Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](S(C)=O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][N:46]([CH2:49][C@H:50]([OH:52])[CH3:51])[CH2:45][CH2:44]2)=[CH:39][CH:38]=1.COCCO>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:36][C:37]4[CH:38]=[CH:39][C:40]([N:43]5[CH2:44][CH2:45][N:46]([CH2:49][C@H:50]([OH:52])[CH3:51])[CH2:47][CH2:48]5)=[CH:41][CH:42]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Reactant: C[C@@H](O)CN1CCN(c2ccc(N)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Product: C[C@@H](O)CN1CCN(c2ccc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)NC(C)(C)C)c5)n4n3)cc2)CC1
Yield: 60 %

Procedure:
N-tert-Butyl-3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (125.1 mg, 0.0003187 mol), N,N-Diisopropylethylamine (0.1665 mL, 0.0009561 mol) and (R)-1-[4-(4-Amino-phenyl)-piperazin-1-yl]-propan-2-ol (150 mg, 0.00064 mol) were dissolved in 2-Methoxyethanol (2.24 mL, 0.0284 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 107.72 mg of N-tert-Butyl-3-(2-{4-[4-((R)-2-hydroxy-propyl)-piperazin-1-yl]-phenylamino}-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide as a lyophilized powder. (M+H)=564.2. 1H NMR (400 MHz, DMSO, d6) δ 9.38 (s, 1H), 9.01 (s, 1H), 8.56 (s, 1H), 8.35 (d, 1H, J=7.92 Hz), 7.85 (d, 1H, J=8.12 Hz), 7.73 (m, 1H), 7.66 (d, 2H, J=9.00 Hz), 7.60 (s, 1H), 7.18 (d, 1H, J=4.76 Hz), 7.02 (d, 2H, J=9.01 Hz), 6.97 (d, 1H, J=4.76 Hz), 4.13 (m, 1H), 3.61 (m, 5H), 3.18 (m, 3H), 3.04 (m, 3H), 1.14 (d, 3H, J=6.16 Hz), 1.12 (s, 9H).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[NH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][N:21]=1)[C:18]([N:22]1[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]1=[O:32])=[N:17][CH:16]=[CH:15]2>C(Cl)Cl>[O:31]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:32])[N:22]1[C:18]1[N:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH:20]=[N:21][C:12]([NH:11][CH:8]=[O:10])=[CH:13]2
Reactant: O=CO
Reactant: Nc1cc2ccnc(N3C(=O)c4ccccc4C3=O)c2cn1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=CNc1cc2ccnc(N3C(=O)c4ccccc4C3=O)c2cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
Acetic anhydride (2.01 mL, 20.6 mmol) was added to formic acid (0.75 mL, 20.6 mmol) at 0° C. The mixture was heated to 60° C. for 30 minutes. After that 2-(6-amino-2,7-naphthyridin-1-yl)isoindoline-1,3-dione 4-7 (300 mg, 1.03 mmol) dissolved in CH2Cl2 (10 mL) was added at 0° C. The mixture was stirred for 1 h at room temperature. The mixture was concentrated and the residue was triturated with CH2Cl2/hexane (1:1) to give 240 mg (73%) of 4-8 as a pale yellow solid: 1H NMR (300 MHz, CDCl3)1H NMR (rotamer ratio: s-cis/s-trans=4:1) δ 9.46 (0.2H, br d, J=10.3 Hz), 9.01 (0.8H, br s), 8.75 (0.2H, br d, J=10.3 Hz), 8.68 (1H, br d, J=5.4 Hz), 8.60 (1H, br s), 8.56 (1H, br s), 8.48 (0.8H, br s), 8.03 (2H, m), 7.86 (2H, m), 7.77 (0.8H, br d, J=5.4 Hz), 7.67 (0.2H, br d, J=5.4 Hz); ESI-MS m/z 319 [C17H10N4O3+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([CH:15]=1)[CH2:7][NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([CH:15]=1)[CH2:7][N:8]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=1
Reactant: CCOC(=O)CNCc1cc(F)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN(Cc1cc(F)ccc1[N+](=O)[O-])C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.15 g (3.95 mmol) of ethyl (5-fluoro-2-nitrobenzyl)aminoacetate was dissolved in 20 ml of dichloromethane. 0.61 ml (4.7 mmol) of 4-chlorobenzoyl chloride and 0.82 ml (5.9 mmol) of triethylamine were added to the obtained solution, and they were stirred at room temperature for 2 hours. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the crude product was obtained.
Reaction SMILES: S(=O)(=O)(O)O.C[Si]([C:10]#[C:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][N:21]=1)[C:15]([O:17][CH3:18])=[O:16])(C)C.C(=O)(O)[O-:23].[Na+]>O1CCCC1.C(OCC)C.C([O-])(=O)C.[Hg+]>[C:11]([C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][N:21]=1)[C:15]([O:17][CH3:18])=[O:16])(=[O:23])[CH3:10]
Reactant: COC(=O)c1ccnc(C#C[Si](C)(C)C)c1
Reactant: O=C([O-])O
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Hg+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(C(C)=O)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Concentrated sulfuric acid (60 mL, 1.1 mol) was added to a suspension of methyl 2-((trimethylsilyl)ethynyl)isonicotinate (127 g, 0.54 mol) in tetrahydrofuran (600 mL) and mercury acetate (51.5 g, 0.16 mol). The suspension was stirred for 3 hours at 50° C. and kept overnight. The reaction mixture was diluted with diethyl ether (1.5 L) and the sulfuric acid was neutralized with saturated sodium bicarbonate (150 g, 1.7 mol). A residue of mercury salts was separated by filtration. The ether solution was washed with water and dried over sodium sulfate. The solvent was removed to give methyl 2-acetylisonicotinate as an oil that was directly used in the next step.
Reaction SMILES: NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:43]=[C:42]3[C:38]([CH2:39][N:40]([C:45]4([C:50]([O:52][CH3:53])=[O:51])[CH2:49][CH2:48][CH2:47][CH2:46]4)[C:41]3=[O:44])=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)([O-])=O>>[NH2:26][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:43]=[C:42]3[C:38]([CH2:39][N:40]([C:45]4([C:50]([O:52][CH3:53])=[O:51])[CH2:49][CH2:48][CH2:47][CH2:46]4)[C:41]3=[O:44])=[CH:37][CH:36]=2)=[CH:33][CH:34]=1
Reactant: COC(=O)C1(N2Cc3ccc(-c4ccc([N+](=O)[O-])cc4)cc3C2=O)CCCC1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)C1(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)CCCC1
Yield: 77 %

