Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[NH2:24][CH:25]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[CH2:26][OH:27]>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:24][CH:25]([CH2:26][OH:27])[CH2:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[O:17])(=[O:11])=[O:12])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: NC(CO)Cc1ccc(Cl)cc1
Reactant: Cc1ccc(C(=O)O)c(NS(=O)(=O)c2cccc3nsnc23)c1
Product: Cc1ccc(C(=O)NC(CO)Cc2ccc(Cl)cc2)c(NS(=O)(=O)c2cccc3nsnc23)c1

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-methyl-benzoic acid was coupled with (±)-2-amino-3-(4-chloro-phenyl)-propan-1-ol as in EXAMPLE 1, Part C. HPLC: RT=9.31 min. MS (ESI−): mass calcd. for C23H21ClN4O4S2, 516.07; m/z found, 515 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.52 (s, 1H), 8.33 (dd, J=7.0, 1.0, 1H), 8.19 (dd, J=8.8, 1.0, 1H), 7.68 (dd, J=8.8, 7.0, 1H), 7.48 (s, 1H), 7.32-7.27 (m, 2H), 7.21-7.17 (m, 2H), 7.09 (d, J=8.0, 1H), 6.75 (d, J=8.0, 1H), 6.28 (br d, J=7.4, 1H), 4.32-4.23 (m, 1H), 3.72 (dd, J=10.8, 3.6, 1H), 3.65 (dd, J=10.8, 4.5, 1H), 2.91 (d, J=7.4, 2H), 2.75 (br s, 1H), 2.27 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].C(N(CC)CC)C.[C:19](Cl)(=[O:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C1C=CC=CC=1>[C:19]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: O=[N+]([O-])c1ccccc1CO
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCCC(=O)OCc1ccccc1[N+](=O)[O-]

Procedure:
In 100 ml benzene were mixed 2-nitrobenzyl alcohol (7.65 g, 0.05 mol) and triethylamine (5.06 g, 0.05 mol). To the solution octadecanoyl chloride (15.14 g, 0.05 mol) was added dropwise with stirring. The mixture was stirred an additional one hour and the precipitated triethyl amine hydrochloride was removed by filtration. The filtrate was evaporated to dryness and the residue crystallized from ethanol (yield 13.0 g, m.p. 60°-61° C.). The tetradecanoate (m.p. 46° C.) (Compound 5), hexadecanoate (m.p. 54° C.) (Compound 6), heptadecanoate (m.p. 48° C.) (Compound 7), and 9-octadecenoate (Compound 8) esters of 2-nitrobenzyl alcohol were similarly prepared using corresponding acyl chlorides in place of octadecanoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:24])=[C:6]([CH:23]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[N:13]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1.C(N(CC)CC)C>O1CCCC1>[Cl:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:31]([C:30]2[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=2)=[O:32])=[CH:23][C:6]=1[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:21][CH2:22]3)=[O:19])[N:16]=2)[N:13]=1
Reactant: Nc1ccc(Cl)c(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2ccc(Cl)c(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)n(C)n1
Yield: 91.6 %

Procedure:
Using N-[6-(5-amino-2-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (131 mg, 0.382 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (91 mg, 0.573 mmol), triethylamine (116 mg, 1.15 mmol) and tetrahydrofuran (5.0 mL) as starting materials and in the same manner as in Example 96, the title compound (163 mg, 92%) was obtained as a white powder.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH:11]([O:14][C:15]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:16]=1[C:17](O)=[O:18])([CH3:13])[CH3:12]>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:17]([C:16]1[CH:20]=[C:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:22]=[CH:23][C:15]=1[O:14][CH:11]([CH3:13])[CH3:12])=[O:18]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2ccccc2C1

