N-diisopropylamine, 3.5 g of 2-phenylacetyl chloride was added dropwise to 2.5 g of N-[1-methyl-1-(3,5-dichlorophenyl)ethyl]-N-(1-methyl-2-oxopropyl)amine at room temperature. After stirring at room temperature for 1 hour, the solution was poured into water, and then extracted with ethyl acetate. Next, the solution was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, concentrated, and then subjected to column chromatography to obtain 1.7 g of N-[1-methyl-1-(3,5-dichlorophenyl)ethyl]-N-(1-methyl-2-oxopropyl)-2-phenylacetamide.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.Cl[C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[O:20]=[C:18]1[NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:9])[CH2:7][O:8]1
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1COC(=O)N1
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
A solution of L-serine methyl ester hydrochloride (3.063 kg) in dichloromethane (24.1 L) at 0° C. was treated with triethylamine (5.908 kg), stirred for 30 minutes, treated with triphosgene (1.949 kg) in dichloromethane (5.356 kg) over 6.5 hours, stirred for 45 minutes, treated with hexanes (12.23 kg), stirred for 55 minutes, and filtered with ethyl acetate (16.013 kg). The filtrate was concentrated to provide a 35% (w/w) solution of the desired product (93.5%, 98% ee) in ethyl acetate. 1H NMR (300 MHz, CDCl3) δ6.55 (br s, 1H), 4.62 (dd, J=9, 9 Hz, 1H), 4.53 (dd, J=4, 9 Hz, 1H), 4.45 (dd, J=4, 9 Hz, 1H), 3.83 (s, 3H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.BrC1C=CC=CC=1C.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].Cl>O1CCCC1>[C:18]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(Br)cc1
Agent: Cc1ccccc1Br
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)C(C)(C)C)cc1
Reaction time: 2 h

Procedure:
To a suspension of 28.5 g (1.17 g. atoms) magnesium turnings in 150 ml tetrahydrofuran under a nitrogen atmosphere there is added 10 ml of 4-bromotoluene (1.17 mole) in 650 ml dry tetrahydrofuran, the reaction is started and the remainder of the bromotoluene solution is added dropwise at a rate that maintains a moderate reflux. After the addition is complete, the mixture is refluxed for an additional 1 1/2 hours. The resulting Grignard solution is added dropwise to a cold solution of 128.0 g pivaloyl chloride (1.06 mole) in 500 ml dry tetrahydrofuran at a rate that maintains the temperature at 0° to -5°C. The solution is stirred for an additional 11/2 hours at 0° and then at room temperature for 18 hours. The mixture is then cooled to 0° and hydrolyzed by the addition of 100 ml 2N hydrochloric acid. The layers are separated and 200 ml of ether is added to the organic phases which is then washed respectively with 100 ml 2N hydrochloric acid, 100 ml. 10% sodium bicarbonate solution and 100 ml. saturated sodium chloride. The resulting layer is dried over anhydrous sodium sulfate, filtered, and the solvent is removed in vacuo to give p-pivaloyl toluene (b.p 80°-84°C/0.7 mm,nD21 1.5108). A mixture of 156.3 g. (0.886 mole) of the resulting p-pivaloyl toluene is then added to 157.8 g. (0.886) mole) N-bromosuccinimide, 4.0 g (0.016 mole) benzoyl peroxide and 150 ml. carbon tetrachloride and heated at reflux for 18 hours. The mixture is cooled and filtered and the resulting precipitate is washed with carbon tetrachloride. The solvents are removed in vacuo and the resulting oil is distilled in vacuo to give α-bromo-p-pivaloyl toluene (b.p. 124°- 132°/ 0.7 mm, nD22 1.5546- V.P.C.96% monobromo 4%-dibromo).
Reaction SMILES: [CH3:1][Ge:2]([CH3:20])([CH3:19])[C:3]1[CH:4]=[C:5]([C:13]2([CH3:18])OCC[O:14]2)[CH:6]=[C:7]([Ge:9]([CH3:12])([CH3:11])[CH3:10])[CH:8]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.O>CC(C)=O>[CH3:11][Ge:9]([CH3:10])([CH3:12])[C:7]1[CH:6]=[C:5]([C:13](=[O:14])[CH3:18])[CH:4]=[C:3]([Ge:2]([CH3:19])([CH3:1])[CH3:20])[CH:8]=1
Reactant: CC1(c2cc([Ge](C)(C)C)cc([Ge](C)(C)C)c2)OCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1cc([Ge](C)(C)C)cc([Ge](C)(C)C)c1
Yield: 98 %

