Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1.Br[CH2:27][CH2:28][CH2:29][C:30]([CH2:44][CH3:45])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:31][C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>>[CH2:44]([C:30]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([CH2:29][CH2:28][CH2:27][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1)[CH2:31][C:32]([O:34][CH:35]([CH3:36])[CH3:37])=[O:33])[CH3:45]
Reactant: CCC(CCCBr)(CC(=O)OC(C)C)c1ccccc1
Reactant: O=C(NC1CCNCC1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Product: CCC(CCCN1CCC(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)CC1)(CC(=O)OC(C)C)c1ccccc1

Procedure:
Prepared from 4′-trifluoromethyl-biphenyl-2-carboxylic acid-piperidin-4-ylamide and isopropyl 5-bromo-2-ethyl-2-phenyl-pentanecarboxylate.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:25])=[C:9]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:25])=[C:9]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2cccc3c2c(C)c(-c2ccccc2)n3Cc2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cccc(-c3ccc(O)cc3)c12

Procedure:
The desired product was prepared using a procedure similar to step 4 of example 3. Thus, 1-benzyl-4-(4-methoxy-phenyl)-3-methyl-2-phenyl-1H-indole (1.029 g, 2.550 mmol) was reacted with BBr3 (3.1 ml of a 1M solution in CH2Cl2) to give the product (0.657 g, 1.687 mmol, 66%) as a white solid, mp 174-176° C. 1H NMR (DMSO-d6) δ 1.73 (s, 3H), 5.28 (s, 2H), 6.79-6.82 (m, 3H), 6.88 (d, J=7.2 Hz, 2H), 7.07-7.10 (m, 1H), 7.15-7.19 (m, 1H), 7.20-7.23 (m, 4H), 7.28 (dd, J=0.8, 8.3 Hz, 1H), 7.32-7.34 (m, 2H), 7.39-7.47 (m, 3H), 9.41 (s, 1H); IR (solid) 3450, 3050, 1600, 1520, 1420, 1310, 1200 and 1180 cm−1; [ESI(+)], m/z 390 (M+H)+; Anal. Calcd. for C28H23NO: C, 86.34; H, 5.95; N, 3.60; Found: C, 86.13; H, 5.98; N, 3.56.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][CH2:8][CH:9]2[CH2:11][CH2:10]2)=[CH:5][N:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[O:18]=[C:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH2:24][C:25](O)=[O:26].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:6]([N:7]([CH2:8][CH:9]2[CH2:11][CH2:10]2)[C:25](=[O:26])[CH2:24][N:20]2[CH2:21][CH2:22][CH2:23][C:19]2=[O:18])=[CH:5][N:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: Clc1nn(-c2cccnc2)cc1NCC1CC1
Reactant: O=C(O)CN1CCCC1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C1CCCN1CC(=O)N(CC1CC1)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 7 mL vial was added 3-chloro-N-(cyclopropylmethyl)-1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.124 g, 0.500 mmol) (prepared according to the U.S. Publication No. 2012/0110702), DMAP (0.183 g, 1.50 mmol), 2-(2-oxopyrrolidin-1-yl)acetic acid (0.143 g, 1.00 mmol), EDCI (0.240 g, 1.25 mmol) followed by CH2Cl2 (1 mL). The reaction mixture was stirred at a temperature of about 25° C. for 18 hours before it was purified by silica gel chromatography (0%-15% MeOH/CH2Cl2) to afford the title compound F98 as a light yellow oil (0.131 g, 70%).
Reaction SMILES: [CH:1]1([O:6][N:7]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.NN.[N+:20]([C:23]1[CH:24]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH:1]1([O:6][NH:7][S:29]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=2)(=[O:30])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCCC1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: NN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccc(S(=O)(=O)NOC2CCCC2)c1
Reaction time: 2.5 h
Yield: 86.7 %