Procedure:
Prepared in analogy to example 1.1 from 1,2,3,4-tetrahydro-isoquinoline (CA [473443-13-9]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: C([NH:4][C@@:5]1([C:22](NC(C)(C)C)=[O:23])[CH2:9][CH2:8][CH2:7][C@H:6]1[CH2:10][CH2:11][CH2:12][B:13]1[O:17]C(C)(C)C(C)(C)[O:14]1)(=O)C.[OH2:29]>Cl>[NH2:4][C@@:5]1([C:22]([OH:23])=[O:29])[CH2:9][CH2:8][CH2:7][C@H:6]1[CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17]
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CCC[C@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: O
Agent: Cl
Product: N[C@@]1(C(=O)O)CCC[C@H]1CCCB(O)O
Temperature: 90 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A stirred mixture of (1S,2R)-1-acetamido-N-tert-butyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)cyclopentanecarboxamide (0.627 g, 1.59 mmol) in 6 N HCl (15 mL) was heated to 90° C. for 20 h, cooled to room temperature, and diluted with water (15 mL). The mixture was extracted with dichloromethane (2×15 mL) and concentrated. Water (20 mL) was then added to the concentrated crude mixture and the aqueous solution is re-concentrated in vacuo (2×) to remove excess HCl. The resulting residue was dissolved in methanol (5 mL) and diluted to a volume of 40 mL with ether and stirred for 1 hour, to remove solid tertbutylamine hydrochloride by filtration. The resultant filtrate, upon concentration was treated with a solution of concentrated ammonium hydroxide (15 mL), followed by removal of the excess ammonium hydroxide under vacuum (3×). The resulting solid white residue was triturated using acetonitrile and dried to afford the target compound (1S,2R)-1-amino-2-(3-boronopropyl) cyclopentanecarboxylic acid (0.397 g, 93%) as a white powder that exists as a 1:1 mixture of the cyclized and uncyclized forms. 1H NMR (DMSO, 300 MHz) δ 6.38 (br d, J=11.4 Hz, NH, 0.5 H), 5.97 (br d, J=12 Hz, NH, 0.5 H), 2.22-2.05 (m, 1 H), 1.98-1.42 (m, 6 H), 1.43-1.00 (m, 3 H), 0.95-0.88 (m, 1 H), 0.60-0.42 (m, 1 H), 0.38-0.20 (m, 1 H); MS (+CI): m/z for C9H18BNO4: expected 215.1: found 215.3 (M+H)30.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([C:32]1[CH:33]=[C:34]([NH:43][CH2:44][C:45]([OH:47])=O)[C:35]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[N:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.CCN(CC)CC>CN(C=O)C>[CH2:25]([C:32]1[CH:33]=[C:34]([NH:43][CH2:44][C:45]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[O:47])[C:35]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[N:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1ncc(Cc2ccccc2)cc1NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc(Cc2ccccc2)cc1NCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
HATU (494 mg, 1.3 mmol) was added via spatula to a solution of N-[5-benzyl-2-(ethoxycarbonyl)pyridin-3-yl]glycine (328 mg, 1.04 mmol), morpholine (0.113 mL, 1.3 mmol) and Et3N (0.18 mL, 1.3 mmol) in DMF (6 mL). After stirring for 45 min at rt, the solvent was removed in vacuo and the resulting material was dissolved in CH2Cl2 and washed with water. The organic layer was dried and concentrated. Purification of the crude material by silica gel chromatography eluting with 0-5% MeOH/CH2Cl2 afforded the product: 1H NMR (CDCl3) δ 8.57 (1H, br), 7.94 (1H, s), 7.23 (3H, m), 7.15 (2H, m), 6.68 (1H, s), 4.46 (2H, q, J=7 Hz), 3.95 (2H, s), 3.90 (2H, d, J=4.2 Hz), 3.68 (6H, br), 3.43 (2H, br), 1.42 (3H, t, J=7 Hz); ES+ MS: 384 (M+H+, 70).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[CH:8]1([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[CH:28]=[N:27][CH:26]=[CH:25][C:21]=3[C:22](O)=[O:23])=[O:18])[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1>>[O:7]=[C:2]1[NH:1][CH2:6][CH2:5][N:4]([C:22]([C:21]2[CH:25]=[CH:26][N:27]=[CH:28][C:20]=2[NH:19][C:17]([C:15]2[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=[C:11]([CH:8]3[CH2:10][CH2:9]3)[N:16]=2)=[O:18])=[O:23])[CH2:3]1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: O=C1CNCCN1
Product: O=C1CN(C(=O)c2ccncc2NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)CCN1
Yield: 14 %