Procedure:
A mixture of 240 mg (0.60 mmol) of 2-[3,5-bis(trimethylgermyl)phenyl]-2-methyl-1,3-dioxolane, 23 mg (0.090 mmol) of PPTS, 10.6 ml of acetone (excess) and 540 mg (30 mmol) of water was refluxed for 2.5 hours. The reaction mixture was evaporated and extracted with ether. The extract was evaporated to give 208 mg of pale yellow crystals, which were sublimed at 70° C., 0.5 mmHg to give 189 mg of white prisms, m.p. 56° C. (yield 89%).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][CH2:6][C@@H:7]([CH3:35])[O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[C:22]([Cl:34])[CH:21]=1)=[N:12][CH:13]=[N:14]2>>[Cl:34][C:22]1[CH:21]=[C:20]([NH:19][C:11]2[C:10]3[C:15](=[CH:16][CH:17]=[CH:18][C:9]=3[O:8][C@H:7]([CH3:35])[CH2:6][NH:5][C:3]([NH:2][CH3:1])=[O:4])[N:14]=[CH:13][N:12]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: C[C@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CN=C=O
Product: CNC(=O)NC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 43 %

Procedure:
The procedure described in Example 120 was repeated using methyl isocyanate and 5-[(1R)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 65, preparation of starting materials) to give the title compound as a solid in 43% yield; NMR spectrum (DMSO-d6 @ 373K) 1.40-1.45 (d, 3H), 2.50-2.55 (d, 3H), 3.38-3.48 (m, 1H), 3.50-3.60 (m, 1H), 4.83-4.92 (m, 1H), 5.28 (s, 2H), 5.55-5.65 (bs, 1H), 6.00-6.10 (bs, 1H), 7.19-7.24 (dd, 2H), 7.31-7.37 (m, 2H), 7.56-7.62 (m, 2H), 7.66-7.73 (t, 1H), 7.81-7.88 (dt, 1H), 8.06-8.08 (d, 1H), 8.48 (s, 1H), 8.55-8.60 (d, 1H), 9.95-10.05 (bs, 1H); Mass spectrum MH+ 493.4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=4)=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)=[CH:13][CH:14]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc(Br)ccc32)cc1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ccc3c(ccn3Cc3ccc(C(C)(C)C)cc3)c2)c1