Procedure:
The compound of example 527 was prepared analogous to the compound of example 6 by reduction of the compound of example 526.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]([NH:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:25][CH2:24]2)=[O:19])[CH:6]=[CH:7][C:8]=1[O:9]COCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]([NH:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([O:29][CH:30]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:27][CH2:28]2)=[O:19])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COCCOCOc1ccc(C=CC(=O)NCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(C=CC(=O)NCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)ccc1O
Yield: 66.3 %

Procedure:
To a solution of 292 mg (0.508 mmol) of the amide compound in methanol (8 ml) was added 112 mg (0.589 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was refluxed for 20 minites. Water was added to the reaction mixture, which was adjusted to a pH value of 11 by the addition of an aqueous solution of sodium carbonate and then extracted with ethyl acetate. The organic layer was washed with water and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (50:1), to give 164 mg (0.337 mmol) of 1-[2-[3-(3-methoxy-4-hydroxyphenyl)-2-propenoyl]aminoethyl]-4-benzhydroxypiperidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[C:21]([NH2:22])=[CH:20][C:19](=[O:23])[N:18]([CH2:24][CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C)C)[C:16]=3[N:17]=2)[CH2:7][CH2:6]1>C(O)(=O)C.C1COCC1.O>[CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[C:21]([NH2:22])=[CH:20][C:19](=[O:23])[N:18]([CH2:24][CH2:25][CH2:26][OH:27])[C:16]=3[N:17]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)NC1CCC(Nc2ncc3c(N)cc(=O)n(CCCO[Si](C)(C)C(C)(C)C)c3n2)CC1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)NC1CCC(Nc2ncc3c(N)cc(=O)n(CCCO)c3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.1 %

