Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=2[F:17])=[CH:6][N:5]=[C:4]([C:27]([NH2:29])=[O:28])[CH:3]=1.C=O.[OH-].[Na+].[C:34](=O)([O-])[O-:35].[Na+].[Na+]>COCCOC>[OH:35][CH2:34][NH:29][C:27]([C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([CH:8]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:19])=[O:20])[C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=2[F:17])=[CH:6][N:5]=1)=[O:28]
Reactant: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: Cc1cc(C(=O)NCO)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 4-methyl-5-[(phenylsulfonyl)(2,3,6-trifluorophenyl)methyl]pyridine-2-carboxamide (215 mg, 0.51 mmol) in ethylene glycol dimethyl ether (6 ml), an aqueous solution of formaldehyde (37%, 0.2 ml) and 5% aqueous sodium hydroxide (0.8 ml) were added at 0° C., and the mixture was stirred for 1 hour at room temperature. Sodium carbonate (40 mg) was added to the reaction mixture, and the mixture was stirred for 20 minutes at room temperature. The mixture was concentrated under reduced pressure, and then the residue was dissolved in chloroform, dried over magnesium sulfate, and filtered. Subsequently, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:2 was concentrated under reduced pressure, and the resulting residue was washed with diethyl ether, and then was collected by filtration, to obtain the title compound (90 mg, 0.20 mmol, 39%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[C:17]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])(=[O:24])=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:6]1[CH3:32].[OH-].[Na+].Cl>O1CCCC1>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:33])=[O:2])[C:6]([CH3:32])=[C:7]2[CH2:15][C:16]1[C:17]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])(=[O:24])=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)Cn1c(C)c(Cc2cccnc2S(=O)(=O)c2ccccc2Cl)c2cc(F)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2cccnc2S(=O)(=O)c2ccccc2Cl)c2cc(F)ccc2n1CC(=O)O
Temperature: 45 °C
Reaction time: 4 h

Procedure:
A mixture of {5-fluoro-3-[2-(2-chlorobenzenesulfonyl)pyridin-3-ylmethyl]-2-methylindol-1-yl}acetic acid methyl ester and tetrahydrofuran (1.0 mL) was treated with 5.0 M aqueous sodium hydroxide solution (1.2 mL), and the resulting mixture was stirred at 45° C. for 4 hours. The mixture was acidified by the addition of 5.0 M aqueous hydrochloric acid solution and extracted with dichloromethane. The combined organic extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (2:3 to 9:1 by volume) to afford the title compound as a white solid (0.10 g).
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[C:18](F)=[C:19]([F:35])[CH:20]=[C:21]2[C:26]=1[N:25]([C@H:27]1[CH2:29][C@H:28]1[F:30])[CH:24]=[C:23]([C:31]([OH:33])=[O:32])[C:22]2=[O:34]>>[Cl:16][C:17]1[C:18]([N:4]2[CH2:3][CH2:2][N:1]([CH2:7][C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[O:9])[CH2:6][CH2:5]2)=[C:19]([F:35])[CH:20]=[C:21]2[C:26]=1[N:25]([C@H:27]1[CH2:29][C@H:28]1[F:30])[CH:24]=[C:23]([C:31]([OH:33])=[O:32])[C:22]2=[O:34]
Reactant: O=C(O)c1cn([C@H]2C[C@H]2F)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Product: O=C(O)c1cn([C@H]2C[C@H]2F)c2c(Cl)c(N3CCN(CC(=O)N4CCOCC4)CC3)c(F)cc2c1=O

Procedure:
The preparation takes place in analogy to Example 1A from 4-[2-(piperazin-1-yl)acetyl]morpholine and 8-chloro-6,7-difluoro-1-[(1S,2R)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (for preparation see Journal of Medicinal Chemistry (1994) 37:3344-3352). The compound is used as a crude product in the subsequent reaction stages.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1.Br[CH2:28][CH2:29][CH2:30][P:31](=[O:38])([O:35][CH2:36][CH3:37])[O:32][CH2:33][CH3:34]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:28][CH2:29][CH2:30][P:31](=[O:38])([O:35][CH2:36][CH3:37])[O:32][CH2:33][CH3:34])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1
Reactant: CCOP(=O)(CCCBr)OCC
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12
Product: CCOP(=O)(CCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1)OCC

