Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[CH:30]=[C:29]([CH2:31][O:32]C(=O)C)[C:28](=[O:36])[N:27]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)(Cl)[Cl:43]>>[ClH:43].[CH:37]1([N:27]2[C:25]3[N:26]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:15][N:16]=4)[N:22]=[CH:23][C:24]=3[CH:30]=[C:29]([CH2:31][OH:32])[C:28]2=[O:36])[CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: CC(=O)OCc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Reactant: ClC(Cl)Cl
Product: Cl
Product: O=c1c(CO)cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
4-[6-(6-Acetoxymethyl-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.21 g, 0.36 mmol), prepared as in Example 28, was dissolved in 1:1 chloroform:methanol (8 ml), and the solution was purged with anhydrous hydrogen chloride gas then allowed to stir for 3 hours at room temperature. This mixture was added to diethyl ether (50 ml) to give a solid which was collected by filtration, washed with diethyl ether, then dried in vacuo to provide 8-cyclopentyl-6-hydroxymethyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride as a solid (0.17 g, 93%). MS (APCI); M++1: Calc'd, 422.5. Found, 422.2. Analyses for C22H27N7O2.1.0 H2O.2.0HCl: Calc'd: C, 51.56; H, 6.10; N, 19.13; Cl (ionic), 13.84; H2O, 3.51. Found: C, 51.13; H, 5.95; N, 19.05; Cl (ionic), 13.70; H2O, 0.67.
Reaction SMILES: C(OC(=O)[N:7]([O:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[C:36]=1[Cl:45])[CH2:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:45][C:36]1[C:37]([C:41]([F:42])([F:43])[F:44])=[CH:38][CH:39]=[CH:40][C:35]=1[CH2:34][N:19]([CH2:20][CH:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:18][CH2:17][CH2:16][O:15][NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=1
Reactant: Cc1ccc(N(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(NOCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)cc1
Reaction time: 1 h
Yield: 38.7 %

Procedure:
To a solution of {3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methyl-phenyl carbamic acid tert-butyl ester (0.09 g, 0.14 mmol) and CH2Cl2 (2 mL), TFA (0.20 mL, 1.2 mmol) was added and the reaction mixture was stirred for 1 h. The mixture was then poured into NaHCO3, extracted with CH2Cl2, dried over Na2SO4, filtered, and concentrated to yield the product as a yellow oil (0.03 g, 39%): MS(ES) m/e 553.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C1(C)C=CC=CC=1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:18]1([S:24]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)n1ccc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.1 %

Procedure:
A mixture of 5-bromoindole (5 g, 25.5 mmol) and tetra-n-butylammonium hydrogen sulfate (866 mg, 2.55 mmol) in 50% NaOE (50 mL) and toluene (200 mL) is stirred at room temperature for 5 min. Benzenesulfonyl chloride (3.57 mL, 28 mmol) is added and the mixture stirred for 1 hr. The mixture is diluted with water (500 mL) and extracted with EtOAc (3×100 mL). The extracts are washed with brine (250 mL), dried over MgSO4, filtered and evaporated to a yellow oil. The oil is purified by medium-pressure column chromatography on silica gel eluting with 10% EtOAc/hexanes to give the title compound as a white solid (7.81 g).
Reaction SMILES: [CH2:1]([O:8][N:9]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@H:10]1[CH2:15][N:14]([C:16]([O:18][CH2:19][CH:20]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]3[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH:13]([C:33]#[N:34])[C:12]([CH2:35][O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=N[OH:54])C>CO.[Cu](Cl)Cl>[CH2:1]([O:8][N:9]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@H:10]1[CH2:15][N:14]([C:16]([O:18][CH2:19][CH:20]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]3[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:17])[CH:13]([C:33](=[O:54])[NH2:34])[C:12]([CH2:35][O:36][Si:37]([C:40]([CH3:41])([CH3:42])[CH3:43])([CH3:39])[CH3:38])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(OCc1ccccc1)[C@@H]1C=C(CO[Si](C)(C)C(C)(C)C)C(C#N)N(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Reactant: CC=NO
Agent: Cl[Cu]Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N(OCc1ccccc1)[C@@H]1C=C(CO[Si](C)(C)C(C)(C)C)C(C(N)=O)N(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Temperature: 65 °C
Reaction time: 6 h
Yield: 89.1 %