Procedure:
According to the general method described in step 3 of example 53, reaction of piperazine-2-one with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (14%) as amorphous light yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].Br.[Br:14][CH2:15][CH2:16][CH2:17][NH2:18].C(N(CC)CC)C>ClCCl>[Br:14][CH2:15][CH2:16][CH2:17][NH:18][S:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCBr
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(S(=O)(=O)NCCCBr)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Cyanobenzenesulfonyl chloride (5 g, 0.0248 mol) was added dropwise to a solution of 3-bromopropylamine hydrobromide (6.61 g, 0.0302 mol) and triethylamine (6.26 g, 0.062 mol) in dry dichloromethane (50 ml) at 0° C. and stirred at room temperature overnight under nitrogen atmosphere. The reaction was quenched with water and extracted with dichloromethane. The organic layer was washed with water, brine and dried over sodium sulfate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH2:30])[CH2:24][CH2:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:30][CH2:29][CH2:28][N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CN1CCN(CCN)CC1
Product: CN1CCN(CCNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 2-(4-methylpiperazin-1-yl)ethanamine (16 mg, 0.12 mmol). The title compound was obtained as a solid (13.6 mg, 29% yield). MS m/z: 476.04, 478.04 [M+H]+.
Reaction SMILES: CC1ON=CC=1C([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=1)=O.[CH3:20][C:21]1[O:25][N:24]=[CH:23][C:22]=1[C:26]([OH:28])=[O:27]>>[F:17][C:16]([F:18])([F:19])[C:13]1[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][CH:12]=1.[CH3:20][C:21]1[O:25][N:24]=[CH:23][C:22]=1[C:26]([OH:28])=[O:27]
Reactant: Cc1oncc1C(=O)Nc1ccc(C(F)(F)F)cc1
Agent: Cc1oncc1C(=O)O
Product: Nc1ccc(C(F)(F)F)cc1

Procedure:
A process for synthesizing leflunomide from 5-methylisoxazole-4-carboxylic acid and 4-trifluoromethylaniline is provided in which the carboxylic acid group of 5-methylisoxazole-4-carboxylic acid is chlorinated, forming 5-methylisoxazole-4-carboxylic acid chloride. The acid chloride is then reacted without intermediate distillation with 4-trifluoromethylaniline in the presence of an alkali metal or alkaline-earth metal bicarbonate acid scavenger.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:22][CH:23]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:2]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]2)=[N:22][CH:23]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(CO)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(C=O)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Compound 21a (500 mg, 1.01 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (2 mL) was added. Dess-Martin periodinane (471 mg, 1.11 mmol) was added as a solid and the reaction was stirred at rt for 20 min. The reaction was diluted with DCM (20 mL) and washed with saturated NaHCO3 solution (2×20 mL). The organic phase was dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude product was chromatographed on a 40 g SiO2 pre-packed column eluting with 0-60% ACN/DCM to afford compound 21b. 1H-NMR (400 MHz, CDCl3) δ (ppm): 10.12 (s, 1H), 8.58 (d, J=2.2 Hz, 1H), 8.06 (d, J=5.6 Hz, 1H), 7.94 (dd, J=9.0, 2.4 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 6.11 (d, J=5.9 Hz, 1H), 4.03-4.11 (m, 4H), 3.91-3.97 (m, 4H), 3.63-3.71 (m, 4H), 3.52-3.60 (m, 4H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H31N7O4: 494.3 (M+H). Found: 494.3.
Reaction SMILES: [CH2:1]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:18]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:30]=1[OH:31])[C:25]([OH:27])=O)([CH3:21])([CH3:20])[CH3:19]>>[CH2:10]([N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:25](=[O:27])[C:24]1[CH:28]=[C:29]([C:32]([CH3:34])([CH3:35])[CH3:33])[C:30]([OH:31])=[C:22]([C:18]([CH3:20])([CH3:19])[CH3:21])[CH:23]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCNCCCCCCCC
Product: CCCCCCCCN(CCCCCCCC)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
In the manner of Example 7, di-n-octylamine was reacted with 3,5-di-t-butyl-4-hydroxybenzoic acid to produce N,N-di-n-octyl-3,5-di-t-butyl-4-hydroxybenzamide; an oil product. When tested by the procedure of Example 2, this compound lasted over 1400 hours, over 4.7 times as long as the control.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8][C:9]1[C:10](=[O:22])[CH2:11][CH:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH:13]=1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].N1C=CN=C1>CN(C)C=O>[Si:23]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8][C:9]1[C:10](=[O:22])[CH2:11][CH:12]([O:14][Si:15]([C:18]([CH3:19])([CH3:21])[CH3:20])([CH3:16])[CH3:17])[CH:13]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)[Si](C)(C)OC1C=C(SCCCCCCO)C(=O)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCSC1=CC(O[Si](C)(C)C(C)(C)C)CC1=O
Yield: 74.4 %