Procedure:
Diethyl 3-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)propylphosphonate was prepared following an analogous procedure to the preparation described for Example 139, but using 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol (from Example 50) with diethyl 3-bromopropylphosphonate. 1H NMR (Acetone-d6): δ 9.52 (s, 1H), 9.47 (s, 1H), 9.03 (d, 1H), 8.21 (s, 1H), 7.93 (d, 1H), 7.84 (d, 1H), 7.60 (br, 2H), 7.53 (s, 1), 7.45 (d, 1H), 4.76-4.91 (m, 6H), 3.93 (t, 2H), 3.81 (t, 2H), 3.24 (s, 3H), 3.06 (s, 3H), 2.76-2.86 (m, 2H), 2.61-2.72 (m, 2H), 2.07 (t, 6H). LRMS [M+H]=522.2
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18](Cl)=[O:19])[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.[NH3:22].O>C1COCC1>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18](=[O:19])[NH2:22])[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC1Cc2ccc(C(=O)Cl)cc2C1
Reactant: N
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCC1Cc2ccc(C(N)=O)cc2C1
Temperature: 0 °C
Yield: 92.1 %

Procedure:
In a 50 ml-round bottomed flask, 5.00 g (18.2 mM) of 2-octylindan-5-carboxylic acid was placed and 7.0 ml of thionyl chloride and one drop of N,N'-dimethylformamide (DMF) were added thereto, followed by heat-refluxing for 30 minute. An excessive thionyl chloride was distilled off under reduced pressure from the above mixture to obtain 2-octylindan-5-carbonyl chloride. A solution of the above-obtained 2-octylindan-5-carbonyl chloride in 50 ml of THF was gradually added dropwise to 45 ml of 30%-ammonia water which had been cooled to about 0° C. on an ice-common salt bath under stirring. After the addition, the resultant mixture was stirred for 4.5 hours at room temperature. After the reaction, 300 ml of water was added to the reaction mixture to precipitate a crystal. The crystal was recovered by filtration and successively washed with water and methanol to obtain 4.59 g of 2-octyl-5-carbamoylindan (Yield: 92.1%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc(CBr)c1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(N2CCCC(Cc3cccc(F)c3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 89 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide to react with 1-(bromomethyl)-3-fluorobenzene in place of 1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound was obtained as a white solid in 89% yield: mp 170-171° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.39-7.17 (m, 6H), 6.99-6.89 (m, 3H), 6.01 (t, J=5.5 Hz, 1H), 4.57 (d, J=5.5 Hz, 2H), 4.33-4.21 (m, 1H), 3.99-3.89 (m, 1H), 3.45-3.36 (m, 1H), 3.86-3.27 (m, 2H), 2.63 (s, 3H), 2.10-1.96 (m, 1H), 1.94-1.73 (m, 2H), 1.61-1.43 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 171.8, 162.9, 162.6, 156.9, 152.1, 141.6, 137.9, 130.1, 128.8, 127.9, 127.7, 124.9, 119.5, 114.9, 114.6, 113.6, 48.0, 44.0, 37.3, 24.9, 21.3, 17.4; MS (ES+) m/z 438.2 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:13][CH2:12]2.[C:27]1([C:33]2[CH:37]=[C:36]([CH:38]=O)[O:35][N:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:38][C:36]3[O:35][N:34]=[C:33]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:37]=3)[CH2:23][CH2:22]1)[CH2:13][CH2:12]2
Reactant: O=Cc1cc(-c2ccccc2)no1
Reactant: O=C1c2ccc(Cl)cc2CCN1CC1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2ccc(Cl)cc2CCN1CC1CCN(Cc2cc(-c3ccccc3)no2)CC1