Procedure:
A mixture of (5R)-(9H-fluoren-9-yl)methyl 5-((benzyloxy)(tert-butoxycarbonyl)amino)-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-cyano-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 160, 1.3 g, 1.87 mmol), acetaldehyde oxime (0.569 mL, 9.34 mmol) and newly activated copper(II) chloride on 4 Å MS (187 mg, 0.15 mmol) (used 100 mg CuCl2/mol sieves per 1 mmol substrate) in MeOH (5 mL) was stirred under nitrogen at 65° C. for 6 h. The mixture was filtered and evaporated. The residue was purified on silica gel column (0-60%, EtOAc/hexanes). The two diastereomers were combined together to afford the title compound (1.190 g, 89%) as a pale yellow foamy solid.
Reaction SMILES: [CH:1]1([C:4]2[N:9]([CH2:10][C:11](O)=[O:12])[C:8](=[O:14])[C:7]([NH:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[CH2:23][CH2:22][CH2:21][NH:20][C:19]=4[N:18]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH2:27]([O:29][C:30](=[O:36])[CH2:31][C@H:32]([NH2:35])[C:33]#[CH:34])[CH3:28]>>[CH2:27]([O:29][C:30](=[O:36])[CH2:31][C@H:32]([NH:35][C:11](=[O:12])[CH2:10][N:9]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][CH:6]=[C:7]([NH:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[CH2:23][CH2:22][CH2:21][NH:20][C:19]=3[N:18]=2)[C:8]1=[O:14])[C:33]#[CH:34])[CH3:28]
Reactant: C#C[C@@H](N)CC(=O)OCC
Reactant: O=C(O)Cn1c(C2CC2)ccc(NCc2ccc3c(n2)NCCC3)c1=O
Product: C#C[C@H](CC(=O)OCC)NC(=O)Cn1c(C2CC2)ccc(NCc2ccc3c(n2)NCCC3)c1=O

Procedure:
Following the procedures described for Scheme 16, the acid 17-7 was coupled with 3-amino-3(S)-(ethynyl)-propionic acid ethyl ester 2-9 (Zablokie et al, J. Med. Chem., 1995, 38, 2378) to afford the title compound 17-12.
Reaction SMILES: C([Li])CCC.[O:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11]#N.Cl.[O:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>CCCCCC.O>[O:14]1[CH2:18][CH2:17][CH2:16][C@@H:15]1[C:10](=[O:6])[CH2:9][CH2:8][CH2:7][CH3:11]
Reactant: C1CCOC1
Reactant: N#C[C@H]1CCCO1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: CCCCC(=O)[C@H]1CCCO1
Reaction time: 1 h

Procedure:
A 1 L reactor at a temperature of 0° C. was added with 0.4 L of 1.6 M n-butyllithium in n-hexane, to which 13.5 g of (R)-2-tetrahydrofuran nitrile as previously obtained, in 0.07 L of tetrahydrofuran was slowly added dropwise. As such, the reaction was carried out for 1 hour with stirring, while the temperature within the reactor was controlled below 15° C. Next, the resulting solution was added dropwise to 65 g of concentrated hydrochloric acid in 0.4 L of water, while the temperature of the reaction was controlled below 25° C. Thereafter, the extraction was conducted by use of ethylacetate, followed by removing the solvent therein under reduced pressure, and the remainder was vacuum distilled off to produce 19.6 g of (R)-1-(2-tetrahydrofuranyl)-1-pentanone having an optical purity of 98.5% ee.
Reaction SMILES: Br[CH2:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][N:6]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16])=O.[C:28]([NH2:31])(=[S:30])[CH3:29].C(OCC)(=O)C>CO.ClCCl>[CH3:14][S:11]([O:10][C@H:8]1[CH2:7][N:6]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@H:5]([C:3]2[N:31]=[C:28]([CH3:29])[S:30][CH:2]=2)[CH2:9]1)(=[O:12])=[O:13]
Reactant: CC(N)=S
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)CBr)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc([C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cs1
Reaction time: 4 h
Yield: 74.2 %