Procedure:
(4-{5-Amino-8-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino}-cyclohexyl)-carbamic acid methyl ester (prepared as described in Example 2) (0.280 mmol) was dissolved in a mixture of glacial acetic acid, THF and water (3/1/1, 25 mL) and the resulting mixture was stirred at RT overnight. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by preparative TLC (MeOH/DCM, 15/85) to give 11 mg of {4-[5-amino-8-(3-hydroxy-propyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-cyclohexyl}-carbamic acid methyl ester as a yellow powder. MS=391 [M+H]+; MP=190.0-191.0° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH3:21])[CH:15]=3)[CH:11]=[C:10]([CH3:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:23]([NH:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([NH:27][S:28]([C:31]1[CH:36]=[C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH3:21])[CH:15]=4)[CH:11]=[C:10]([CH3:22])[N:9]=3)[CH:3]=2)[CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
3′-[4-(4-Chloro-3-methyl-phenyl)-6-methyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-3-methyl-phenyl)-6-methyl-pyrimidine (example E.77) (0.37 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as white foam (0.45 g), which was subsequently deprotected.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[CH2:10][C:11]([CH3:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15]Br.C(=O)([O-])[O-].[Na+].[Na+]>CCOCC>[CH2:1]([O:8][C:9](=[O:14])[CH2:10][C:11]([CH2:13][Br:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: CC(=O)CC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CBr)CC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4.00 g (21.0 mmol) of acetoacetic acid benzyl ester was dissolved in 40 ml of ether. 1.1 ml (21.0 mmol) of bromine was dropped at 0° C. After stirring at 0° C. for 30 minutes and then at room temperature for 5 hours, about 4 g of ice and sodium carbonate were added so that pH showed 7 or more. The organic layer extracted with ether was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated and dried in vacuo to obtain 4-bromoacetoacetic acid benzyl ester. 1.68 g (24.0 mmol) of sodium hydride (60% oily substance) was suspended in 20 ml of THF and 11.7 g (21.0 mmol) of 2-chloroethanol was added at −40° C. 4-bromoacetoacetic acid benzyl ester was dropped at −40° C., gradually heated and stirred at room temperature for 16 hours. After adding 1 N hydrochloric acid and extracting with ethyl acetate, the obtained mixture was washed with water and saturated aqueous sodium chloride solution. The mixture was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=7/3) to obtain the title compound.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](O)=[O:36].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:35](=[O:36])[C:34]1[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=1[Cl:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(O)c1ccccc1Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1Cl)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Yield: 67.7 %

Procedure:
200 mg (0.467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4a with 88 mg (0.560 mmol) of 2-chlorobenzoic acid, 143 mg (0.561 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine. The title compound (179 mg, 68%) is obtained as whim foam. TLC: methylene chloride/methanol/conc. ammonia (2000:50:1) Rf =0.42, FD-MS: M+ =565, 567.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=1)[C@@H:3]([C@H:5]1[CH2:14][C:13]2[C:8](=[C:9]([O:16][CH3:17])[CH:10]=[CH:11][C:12]=2[Br:15])[CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[OH:4].C(N(CC)CC)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>O1CCCC1>[C:41]([NH:1][C@@H:2]([CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=1)[C@@H:3]([C@H:5]1[CH2:14][C:13]2[C:8](=[C:9]([O:16][CH3:17])[CH:10]=[CH:11][C:12]=2[Br:15])[CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[OH:4])(=[O:43])[CH3:42]
Reactant: COc1ccc(Br)c2c1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1)C2
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Br)c2c1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(C)=O)C2
Yield: 88 %

Procedure:
Slurry tert-butyl (3R)-3-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxy-propyl]-5-bromo-8-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (59.4 mg, 0.000113 mol) in tetrahydrofuran (1.00 mL). Add triethylamine (15.7 uL, 0.000113 mol) and acetic anhydride (10.6 uL, 0.000113 mol) and stir for 45 minutes. Dilute dichloro-methane (25 mL) and wash with water (1×10 mL), 0.1N HCl (1×10 mL), saturated aqueous sodium bicarbonate (1×10 mL), saturated aqueous sodium chloride (1×10 mL) and dry over magnesium sulfate. Concentrate the filtrate to give the desired product (57.9, 88%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([NH2:15])[CH3:14].Cl.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:15][CH2:13][CH3:14])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
t-butoxycarbonyl- glycine (3 g), ethylamine.HCl (1.39 g), TEA (1.72 g), Hobt (2.3 g) and dry DMF (100 ml) were combined and DCC (3.5 g) was added. The mixture was stirred for three days at room temperature under nitrogen, then filtered and evaporated to dryness. 6 g of material was recovered. This material was subjected to column chromatography eluting with a gradient of ethyl acetate to ethyl acetate/methanol (1:1) providing 4.01 g of (CH3)3COC(O)NHCH2C(O)NHCH2CH3.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[N:66]1([CH2:72][CH2:73][NH2:74])[CH2:71][CH2:70][CH2:69][CH2:68][CH2:67]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:74][CH2:73][CH2:72][N:66]5[CH2:71][CH2:70][CH2:69][CH2:68][CH2:67]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NCCN1CCCCC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(C(=O)NCCN2CCCCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 77.1 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.015 g (0.12 mmole) 2-Piperidin-1-yl-ethylamine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.043 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(2-piperidin-1-yl-ethyl)-benzamide (I-114) as a white solid.
Reaction SMILES: C([Li])CCC.[C:6]1([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN(C)[CH:21]=[O:22].OS(O)(=O)=O>CCOCC>[O:12]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[CH:21]=[O:22])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN(C)C=O
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1ccccc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 68.7 %