Procedure:
According to the same procedure described in Example 35, using the compound prepared in Example 62 instead of the compound prepared in Example 11 and the compound prepared in Example 7 instead of 4-phenylthiophene-2-carbaldehyde, the title compound having the following physical data was obtained.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1[C:28](C2C=CC=CC=2)=CS[C:25]=1[C:35](OC)=O.C(OCC)(OCC)OCC.[C@@H]1(N)C2C(=CC=CC=2)CCC1>C(O)(=O)C>[C:17]1([C:16]2[C:10]3[N:9]=[CH:8][N:7]([C@@H:1]4[C:6]5[C:5](=[CH:28][CH:24]=[CH:25][CH:35]=5)[CH2:4][CH2:3][CH2:2]4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: N[C@H]1CCCc2ccccc21
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3)c2ncn1[C@H]1CCCc2ccccc21
Yield: 53.3 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), (S)-1,2,3,4-tetrahydronaphthalen-1-amine (0.141 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 82.1 mg (0.23 mmol, 53.3% yield) of the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[N:47]([C:50]1[CH:58]=[CH:57][CH:56]=[C:55]2[C:51]=1[CH:52]=[CH:53][N:54]2[CH3:59])=[C:48]=[O:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([C:48]([NH:47][C:50]2[CH:58]=[CH:57][CH:56]=[C:55]3[C:51]=2[CH:52]=[CH:53][N:54]3[CH3:59])=[O:49])[CH2:42][CH2:41]1)=[O:39]
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Reactant: Cn1ccc2c(N=C=O)cccc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccc2c(NC(=O)N3CCC(C(=O)Nc4ccc5cc4CCc4cccc(c4)Nc4ncc(Cl)c(n4)N5)CC3)cccc21
Yield: 34 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 4-isocyanato-1-methyl-1H-indole as starting materials in 34% yield. LCMS for C34H34ClN8O2 (M+H)+: m/z=621.2.
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[NH2-].[Na+].O>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[C:2]1([CH:1]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:8]#[N:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1ccccc1
Reactant: Clc1ccccn1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#CC(c1ccccc1)c1ccccn1
Yield: 41 %

Procedure:
To a solution of benzyl cyanide (5.00 g, 42.7 mmol) and 2-chloropyridine (4.85 g, 42.7 mmol) in 15 ml of toluene was added finely powdered sodium amide (3.33 g, 85.4 mmol) in portions keeping the temperature between 20-30° C. The suspension was refluxed for 6 h. After cooling, 100 ml water is added and the product is worked up with ethyl acetate/water. After drying (MgSO4) and concentration, the crude material is purified by flash chromatography on silicagel using a 1:4 mixture of ethyl acetate and hexane as eluant to yield 3.40 g (17.5 mmol, 41%) of (RS)-phenyl-pyridin-2-yl-acetonitrile as a white solid, m.p. 89° C. and MS: m/e=194 (M+).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=1.CN(C=O)C.C(N(C(C)C)CC)(C)C.C(Cl)(=O)C([Cl:37])=O>C(Cl)Cl>[Cl:37][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]([C:2]([F:19])([F:18])[F:1])[N:12]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Oc1nc(C(F)(F)F)nc2ccc(C(F)(F)F)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: FC(F)(F)c1ccc2nc(C(F)(F)F)nc(Cl)c2c1
Temperature: 25 °C