Procedure:
To a solution of (2S,4R)-2-bromoacetyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.15 g) in a mixture of methanol (20 ml) and dichloromethane (15 ml) was added thioacetamide (388 mg) at room temperature. After stirring at the same temperature for 4 hours, the mixture was poured into ethyl acetate and washed in turn with saturated aqueous sodium bicarbonate and brine. The dried organic layer was evaporated and the resulting oil was subjected to a column chromatography on silica gel (50 g) eluting with a mixture of acetone and dichloromethane (1:20 V/V) to give (2S,4R)-4-methanesulfonyloxy-2-(2-methylthiazol-4-yl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (810 mg).
Reaction SMILES: [CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6]2.[CH3:24][N:25]([CH3:30])[S:26](Cl)(=[O:28])=[O:27].[OH2:31].ClCCl>N1C=CC=CC=1>[C:21]([OH:27])(=[O:31])[CH3:22].[CH3:24][N:25]([CH3:30])[S:26]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:2]2([CH3:1])[CH:3]3[CH:7]2[CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]3)[CH:18]=1)(=[O:28])=[O:27]
Reactant: O
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC1(c2cccc(N)c2)C2CN(CCCc3ccccc3)CC21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O
Product: CN(C)S(=O)(=O)Nc1cccc(C2(C)C3CN(CCCc4ccccc4)CC32)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 3 %