Procedure:
A mixture of 2-(cyclopentyloxy)-1H-isoindole-1,3(2H)-dione (3.00 g, 12.99 mmol) in anhydrous tetrahydrofuran (25 mL) under an Argon atmosphere was treated with anhydrous hydrazine (0.448 mL, 14.29 mmol). After stirring vigorously for 2.5 hours, the resulting slurry was filtered and washed with approximately 15 mL of anhydrous tetrahydrofuran. The filtrate was combined with 3-nitro-1-benzenesulphonyl chloride (3.17 g, 14.29 mmol) and N,N-diisopropylethylamine (2.72 mL, 15.6 mmol). After stirring at ambient temperature for approximately 18 hours, the reaction mixture was evaporated in vacuo to a residue and partitioned between ethyl acetate and 1N hydrochloric acid. The phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with 5% w/v potassium carbonate and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue. The crude material was purified on flash grade silica gel eluting with 15:85 ethyl acetate:hexane. Fractions containing the product were combined, evaporated in vacuo, and dried under high vacuum to provide N1-(cyclopentyloxy)-3-nitro-1-benzenesulfonamide (3.224 g, 87%) as a solid. H1-NMR (chloroform-D3): 1.71 (m, 8H), 4.71 (m, 1H), 6.93 (bs, 1H), 7.83 (m, 1H), 8.28 (m, 1H), 8.55 (m, 1H), 8.81 (m, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16]C=2)[CH:6]=[CH:7][CH:8]=1.Cl.N1C=CC=C[CH:22]=1>Cl.O>[OH:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:22])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCCCCc2ccccc2)c1
Reactant: c1ccncc1
Agent: Cl
Solvent: O
Product: CC(CCCc1ccccc1)c1cccc(O)c1
Temperature: 190 °C

Procedure:
A mixture of 2-(3-methoxyphenyl-5-phenylpentane (20 g.) and pyridine hydrochloride (94 g.) under nitrogen is heated to 190° C. for 2 hours with vigorous stirring. The reaction mixture is cooled, dissolved in 6 N hydrochloric acid (200 ml.) and diluted with water to 600 ml. The aqueous solution is extracted with ethyl acetate (4×100 ml.), the ethyl acetate extracts dried over sodium sulfate and concentrated under vacuum to yield the crude product which is purified by silica gel chromatography to yield 2-(3-hydroxyphenyl)-5-phenylpentane as an oil.
Reaction SMILES: [OH-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([S:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=2)[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:4]=1.Cl>CO>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([S:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:4]=1
Reactant: COC(=O)c1ccc(SC(Cn2ccnc2)c2cccnc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(SC(Cn2ccnc2)c2cccnc2)cc1
Temperature: 40 °C
Reaction time: 5 h
Yield: 55.3 %

Procedure:
3.39 ml of a 1N aqueous solution of sodium hydroxide were added to 575 mg of methyl-4-[1-(3-pyridyl)-2-(imidazol-1-yl)ethylthio]benzoate (prepared as described in Example 45) in 7 ml of methanol, and the resulting mixture was stirred at 40° C. for 5 hours. At the end of this time, the resulting mixture was neutralized with 3.39 ml of 1N aqueous hydrochloric acid, and the reaction mixture was treated and purified by the same method as described in Example 34, to give 305 mg of the title compound as a powder, melting at 80°-83° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[S:12][C:11]([NH2:14])=[N:10][C:9]=2[C:8]([O:15][CH3:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[C:1]([NH:4][C:5]1[C:13]2[S:12][C:11]([NH:14][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:18]([F:17])=[CH:19][CH:20]=3)=[N:10][C:9]=2[C:8]([O:15][CH3:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(NC(C)=O)c2sc(N)nc12
Reactant: O=C(Cl)c1ccc(F)cc1
Product: COc1ccc(NC(C)=O)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
Using 7-acetylamino-4-methoxy-benzothiazol-2-ylamine and 4-fluoro-benzoyl chloride the title compound was obtained as a tan solid (25% yield), MS: m/e=359.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][CH3:12])=[C:4]([NH2:10])[C:5]([CH2:8][CH3:9])=[CH:6][CH:7]=1.[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[Cl:1][C:2]1[C:3]([CH2:11][CH3:12])=[C:4]([NH2:10])[C:5]([CH2:8][CH3:9])=[C:6]([N+:13]([O-:15])=[O:14])[CH:7]=1
Reactant: CCc1ccc(Cl)c(CC)c1N
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCc1c(Cl)cc([N+](=O)[O-])c(CC)c1N
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 84.3 %