Procedure:
A mixture of 2,6-bis(trifluoromethyl)quinazolin-4-ol (200 mg, 0.666 mmol, prepared in the previous step), DMF (0.01 mL, 0.129 mmol) and diisopropylethylamine (0.17 mL, 0.986 mmol) suspended in dry DCM (10 mL) and treated dropwise with oxalyl chloride (0.11 mL, 1.26 mmol) under argon. After the addition, the reaction mixture was heated to reflux for 4 hours. After cooling to room temperature, the reaction was quenched by the cautious addition of potassium phosphate dibasic solution (20% w/w) and extracted with dichloromethane. The combined organic layers were washed with brine and dried over Na2SO4 and concentrated to yield the product as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:5][C:6]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9])[CH3:4].[C:28](OC(=O)C)(=[O:30])[CH3:29]>ClCCl>[C:28]([NH:1][CH2:2][C@@H:3]([NH:5][C:6]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9])[CH3:4])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)CN)cc1OC
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)CNC(C)=O)cc1OC
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of (S)-2-(2-amino-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (99 mg) in dichloromethane (3 mL) was added acetic anhydride (38 mg), and the mixture was stirred for an hour at ambient temperature. The resulting mixture was evaporated in vacuo. The residue was triturated with diisopropyl ether to give (S)-2-[2-(acetamido)-1-methylethylamino]-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (107 mg) as a solid substance.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([CH3:24])[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[CH3:25][O:26][CH2:27][C:28](O)=[O:29]>>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[OH:22])[NH:15][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[CH:14][C:5]=2[O:4][C@H:3]([CH3:24])[CH2:2][NH:1][C:28](=[O:29])[CH2:27][O:26][CH3:25])[N:10]=[CH:9][N:8]=1
Reactant: COCC(=O)O
Reactant: C[C@H](CN)Oc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Product: COCC(=O)NC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Yield: 83 %

Procedure:
4-({5-[(1R)-2-Amino-1-methylethoxy]quinazolin-4-yl}amino)-2-chlorophenol was reacted with methoxyacetic acid using an analogous process to that described in Example 3 (preparation of starting materials) to give N-[(2R)-2-({4-[3-chloro-4-hydroxyanilino]quinazolin-5-yl}oxy)propyl]-2-methoxyacetamide in 83% yield; NMR spectrum (DMSO-d6) 1.4 (d, 3H), 3.1 (s, 3H), 3.35-3.45 (m, 1H), 3.72-3.85 (m, 3H), 4.95-5.05 (m, 1H), 7.05 (d, 1H), 7.31 (d, 1H), 7.4 (dd, 1H), 7.48 (d, 1H), 7.81 (m, 1H), 7.95 (t, 1H), 8.25 (t, 1H), 8.8 (s, 1H), 10.39 (s, 1H), 10.74 (s, 1H) Mass spectrum MH+ 417.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7](B(O)O)[N:8]2[CH3:11])=[CH:4][CH:3]=1.Br[C:16]1[CH:17]=[C:18]([CH2:22][N:23]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:33])[CH:19]=[N:20][CH:21]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:16]3[CH:17]=[C:18]([CH2:22][N:23]4[C:24](=[O:33])[C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[C:31]4=[O:32])[CH:19]=[N:20][CH:21]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cncc(Br)c1
Reactant: Cn1c(B(O)O)cc2ccc(Cl)cc21
Product: Cn1c(-c2cncc(CN3C(=O)c4ccccc4C3=O)c2)cc2ccc(Cl)cc21

Procedure:
6-Chloro-1-methyl-indole-2-boronic acid and 2-(5-bromo-pyridin-3-ylmethyl)-isoindole-1,3-dione are processed according to the method described in Example 100 to give 2-[5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]isoindole-1,3-dione. MS (ESI) m/z 402.1 (M+H)+.
Reaction SMILES: Br[C:2]1[C:13](=[O:14])[N:12]([CH2:15][CH3:16])[C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=2[CH:3]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([N:12]1[C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=2[CH:3]=[C:2]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]1=[O:14])[CH3:16]
Reactant: OB(O)c1ccccc1
Reactant: CCn1c(=O)c(Br)cc2cnc(SC)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCn1c(=O)c(-c2ccccc2)cc2cnc(SC)nc21
Temperature: 120 °C
Yield: 82 %