Procedure:
To a solution of 3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine (Preparation 8, 200 mg, 0.65 mmol) in pyridine (2 ml) under nitrogen at 0° C. was added dimethylsulfamoyl chloride (140 mg, 0.98 mmol), then the mixture was stirred at room temperature for 16 hours. Water (5 ml) and dichloromethane (5 ml) were added, and the mixture was stirred for 30 minutes. The organic phase was washed further with water (5 ml) for 30 minutes, separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica (10 g) column chromatography eluting with ethyl acetate:hexane:ammonia solution (0.880) (20:80:1 then 50:50:1). Product-containing fractions were combined and concentrated in vacuo. The residue was further purified by preparative HPLC (condition 4). Combination and evaporation of appropriate fractions gave the title compound as a pale brown solid (7 mg, 3%).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[Cr:9]([Cl:13])([O-:12])(=[O:11])=[O:10].[NH+:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCOCC>C(Cl)Cl>[Cr:9]([Cl:13])([O-:12])(=[O:11])=[O:10].[NH+:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:1][C:2]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1(CO)CCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C=O)CCCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Pyridinium chlorochromate was prepared by following the procedure of E. J. Corey and J. W. Suggs, Tetrahedron Letters, 31, 2647 (1975). A solution of 11.8 g of 1-methylcyclopentanemethanol in 32 ml of anhydrous methylene chloride was added to a stirred suspension of 39.2 pyridinium chlorochromate in 312 ml of methylene chloride under argon. The resultant dark mixture was stirred for 1.5 hours at ambient temperature. A portion of ether was added to the resultant mixture and then the supernatant was decanted. The remaining dark residue was rinsed several times with ether. The combined ether solutions were filtered through a short pad of Florisil. The resultant solution was concentrated by distillation of ether and then the residue was distilled at 110 mm Hg to yield 6.41 g of 1-methylcyclopentanecarboxaldehyde as a colorless oil: bp 98°-100°; nmr (CDCl3) δ 1.12 (3H, s), 1.0-2.2 (8H, m) and 9.50 ppm (1H, s).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:8][CH:7]=[CH:6][C:5]=12.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.Cl.[O:46]=[S:47]1(=[O:69])[CH2:52][CH2:51][CH2:50][N:49]2[C:53](=[O:68])[N:54]([CH2:64][CH2:65][CH2:66][NH2:67])[C:55](=[O:63])[C:56]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:48]12>O.ClCCl>[O:69]=[S:47]1(=[O:46])[CH2:52][CH2:51][CH2:50][N:49]2[C:53](=[O:68])[N:54]([CH2:64][CH2:65][CH2:66][NH:67][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][S:10][C:9]3[N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=3)[C:55](=[O:63])[C:56]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:48]12
Reactant: NCCCn1c(=O)c(-c2ccccc2)c2n(c1=O)CCCS2(=O)=O
Reactant: O=C(O)CCCSc1cccc2nccn12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(CCCSc1cccc2nccn12)NCCCn1c(=O)c(-c2ccccc2)c2n(c1=O)CCCS2(=O)=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a dichloromethane solution of 590 mg (2.5 mmol) of 4-(imidazo[1,2-a]pyridine-5-ylthio)butanoic acid and 383 mg (2.5 mmol) of HOBt, 479 mg (2.5 mmol) of WSC and 0.42 ml (3 mmol) of triethylamine were added. After the reaction mixture was stirred at 0° C. for 1.5 hours, 1.158 g (3 mmol) of 3-(1,1,6,8-tetraoxo-9-phenyl-2,3,4,8-tetrahydropyrimido[6,1-b][1,3]thiazin-7-yl)propylamine hydrochloride and 0.84 ml (6 mmol) of triethylamine were added, followed by stirring at room temperature for 16 hours. After water was added, the mixture was extracted with dichloromethane and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform→chloroform/methanol=25/1) to yield 683.9 mg (48.2%, white oily substance) of the desired product.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1.[C:13]([OH:17])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[C:1]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of isobutyryl chloride (47 g, 0.44 mol) in CH2Cl2 (75 ml) and tert-butanol (75 ml) at 0° C., pyridine (39.3 ml, 486 mmol) was added slowly by syringe. The mixture was allowed to warm to room temperature, stirred overnight, diluted with CH2Cl2 (400 ml) and washed with H2O, HCl (2N, two times), H2O (two times) and saturated NaHCO3. The organic phase was dried over MgSO4 and filtered. The filtrate was then concentrated under reduced pressure without heat. The resulting oil was simply distilled, collecting the fraction boiling at 128-129° C. to give tert-butyl isobutyrate, 21 (35.9 g, 56%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:13][CH2:14][C:15](Br)=[O:16]>CN(C=O)C.O1CCOCC1.O>[Br:13][CH2:14][C:15]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:16]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(N)c(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(NC(=O)CBr)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a solution of 2-amino-5-methoxybenzoic acid (5.0 g, 0.03 mol) in anhydrous DMF (30 mL) and dioxane (30 mL) was added, dropwise, bromoacetyl bromide (6.0 g, 2.6 mL, 100 mol %) while keeping the internal temperature between 0° and 2° C. After the addition was completed (~30 min), the reaction mixture was stirred overnight at rt. The reaction mixture was diluted with water (100 mL), and then the precipitated product was filtered, washed sequentially with 5% HBr (300 mL) and water (300 mL), and then dried in a vacuum oven at 40°-45° C., affording 5.6 g (65%) of the title compound as a light grey solid: mp 171.5°-172.7° C.; 1H NMR (DMSO-d6) δ11.26 (s, 1H, NH), 8.30 (d, 1H, J=9.2), 7.44 (d, 1H, J=3.2), 7.22 (dd, 1H, J=3.2, J=9.2), 4.22 (s, 2H), 3.78 (s, 3H); 13C NMR (DMSO-d6) δ168.69, 164.52, 154.75, 133.03, 122.13, 119.83, 119.04, 114.87, 55.40, 30.59; MS (EI, m/z)287 (M+). HRMS (EI) calcd for C10H10NO4Br 286.9793, found 286.9793.
Reaction SMILES: [C:1](O)(=O)[C:2]1C=CC=C[CH:3]=1.[F:10][C:11]([F:21])([F:20])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[CH:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)([CH3:24])[CH3:23].C([Sn](CCCC)(CCCC)CCCC)C=C>CC#N.[O-]S(C(F)(F)F)(=O)=O.[La+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH:22]([C:25]1[CH:31]=[CH:30][C:28]([NH:29][CH:16]([C:15]2[CH:18]=[CH:19][C:12]([C:11]([F:21])([F:20])[F:10])=[CH:13][CH:14]=2)[CH2:3][CH:2]=[CH2:1])=[CH:27][CH:26]=1)([CH3:24])[CH3:23]
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [La+3]
Solvent: CC#N
Product: C=CCC(Nc1ccc(C(C)C)cc1)c1ccc(C(F)(F)F)cc1
Yield: 89.7 %