Procedure:
440 mg (1.28 mmoles) of 2-(6-hydroxyhexylthio)-4-t-butyldimethylsilyloxy-2-cyclopentenone and 225 mg (1.50 mmoles) of t-butyldimethylsilyl chloride were treated at room temperature for 2 hours in 3 ml of N,N-dimethyl formamide in the presence of 204 mg (3.0 mmoles) of imidazole. After the reaction, the reaction mixture was extracted with hexane to give 640 mg of a crude product. The crude product was purified by thin-layer chromatography (cyclohexane/ethyl acetate=4/6) to give 437 mg (75%) of 2-(6-t-butyldimethylsilyloxyhexylthio)-4-t-butyldimethylsilyloxy-2-cyclopentenone.
Reaction SMILES: [CH2:1]([C:4]1([CH2:10][CH2:11][OH:12])[O:9][CH2:8][CH2:7][CH2:6][O:5]1)CC.C(OCC)(=O)CC(C)=O>>[CH3:1][C:4]1([CH2:10][CH2:11][OH:12])[O:9][CH2:8][CH2:7][CH2:6][O:5]1
Reactant: CCCC1(CCO)OCCCO1
Solvent: CCOC(=O)CC(C)=O
Product: CC1(CCO)OCCCO1
Yield: 49 %

Procedure:
The same procedure as in the steps (8a) and (8b) of Example 8, was repeated using ethyl acetoacetate to obtain the title compound (5.4 g, total yield: 49%) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH2:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:20])=[CH:13][CH:14]=2)[N:9]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[NH:24][CH:25]=[N:26]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH:19][C:22]2[N:30]=[CH:29][N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][NH:26]3)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:20])=[CH:13][CH:14]=2)[N:9]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCc1cc2ccc(F)cc2nc1-c1ccccc1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc2cc(CNc3ncnc4[nH]cnc34)c(-c3ccccc3Cl)nc2c1

Procedure:
Prepared according to Procedure H using (2-(2-chlorophenyl)-7-fluoroquinolin-3-yl)methanamine (0.080 g, 0.279 mmol), 6-chloropurine (0.065 g, 0.42 mmol, 1.5 eq) and DIEA (0.56 mmol, 2.0 eq) in n-butanol (3 mL). N-((2-(2-chlorophenyl)-7-fluoroquinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=225 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.49 (s, 1H), 8.14 (s, 1H), 8.03-8.10 (m, 2H), 7.66-7.73 (m, 2H), 7.47-7.56 (m, 2H), 7.43-7.44 (m, 1H), 7.33-7.40 (m, 1H), 4.10-4.18 (m, 2H), Mass Spectrum (ESI) m/e=405 (M+1).
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C:4]3=O)[CH2:2]1)[CH2:8]2.[NH2:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1.N>>[Br:19][C:17]1[CH:18]=[C:13]([NH:12][C@@H:4]2[CH:5]3[CH2:10][N:1]4[CH2:8][CH:7]([CH2:9][CH:3]2[CH2:2]4)[CH2:6]3)[CH:14]=[N:15][CH:16]=1
Reactant: Nc1cncc(Br)c1
Reactant: O=C1C2CC3CC1CN(C3)C2
Agent: N
Product: Brc1cncc(NC2C3CC4CC2CN(C4)C3)c1

Procedure:
Prepared from 1-azatricyclo[3.3.1.13,7]decan-4-one (1.51 g, 10 mmol; see Becker, D. P.; Flynn, D. L. Synthesis 1992, 1080) and 3-amino-5-bromopyridine (2.06 g, 12 mmol; Aldrich) according to the procedure described in Example 65A: 1H NMR (300 MHz, methanol-D4) δ ppm 1.81-1.99 (m, 2H), 2.02-2.15 (m, 1H), 2.17-2.40 (m, 4H), 3.44-3.51 (m, 2H), 3.53-3.66 (m, 4H), 3.91 (s, 1H), 7.26-7.41 (m, 1H), 7.84 (d, J=1.7 Hz, 1H), 8.01 (d, J=2.7 Hz, 1H). MS (DCI/NH3) m/z=308/310 (M+H)+.
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:14](=[O:17])[CH2:15][CH3:16])=[CH:7]2.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl.C1(C)C=C(C)C=C(C)C=1>[CH3:13][O:12][C:11]1[CH:2]=[C:3]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([C:14](=[O:17])[CH2:15][CH3:16])[CH:5]=[CH:4]2
Reactant: CCC(=O)c1ccc2c(Br)c(OC)ccc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1cc(C)cc(C)c1
Solvent: ClCCl
Product: CCC(=O)c1ccc2cc(OC)ccc2c1
Temperature: -5 °C