Procedure:
6-bromo-8-ethyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (150 mg, 0.50 mmol), phenylboronic acid (183 mg, 1.50 mmol), K3PO4 (318 mg, 1.50 mmol) and Pd(PPh3)4 (29 mg, 0.02 mmol) were mixed as solids and placed under argon. Argon was bubbled through the mixture of dimethoxyethane:ethanol:water (1:1:1, 2.0 mL) for 20 min. The solvent was added to the solid and the suspension was heated under microwave irradiation at 120° C. for 1 h. After completion, the reaction mixture evaporated to dryness, the crude product was purified by silica gel column chromatography using dichloromethane:ethyl acetate (100:0.5) to yield 8-ethyl-2-(methylthio)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one as an off-white solid (121 mg, 0.41 mmol, 81%). ESMS m/z 298 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.59 (s, 1H), 8.03 (s, 1H), 4.55 (q, J=7.2 Hz, 2H), 2.63 (s, 3H), 1.35 (t, J=7.2 Hz, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]=[N:13][C:12]=3[CH:16]=2)[CH2:7][CH2:6]1)=[O:4].O>CCS>[O:15]1[C:11]2[CH:10]=[CH:9][C:8]([C:5]3([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]3)=[CH:16][C:12]=2[N:13]=[CH:14]1
Reactant: COC(=O)C1(c2ccc3ocnc3c2)CC1
Solvent: CCS
Solvent: O
Product: O=C(O)C1(c2ccc3ocnc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.3 %

Procedure:
To a solution of crude 1-benzooxazol-5-yl-cyclopropanecarboxylic acid methyl ester (2.9 g) in EtSH (30 mL) was added A1Cl3 (5.3 g, 40.1 mmol) in portions at 0° C. The reaction mixture was stirred for 18 hours at room temperature. Water (20 mL) was added dropwise at 0° C. The resulting mixture was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/EtOAc 1:2) to give 1-(benzo[d]oxazol-5-yl)cyclopropanecarboxylic acid (280 mg, two steps: 11%). 1H NMR (DMSO, 400 MHz) δ 12.25 (brs, 1H), 8.71 (s, 1H), 7.70-7.64 (m, 2H), 7.40 (dd, J=1.6, 8.4 Hz, 1H), 1.49-1.46 (m, 2H), 1.21-1.18 (m, 2H). MS (ESI) m/e (M+H+) 204.4.
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.N1C=CC=CC=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C(#N)C.O>[C:1]1([NH:11][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Nc1nccc2ccccc12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(Nc1nccc2ccccc12)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
Isoquinolin-1-amine (300 mg, 2.08 mmol) was dissolved in acetonitrile. The reaction mixture was added pyridine (0.02 mL, 2.50 mmol) and phenyl chloroformate (0.27 mL, 2.18 mmol) and stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The crude was purified by column chromatography to give phenyl isoquinolin-1-ylcarbamate (285 mg, 52%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH:26]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([C:36](O)=[O:37])[C:30]=2[CH:29]=[CH:28][N:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:31]4[CH:32]=[CH:33][CH:34]=[C:35]5[C:30]=4[CH:29]=[CH:28][N:27]=[CH:26]5)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(O)c1cccc2cnccc12
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc5cnccc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and isoquinoline-5-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[N:9]=[CH:10][C:5]2=[C:4]([N:17]2[CH2:23][CH:22]3[O:24][CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[N:3]=1.C(N(CC)CC)C.Cl[C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34]>ClCCl.C1(C)C=CC=CC=1>[CH:22]12[O:24][CH:19]([CH2:20][CH2:21]1)[CH2:18][N:17]([C:4]1[N:3]=[C:2]([Cl:1])[N:7]=[C:6]3[N:8]([CH:11]4[CH2:12][CH2:13][N:14]([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[CH2:15][CH2:16]4)[N:9]=[CH:10][C:5]=13)[CH2:23]2
Reactant: CC(C)OC(=O)Cl
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cnn(C3CCNCC3)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(Cl)nc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
650 mg (1.7 mmol) of 3-(6-chloro-1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane was suspended in 15 mL dichloromethane and triethylamine (0.5 mL) was added followed by addition of a 1N solution of isopropyl chloroformate in toluene. The mixture was stirred at room temperature overnight, diluted with dichloromethane and washed with sat. aqueous NaHCO3. The organic phase was dried over MgSO4, filtered and concentrated to give 696 mg (1.6 mmol) of the title compound. MS: 435.3/437.3 [M+H].