Procedure:
Lanthanum triflate (0.141 g, 0.24 mmol, 2 mol %) and benzoic acid (1.49 g, 12.2 mmol) were dissolved in CH3CN (20 ml) and the suspension was stirred under nitrogen until dissolved. 4-(Trifluoromethyl)benzaldehyde (2.12 g, 12.2 mmol) was added followed by 4-isopropylaniline (1.65 g). Allyl(tributyl)stannane (4.54 ml, 14.6 mmol) was then added and the mixture was stirred at room temperature overnight. The mixture was then quenched with NaOH (2M, 20 ml) and extracted into DCM (3×100 ml). The combined extracts were dried (MgSO4) and the solvent was removed in vacuo to yield the crude homoallylic amine product. This was purified by chromatography on silica using 10-30% ether in hexane as eluant to yield the product as a colourless oil (3.65 g, 90%). 1H NMR (500 MHz, CDCl3) δ: 1.16 (6H, dd, J 1.3, 6.9), 2.42-2.48 (1H, m), 2.56-2.62 (1H, m), 2.71-2.79 (1H, qn, J 6.7), 4.07 (1H, s), 4.38 (1H, dd, J 4.9, 8.1), 5.18 (2H, m), 5.69-5.77 (1H, m), 6.40 (2H, d, J 8.4), 6.95 (2H, d, J 8.5), 7.49 (2H, d, J 8.1), 7.57 (2H, d, J 8.1); M/Z (ES+) 334 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:7][CH2:8][C:9](=[O:12])[NH:10][CH2:11][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])[C:25]([Cl:39])=[CH:24][N:23]=1>>[Cl:39][C:25]1[C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])=[N:27][C:22]([NH:1][C:2]2[CH:20]=[CH:19][C:5]3[N:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:7][CH2:8][C:9](=[O:12])[NH:10][CH2:11][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: Nc1ccc2c(c1)CNC(=O)CCN2C(=O)C(F)(F)F
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CNC(=O)CCN3C(=O)C(F)(F)F)ncc1Cl