Procedure:
The title compound was prepared from 5-bromo-1-[4-(tert-butyl)benzyl]-1H-indole (Step 1 of Example 34) and 3-methoxyphenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 370. 1HNMR (400 MHz, DMSO-d6): δ 7.81 (s, 1H), 7.53 (s, 1H), 7.51 (d, 1H, J=8.55 Hz), 7.39 (d, 1H, J=8.55 Hz), 7.34-7.30 (m, 3H), 7.20 (d, 1H, J=7.64 Hz), 7.15-7.13 (m, 3H), 6.85 (d, 1H, J=8.25 Hz), 6.52 (d, 1H, J=3.05 Hz), 5.39 (s, 2H), 5.81 (s, 3H), and 1.21 ppm (s, 9H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:13])([CH:7]([OH:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:5][OH:6].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Cl.[Cl-].[NH4+]>CN(C=O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][O:6][CH2:5][C:4]([CH3:13])([CH3:3])[CH:7]([OH:12])[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: COc1cccc(CCl)c1
Reactant: CC(C)(C)C(O)C(C)(C)CO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cccc(COCC(C)(C)C(O)C(C)(C)C)c1
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
In a nitrogen atmosphere, to a solution having 2.12 g (53.0 mmol) of 60% sodium hydride suspended in 80 ml of DMF at 0° C., 7.05 g (44.1 mmol) of 2,2,4,4-tetramethyl-1,3-pentanediol (compound (2)) dissolved in 15 ml of DMF, was dropwise added over a period of 30 minutes, followed by further stirring for 30 minutes. To this solution, 9.07 g (57.9 mmol) of 3-methoxybenzyl chloride (compound (1)) dissolved in 15 ml of DMF was dropwise added over a period of 30 minutes, followed by stirring for 12 hours. The reaction mixture was put into an aqueous saturated ammonium chloride solution and extracted with ethyl acetate. The extract layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated. The concentrated product was subjected to a silica gel column and eluted with a 10:1 mixed solvent of hexane and ethyl acetate, to obtain 10.7 g of 1-(3-methoxybenzyloxy)-2,2,4,4-tetramethyl-3-pentanol (compound (3)) in a yield of 86.7% as a colorless oily substance.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[C:8]([NH:22][CH2:23][CH2:24][CH3:25])=[N:9][C:10]([NH:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[N:11][CH:12]=1.[NH2:26][C:27]([CH3:39])([CH3:38])[CH2:28][N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C.C(O)(=O)C>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([NH:13][C:10]2[N:9]=[C:8]([NH:22][CH2:23][CH2:24][CH3:25])[C:7]([C:6]#[C:5][CH2:4][CH2:3][CH2:2][NH:26][C:27]([CH3:39])([CH3:38])[CH2:28][N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[CH:12][N:11]=2)=[CH:15][CH:16]=1)#[N:19]
Reactant: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C#CCCC=O
Reactant: CN(CC(C)(C)N)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C#CCCCNC(C)(C)CN(C)C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
To a solution of 4-((5-(5-oxo-1-pentyn-1-yl)-4-(propylamino)pyrimidin-2-yl)amino)benzonitrile (G12, 300 mg) and tert-butyl (2-amino-2-methylpropyl)(methyl)carbamate (G10, 112 mg) in methylene chloride (4 mL), sodium triacetoxyborohydride (195 mg) and acetic acid (21 μL) were added at room temperature, and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 80% ethyl acetate in methanol) to obtain tert-butyl (2-((5-(2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-2-methylpropyl)(methyl)carbamate (G13, 80 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.OS(O)(=O)=O.[N+:24]([O-])([OH:26])=[O:25]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[O:9])=[CH:6][C:7]=1[N+:24]([O-:26])=[O:25]
Reactant: O=C(c1ccc(Br)cc1)c1cccc([N+](=O)[O-])c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(Cl)Cl
Product: O=C(c1cccc([N+](=O)[O-])c1)c1ccc(Br)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
The crude (4-bromo-phenyl)-(3-nitro-phenyl)-methanone (11.1 g, 36.27 mmol) was dissolved in dichloroethane (35 mL) and added dropwise via addition funnel to a mixture of concentrated H2SO4(aq) (16 mL, 290 mmol) and fuming HNO3(aq) (13 mL, 290 mmol). The mixture was stirred at 60° C. overnight. Subsequently the mixture was poured over ice water and allowed to stir resulting in precipitation of the product. The product was filtered and dried affording 72% yield of the (4-Bromo-3-nitro-phenyl)-(3-nitro-phenyl)-methanone (9.17 g, 26.1 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].I[CH3:14]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:14])[CH:6]=[CH:5]2
Reactant: CI
Reactant: Clc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 49.9 %

Procedure:
In an oven dried, nitrogen purged, 3 neck, 50 mL round bottom flask, 1.00 g (6.60 mmol) of 5-chloroindole in 10 mL of dry dimethylformamide is reacted with 0.260 g (6.60 mmol) of 60% sodium hydride dispersed in mineral oil at room temperature for 4 h. 0.411 mL (6.60 mmol) of iodomethane is added and the reaction is allowed to stir at room temperature 15 h. The reaction is quenched with 50 mL of water, extracted 3×50 mL of ethyl acetate, dried (MgSO4), and concentrated. The crude product is purified by chromatography using hexanes:ethyl acetate as a solvent system to obtain 0.545 g of the title compound, 50% yield. MS, ES=166.0 (M+1); 1H NMR (DMSO-d6) δ 7.567-7.564 (m, 1H); 7.453-7.431 (m, 1H); 7.381-7.374 (m, 1H); 7.131-7.105 (m, 1H); 6.393-6.386 (m, 1H); 2.768 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[OH:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][OH:19])=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NCCCCO
Product: O=C(NCCCCO)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-(4-hydroxybutyl)isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.5 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.63 mmol of 4-hydroxy-butylamine. LC/MS [8.42 min; 430 (M+1)]