Procedure:
1.83 ml (10.9 mmol) 3-Chloro-2,6-diethyl-phenylamine (1) is dissolved on an ice-bath at 0° C. in 8 ml conc. H2SO4. 562 μl (12.0 mmol; 1.1 eq.) 90% ige HNO3 is added and the reaction mixture is stirred for 2.5 hours at 0° C. The reaction mixture is pored on ca. 200 ml ice and the obtained solution is extracted 8 times with 50 to 100 ml EE each. The combined organic layers are dried over magnesium sulphate and the solvent is removed under reduced pressure yielding 2.1 g of crude product. After purification by flash chromatography 1.24 g (5.42 mmol; 50%) of 2 could be obtained.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=[O:7])(C)(C)C.[F:44][C:45]1[CH:53]=[CH:52][C:48](C(Cl)=O)=[CH:47][CH:46]=1>>[F:44][C:45]1[CH:53]=[CH:52][C:48]([C:6]([NH:8][C@@H:9]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@@H:11]([CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]3)[CH2:10]2)=[O:7])=[CH:47][CH:46]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)c3ccc(F)cc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 34 in Step A and 4-fluorobenzoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [CH3:1][C@@:2]([S:30]([CH3:33])(=[O:32])=[O:31])([CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:29]=[N:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH:17]=[N:16]1)[C:3]([NH:5][O:6]C1CCCCO1)=[O:4].Cl>CCO>[OH:6][NH:5][C:3](=[O:4])[C@:2]([CH3:1])([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:29]=[N:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH:17]=[N:16]1
Reactant: C[C@@](CCn1cc(-c2cnc3ccccc3n2)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CCO
Product: C[C@@](CCn1cc(-c2cnc3ccccc3n2)cn1)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
To a solution of (2R)-2-methyl-2-(methylsulfonyl)-4-[4-(quinoxalin-2-yl)-1H-pyrazol-1-yl]-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (0.685 g, 1.62 mmol, 1 eq) in EtOH (8 mL) was added 1M HCl (4 mL). The reaction mixture was allowed to stir at RT overnight. The reaction mixture was concentrated and azeotroped with MeOH to remove water to give (2R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-4-[4-(quinoxalin-2-yl)-1H-pyrazol-1-yl]butanamide (38 mg, 86% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 1.51 (s, 3H) 2.26-2.37 (m, 1H) 2.72-2.85 (m, 1H) 3.07 (s, 3H) 4.10-4.20 (m, 1H) 4.27-4.38 (m, 1H) 7.73 (s, 1H) 7.80 (s, 1H) 7.98 (d, J=8.39 Hz, 1H) 8.02 (d, J=0.78 Hz, 1H) 8.31 (s, 1H) 8.72 (s, 1H) 9.30 (s, 1H) 10.23 (s, 1H) 11.01 (br. s., 1H). LC-MS M+H+390.1.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][C:34]=1[CH3:35])[C:12]([NH:14][C:15]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[C:17]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:16]=1[O:30][CH3:31])=[O:13])C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[Pd]>[C:21]([C:19]1[CH:18]=[C:17]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:16]([O:30][CH3:31])=[C:15]([NH:14][C:12](=[O:13])[C:11]2[CH:32]=[CH:33][C:34]([CH3:35])=[C:9]([OH:8])[CH:10]=2)[CH:20]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: [H][H]
Reactant: COc1c(NC(=O)c2ccc(C)c(OCc3ccccc3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(NC(=O)c2ccc(C)c(O)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
7.10 g 3-benzyloxy-N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-methyl-benzamide are hydrogenated in a mixture of 70 ml of methanol and 40 ml of tetrahydrofuran in the presence of 800 mg palladium on activated charcoal (10% Pd) at ambient temperature and 50 psi partial hydrogen pressure. Then the catalyst is suction filtered and the filtrate is evaporated down using the rotary evaporator. A white solid remains, which is reacted further without any further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15]([CH2:25][CH3:26])[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:12]3=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]3[N:10]=2)=[CH:6][C:5]([C:32]#[N:33])=[CH:4][C:3]=1[N:34]1[CH2:39][CH2:38][C@@H:37]([NH:40][C:41](=[O:44])[O:42][CH3:43])[C@H:36]([OH:45])[CH2:35]1.[C:46]([O:50][P:51]([O:58][CH2:59][CH2:60][CH2:61][C:62](O)=[O:63])([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])([CH3:49])([CH3:48])[CH3:47].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:46]([O:50][P:51]([O:58][CH2:59][CH2:60][CH2:61][C:62]([O:45][C@H:36]1[C@H:37]([NH:40][C:41]([O:42][CH3:43])=[O:44])[CH2:38][CH2:39][N:34]([C:3]2[CH:4]=[C:5]([C:32]#[N:33])[CH:6]=[C:7]([NH:8][C:9]3[N:14]=[C:13]([N:15]([CH2:25][CH3:26])[CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[C:12]4=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]4[N:10]=3)[C:2]=2[Cl:1])[CH2:35]1)=[O:63])([O:53][C:54]([CH3:55])([CH3:56])[CH3:57])=[O:52])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)OP(=O)(OCCCC(=O)O)OC(C)(C)C
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](OC(=O)CCCOP(=O)(OC(C)(C)C)OC(C)(C)C)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
To a suspension of methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (100 mg, 0.158 mmol) and 4-((di-tert-butoxyphosphoryl)oxy)butanoic acid (141 mg, 0.475 mmol) in DCM (5 mL) at 0° C., was added DCC (98 mg, 0.475 mmol) followed by DMAP (1.936 mg, 0.016 mmol) and stirred at room temperature for overnight. After completion of the starting material (by LC-MS), reaction mixture was diluted with DCM (2 mL) and filtered through celite and filtrate was washed with water and brine. Combined organic extracts were dried over anhydrous Na2SO4, concentrated. The resultant residue was purified by flash chromatography on silica gel using an ISCO system (eluted with 7:3 Hexanes and EtOAc) to afford (3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4 (ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((meth oxycarbonyl)amino)piperidin-3-yl 4-((di-tert-butoxyphosphoryl)oxy)butanoate (72 mg) as pale yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:13]2[CH2:18][CH:19]([CH3:21])[CH3:20])C1C=CC=CC=1>[C].[Pd]>[OH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:13]2[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2n1CC(C)C
Agent: [Pd]
Product: CCOC(=O)c1cc2c(O)cccc2n1CC(C)C