Procedure:
29.3 Grams of 5-bromo-6-methoxy-2-propionylnaphthalene are dissolved in 100 ml of anhydrous methylene chloride and in 20.8 ml of mesitylene. 20 Grams of anhydrous aluminum chloride are added portionwise to the reaction mixture cooled to -5° C. under strong stirring, while keeping the temperature below 20° C. The reaction mixture is kept for over 3 hours under stirring at room temperature, then it is slowly poured under strong stirring into a mixture made of 110 g of ice and of 35 ml of a 35% (w/v) aqueous solution of hydrochloric acid. The layers are separated after 15 minutes of stirring and the aqueous layer is discarded. The organic layer first is twice washed with 50 ml of a 6N aqueous solution of hydrochloric acid and then with 50 ml of water. The organic solution is then added with 50 ml of water and the pH is brought to 12 by means of a 30% (w/v) aqueous solution of sodium hydroxide.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]([NH:15][C:16]3[CH:21]=[N:20][CH:19]=[CH:18][N:17]=3)=[O:14])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C@H:22]12[CH2:28][C@H:25]([NH:26][CH2:27]1)[CH2:24][N:23]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[N:17]1[CH:18]=[CH:19][N:20]=[CH:21][C:16]=1[NH:15][C:13](=[O:14])[NH:12][C:6]1[C:5]2[C:10](=[CH:11][C:2]([N:26]3[CH2:27][C@@H:22]4[CH2:28][C@H:25]3[CH2:24][N:23]4[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:3][CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: O=C(Nc1cnccn1)Nc1ccnc2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc2c(NC(=O)Nc3cnccn3)ccnc2c1

Procedure:
The compound was prepared by the method described for Example 1 using 1-(7-bromoquinolin-4-yl)-3-(pyrazin-2-yl)urea and (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]-heptane-2-carboxylate as starting compounds.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].[C:5]1(=O)[CH:10]=[CH:9][C:8](=[O:11])[CH:7]=[CH:6]1>>[OH:11][C:8]1[CH:7]=[CH:6][C:5]2[S:4][CH2:3][CH2:2][NH:1][C:10]=2[CH:9]=1
Reactant: O=C1C=CC(=O)C=C1
Reactant: NCCS
Product: Oc1ccc2c(c1)NCCS2

Procedure:
The reaction of 2-amino-ethyl thiol with benzoquinone followed by air oxidation affords 6-hydroxy-dihydro-1,4-benzothiazine.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:18][C:19]3[C:24]([N:25]=2)=[CH:23][C:22]([C:26]([O:28]C)=[O:27])=[CH:21][CH:20]=3)=[CH:12][CH:11]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].CI>C1COCC1>[C:3]([O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:18][C:19]3[C:24]([N:25]=2)=[CH:23][C:22]([C:26]([OH:28])=[O:27])=[CH:21][CH:20]=3)=[CH:14][CH:15]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3ccc(C(=O)OC(C)(C)C)cc3)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)(C)OC(=O)c1ccc(-c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)cc1
Reaction time: 1 h
Yield: 119.2 %

Procedure:
Sodium hydride (60 mg, 2.50 mmol, 5.60 equiv) was added to a solution of methyl 3-(4-(t-butoxycarbonyl)phenyl)-2-phenylquinoxaline-6-carboxylate (200 mg, 0.42 mmol, 1.00 equiv, 95%) in THF (10 mL) at 0° C. under an inert atmosphere and stirred for 1 h. A solution of CH3I (125 mg, 0.88 mmol, 2.00 equiv) in THF (1 mL) was added dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was quenched by the addition of water. The pH value of the solution was adjusted to 3-4 with 1N HCl. The resulting mixture was concentrated under vacuum, yielding 213.5 mg (crude) of 3-(4-(t-butoxycarbonyl)phenyl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([C:38](=[O:40])[CH3:39])[CH:34]=[C:35]([OH:37])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:37][C:35]2[CH:36]=[C:31]([Br:30])[CH:32]=[C:33]([C:38](=[O:40])[CH3:39])[CH:34]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: CC(=O)c1cc(O)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(C)=O)c2)c1CCC(=O)OCC
Yield: 79.3 %

Procedure:
A similar procedure as described in Example 43, step 3 was used, starting from 4-[3-[6-bromo-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (2.36 g, 5.0 mmol), 1-(3-bromo-5-hydroxy-phenyl)-ethanone (965 mg, 4.48 mmol), and potassium carbonate (1.38 g, 10 mmol) to afford 4-[3-[6-(3-acetyl-5-bromo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (2.15 g, 79%) as a colorless viscous oil: EI(+)-HRMS m/e calcd for C31H41BrO7 (M+Na)+ 627.1928. found 627.1925.