Procedure:
At room temperature, under an argon atmosphere, n-butyllithium (15.45 mL of a 2.5M solution in hexanes, 38.61 mmol) was added to a solution of diphenyl ether (5.0 g; 29.38 mmol) in 100 mL of ether, and the reaction mixture was gently refluxed for 4 hrs. After cooling to 0° C., N,N-dimethylformamide (22.73 mL; 0.293 mol) was added dropwise and the reaction was stirred for 15 min at 0° C. and 1.5 hr at room temperature. After adding 10% H2SO4 to pH 1, it was stirred for 15 min and extracted into ethyl acetate. Chromatography of the crude product (10% ethyl acetate/hexane) provided 4.0 g (69%) of the aldehyde, 1H NMR (CDCl3): δ 6.97 (d, 1H); 7.02-7.11 (m, 2H); 7.18-7.22 (m, 2H); 7.29 (t, 1H); 7.39 (t, 1H); 7.43 (t, 1H); 7.95 (t, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:10][CH2:9][CH:5]([C:6](O)=[O:7])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.Cl.[CH3:31][NH:32][O:33][CH3:34].Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:34][O:33][N:32]([CH3:31])[C:6](=[O:7])[CH:5]1[CH2:9][CH2:10][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CCN(C)CC1
Reaction time: 0.08 h
Yield: 132.8 %

Procedure:
1-Methylisonipecotic acid (5.5 g, 38.4 mmol) was dissolved in dimethylformamide (100 ml) with heating. Diisopropylethylamine (8.0 ml, 46.1 mmol), 1-hydroxybenzotriazole (5.2 g, 38.4 mmol), and N,O-dimethylhydroxylamine hydrochloride (4.1 g, 42.2 mmol) were added and the reaction mixture was stirred 5 min. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.4 g, 38.4 mmol) was added and the resulting homogeneous solution was stirred for 63 hours at ambient temperature. The solvent was removed under reduced pressure. The residue was dissolved in water and the solution was basified to pH 9 with 5N sodium hydroxide solution. This aqueous solution was extracted with methylene chloride then saturated with sodium chloride and extracted with chloroform/isopropanol (3/1). The combined organic extracts were dried over sodium sulfate and the solvent was removed under reduced pressure to give 9.5 g of a yellow liquid. Purification by flash chromatography (silica gel, methylene chloride:methanol:ammonium hydroxide, 100:10:1) gave 5.7 g (80%) of product as a light yellow liquid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH3:19][NH:20][CH3:21].C(N(CC)CC)C>C1COCC1>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([N:20]([CH3:21])[CH3:19])=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N(C)C)n2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above, (110 mg; 0.36 mmol; 1 eq.) is dissolved in anhydrous THF (10 ml). Under nitrogen, dimethylamine (0.27 ml; 0.55 mmol; 1.5 eq) and triethylamine (0.08 ml; 0.55 mmol; 1.5 eq) are added. The reaction mixture is stirred at RT for 1 hour. The solvents are evaporated and the crude product is directly purified by preparative HPLC, affording Compound (61) as a white-off solid (65.0 mg; 57%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[C:13]3[S:15][C:16]([NH:18][C:19](=[O:22])[CH2:20]Cl)=[N:17][C:12]3=[CH:11][CH:10]=2)=[CH:6][C:5]([NH:23][C:24](=[O:36])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([C:34]#[N:35])([CH3:33])[CH3:32])[CH:26]=2)=[C:4]([F:37])[CH:3]=1.C(N(CC)CC)C.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[C:13]3[S:15][C:16]([NH:18][C:19](=[O:22])[CH2:20][N:49]4[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]4)=[N:17][C:12]3=[CH:11][CH:10]=2)=[CH:6][C:5]([NH:23][C:24](=[O:36])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([C:34]#[N:35])([CH3:32])[CH3:33])[CH:26]=2)=[C:4]([F:37])[CH:3]=1
Reactant: CN1CCNCC1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)CCl)sc4n3)c(Cl)cc2F)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCN(CC(=O)Nc2nc3ccc(Oc4cc(NC(=O)c5cccc(C(C)(C)C#N)c5)c(F)cc4Cl)nc3s2)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
N-[4-Chloro-5-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-2-fluorophenyl]-3-(1-cyano-1-methylethyl)benzamide synthesized above was dissolved in tetrahydrofuran (3.0 mL), triethylamine (171 μL, 1.25 mmol) and 1-methylpiperazine (138 μL, 1.25 mmol) were added, and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (30 mL) and saturated brine (30 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→85/15), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give the title compound (193 mg, 75%) as a colorless powder.