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 10 using ethyl 4-benzyloxy-1-(2-methylpropyl)indole-2-carboxylate (6.0 g) and 10% palladium-carbon (0.6 g), the title compound was obtained as pale-brown crystals.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=O)[O:3][C:2]1=O.[Br:13][C:14]1[C:15]([CH3:21])=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].COC(OC)OC>C1COCC1>[Br:13][C:14]1[C:15]([CH3:21])=[C:16]([N:17]2[C:4](=[O:3])[C:5]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:1]=[CH:2]2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Cc1c(N)cccc1Br
Solvent: C1CCOC1
Solvent: COC(OC)OC
Product: Cc1c(Br)cccc1-n1cnc2ccccc2c1=O
Temperature: 100 °C
Yield: 36.2 %

Procedure:
A mixture of 1H-benzo[d][1,3]oxazine-2,4-dione (200 mg, 1.226 mmol), 3-bromo-2-methylaniline (228 mg, 1.226 mmol), and trimethoxymethane (390 mg, 3.68 mmol) in THF (2 mL) was heated overnight in a sealed tube at 100° C. The mixture was cooled to rt and concentrated, and the residue was purified by column chromatography (eluting with 90:10 to 50:50 hexane-EtOAc) to give 3-(3-bromo-2-methylphenyl)quinazolin-4(3H)-one (140 mg, 36%). 1H NMR (400 MHz, chloroform-d) δ 8.37 (1 H, dd, J=8.3, 1.2 Hz), 7.97 (1 H, s), 7.76-7.86 (2 H, m), 7.72 (1 H, t, J=4.6 Hz), 7.57 (1 H, ddd, J=8.0, 6.7, 1.5 Hz), 7.21-7.28 (2 H, m), 2.26 (3 H, s). Mass spectrum m/z 315, 317 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.Br[C:13]1[N:14]=[CH:15][S:16][CH:17]=1>>[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][O:10][C:13]2[N:14]=[CH:15][S:16][CH:17]=2)[CH2:6][O:5]1
Reactant: Brc1cscn1
Reactant: CC1(C)OCC(CO)O1
Agent: [H-]
Agent: [Na+]
Product: CC1(C)OCC(COc2cscn2)O1

Procedure:
NaH (60% dispersion in mineral oil, 12.19 g, 305.3 mmol) was added portionwise to DL-1,2-isopropylideneglycerol (16.11 g, 1218 mmol) and the mixture was stirred until gas evolution had ceased (ca. 30 min RT, followed by 2 h at 60° C.). Subsequently, 4-bromothiazole (20.00 g, 121.9 mmol) was added and the mixture was stirred at 140° C. for 45 min. Subsequently, the reaction mixture was quenched with aq. sat. NH4Cl and extracted with EtOAc. The comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo. The residue was subjected to distillation and the volatiles (HV, 60° C.) were removed. The residue was purified by means of CC (5-40% EtOAc/Hept) to provide a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[S:18][C:19]([S:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([C:29]([O:31]C)=[O:30])[C:24]=3[F:33])=[CH:20][N:21]=2)=[N:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.O>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[S:18][C:19]([S:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([C:29]([OH:31])=[O:30])[C:24]=3[F:33])=[CH:20][N:21]=2)=[N:14][CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1nccc(Sc2cnc(Nc3ccc(CNC(=O)OC(C)(C)C)cn3)s2)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)nc1
Reaction time: 2 h
Yield: 87 %