Procedure:
2-{5-Chloro-2-[4-oxo-1-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-benzo[b][1,5]diazocin-8-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide was prepared from 8-Amino-1-(2,2,2-trifluoro-acetyl)-2,3,5,6-tetrahydro-1H-benzo[b][1,5]diazocin-4-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide in an analogous manner to Example 1221d. Title compound isolated as an off-white solid (27 mg, 14%). mp 191-194° C.; LCMS: m/z=548.25 (M+H+), HPLC (98% purity), 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 9.78 (s, 1H), 8.72 (m, 2H), 8.27 (s, 1H), 7.90 (m, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.71 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.46 (t, J=8.3 Hz, 1H), 7.29 (d, J=8.3 Hz, 1H), 7.16 (t, J=7.8 Hz, 1H), 4.65 (m, 1H), 4.43 (m, 1H), 3.70 (m, 1H), 3.18 (m, 1H), 2.81 (m, 4H), 2.36 (m, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[CH3:13].[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CS(C)=O.O>[CH3:9][O:8][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]([CH3:13])=[C:2]([N:24]2[CH2:23][CH2:22][CH:21]([N:18]3[CH2:17][CH2:16][N:15]([CH3:14])[CH2:20][CH2:19]3)[CH2:26][CH2:25]2)[CH:7]=1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(C)cc1[N+](=O)[O-]

Procedure:
1-Fluoro-5-methoxy-2-methyl-4-nitrobenzene (INTERMEDIATE 7, 0.370 g, 2.00 mmol), 1-methyl-4-(piperidin-4-yl)piperazine (0.367 g, 2.00 mmol), and potassium carbonate (0.415 g, 3.00 mmol) in DMSO (2.0 mL) were stirred at 80° C. for 15 h. DCM (20 mL) and water (20 mL) were added to the reaction mixture. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the title product. (0.640 g, 92%).
Reaction SMILES: [SH2:1].[CH3:2][C:3]1[N:7]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]#[N:18])[CH2:13][CH2:12]2)=[O:10])[N:6]=[C:5]([C:19]([F:22])([F:21])[F:20])[CH:4]=1.N(CCO)CCO>CN(C)C=O>[CH3:2][C:3]1[N:7]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17](=[S:1])[NH2:18])[CH2:13][CH2:12]2)=[O:10])[N:6]=[C:5]([C:19]([F:22])([F:20])[F:21])[CH:4]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(C#N)CC1
Reactant: S
Solvent: OCCNCCO
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(C(N)=S)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Hydrogen sulfide gas was passed into a solution of 1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinecarbonitrile (i.e. the product of Example 8, Step B) (9.0 g, 30 mmol) and diethanolamine (3.15 g, 30 mmol) in N,N-dimethylformamide (15 mL) at 50° C. in a flask equipped with dry-ice condenser. The hydrogen sulfide feed was stopped when the reaction mixture became saturated with hydrogen sulfide, as indicated by condensation on the cold-finger. The reaction mixture was stirred for an additional 30 minutes at 50° C. Then excess hydrogen sulfide gas was sparged into the scrubber by a subsurface nitrogen flow, and water (70 mL) was gradually added. The reaction mixture was cooled to 5° C., filtered, and washed with water (2×30 mL). The filter cake was dried at 50° C. in a vacuum-oven to give 8.0 g of the title compound as a solid, melting at 185-186° C.
Reaction SMILES: [OH-:1].[Na+].[Cl-:3].[Al+3:4].[Cl-:5].[Cl-:6]>O.[O-2].[O-2].[O-2].[Fe+3].[Fe+3]>[Al:4]([Cl:6])([Cl:5])[Cl:3].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1]
Reactant: [Al+3]
Reactant: [OH-]
Reactant: [Cl-]
Agent: [Fe+3]
Agent: [Na+]
Agent: [O-2]
Solvent: O
Product: Cl[Al](Cl)Cl
Reaction time: 0.5 h

Procedure:
Into 1000 ml of water is dispersed 40 g of iron oxide red. 7.79 g Of Rondis R and 1.05 g of sodium hydroxide are separately dissolved at 70° C. in 100 ml of hot water to be added to the dispersion of iron oxide red. A solution of 2.11 g of aluminium chloride in 50 ml of water is added gradually to the mixture under stirring, and stirring is continued for 30 minutes. The precipitate is recovered by filtration, washed with water and dried, thus resulting in iron oxide red with exceedingly superior oil dispersability, improved chroma and brightness and gloss.