Procedure:
A solution of methyl 4-(2-(5-((tert-butoxycarbonylamino)methyl)pyridin-2-ylamino)thiazol-5-ylthio)-3-fluoropicolinate (1.28 g, 2.60 mmol) in tetrahydrofuran (40 mL) was treated with sodium hydroxide (5N, 3.12 mL, 15.6 mmol) at 23° C. The reaction was stirred for 2 hours, then acidified with conc. HCl to pH ˜2.0. Water was then added and the aqueous phase was extracted with ethyl acetate/THF. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to give the title material (1.08 g, 87%) as a solid which was used as such in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si:13]([CH3:18])([CH3:17])[CH2:14][CH2:15]O>ClCCl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:15][CH2:14][Si:13]([CH3:18])([CH3:17])[CH3:12])=[O:5]
Reactant: O=C(O)c1ccc(I)cc1F
Reactant: C[Si](C)(C)CCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)c1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 115.5 mg (0.4 mmol) of 2-fluoro-4-iodobenzoic acid (Compound B) in 10 mL of dichloromethane (under a blanket of argon) was added 91.5 mg (0.5 mmol) of 1-(3-dimethylaminopropyl-3-ethyl carbodiimide hydrochloride) and 53 mg (0.4 mmol) of 4-dimethylaminopyridine. To this reaction mixture was added 0.16 ml (132 mg, 1.1 mmol) of 2-trimethylsilylethanol and the resultant mixture was allowed to stir at ambient temperature for 23 hours. The reaction mixture was extracted between ethyl ether and water and the layers were separated. The aqueous phase was washed with ethyl ether (2×50 mL) and the organic phases were combined. The combined organic phase was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to a clear, colorless oil. Purification by flash chromatography (silica, 3% ethyl acetate in hexane) gave the title compound as a clear, colorless oil. PMR (CDCl3): δ 0.07 (9 H, s), 1.13 (2 H, dd, J=8.5, 10.3 Hz), 4.42 (2 H, q, J=8.5, 10.3 Hz), 7.50-7.70 (3 H, m).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5](C)[CH2:4][CH2:3]1.Cl[C:10]([O:12][CH:13]([Cl:15])[CH3:14])=[O:11]>>[Cl:15][CH:13]([O:12][C:10]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:11])[CH3:14]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CN1CCN(C)CC1
Product: CC(Cl)OC(=O)N1CCN(C)CC1

Procedure:
In a similar manner, N,N'-di-methylpiperazine is reacted with α-chloroethyl chloroformate (ACE-Cl) to give the intermediate N-α-chloroethoxycarbonyl N'-methyl piperazine, which is then dehydrohalogenated as in Example 21b to give N-(vinyloxycarbonyl)N'-methylpiperazine.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC[C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH2:15][C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Clc1cccc(CCBr)c1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CCc3cccc(Cl)c3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(2-bromoethyl)-3-chlorobenzene and isolated as light-yellow gum. MS(m/e): 421.3 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH2:24][CH2:25][CH3:26])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([O:21]C)[N:11]2[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:7]([NH2:23])[N:6]=1.Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:23][C:7]1[N:6]=[C:5]([O:4][CH2:3][C:2]([CH3:1])([CH3:27])[CH2:24][CH2:25][CH3:26])[N:13]=[C:12]2[C:8]=1[NH:9][C:10](=[O:21])[N:11]2[CH2:14][CH:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: CCCC(C)(C)COc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCCC(C)(C)COc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To a solution of 2-[(2,2-dimethylpentyl)oxy]-8-methoxy-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (116 mg) in dry MeOH (14.5 mL) was added 4N HCl in 1,4-dioxane (2.48 mL). The mixture was stirred at room temperature for 3 h. The reaction was neutralised to pH 7 with 2M sodium hydroxide solution and was concentrated in vacuo to give and off-white solid. The solid was triturated with water (30 mL) and was filtered under reduced pressure to give the title compound as an off-white solid (76 mg).