Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[S:4].[C:6]([C:8]([C:20]#[N:21])=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1)#[N:7]>C(O)C>[NH2:21][C:20]1[C:8]([C:6]#[N:7])=[C:9]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=2)[NH:2][CH:3]([SH:4])[N:5]=1
Reactant: CC(=O)Nc1ccc(C=C(C#N)C#N)cc1
Reactant: NC(N)=S
Agent: [Na]
Solvent: CCO
Product: CC(=O)Nc1ccc(C2=C(C#N)C(N)=NC(S)N2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To 20 mL of absolute ethanol, 250 mg of metallic sodium was added in small portions. After dissolved completely, 760 mg of thiourea was added to the above solution, and the mixture was stirred at room temperature for 1 hour. To the reaction, 2.11 g of N-[4-(2,2-dicyanovinyl)phenyl]acetamide was added, and the mixture was heated to reflux for 3 hours. Then, the solvent was removed under reduced pressure from the reaction mixture, the residue was dissolved in 30 mL of water. In addition, the mixture was acidified by adding acetic acid in small portions, thereto 30 mL of ethyl acetate was added and then the solution was stirred overnight. Filtration of the precipitated material gave 1.2 g of N-[4-(6-amino-5-cyano-2-mercapto-2,3-dihydropyrimidin-4-yl)phenyl]acetamide as a white powder.
Reaction SMILES: [OH:1][CH2:2][CH:3](CO)O.CC(OCC(O)CO)=O.[CH3:16][C:17]([O:19][CH2:20][CH:21]([O:24][C:25]([CH3:27])=[O:26])[CH2:22][OH:23])=[O:18]>O>[CH3:16][C:17](=[O:18])[O:19][CH2:20][CH:21]([CH2:22][O:23][C:2](=[O:1])[CH3:3])[O:24][C:25](=[O:26])[CH3:27]
Reactant: OCC(O)CO
Reactant: CC(=O)OCC(CO)OC(C)=O
Agent: CC(=O)OCC(O)CO
Solvent: O
Product: CC(=O)OCC(COC(C)=O)OC(C)=O

Procedure:
When the reaction is performed correctly, the reaction product contains only traces of glycerol, monoacetin, diacetin and water, so that the OH number normally lies below 1. Pure triacetin can be obtained readily by distillation in a rectification column of the obtained crude product, since, at atmospheric pressure, acetic acid boils at about 118° C., acetic acid anhydride boils at about 140° C., and glyceryl triacetate (triacetin) boils at about 258° C. Any catalyst that may still be present remains in the distillation residue.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[N:3]=1.[Cl:13]N1C(=O)CCC1=O>C(Cl)Cl.C(Cl)(Cl)Cl.[Cl-].[Zr+4].[Cl-].[Cl-].[Cl-]>[Cl:13][C:5]1[C:6]([OH:12])=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc2ccc(O)cc2n1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccc2ccc(O)c(Cl)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.9 %

Procedure:
2-Methylquinolin-7-ol (200 mg, 1.26 mmol) was added to a solution of 1-chloropyrrolidine-2,5-dione (168 mg, 1.26 mmol) and zirconium(IV) chloride (14.6 mg, 0.0628 mmol) in DCM (10 mL) and the reaction was stirred at ambient temperature for 24 hours. The reaction was diluted with chloroform (30 mL) and washed with an aqueous sodium carbonate solution followed by brine. After drying (MgSO4), the solution was filtered and concentrated under reduced pressure and the residue was purified by reverse phase chromatography (SP4, 25 M, eluting with a gradient of water/ACN 90:10 to 0:100, 30 column volumes) to yield 8-chloro-2-methylquinolin-7-ol (134 mg, 55.1% yield) as a thick oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)[N:16]=[C:15]([C:25](O)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(N3CC(=O)NC3)=O)C=2)C=C(F)C=1.[S:55]1[CH2:59][CH2:58][NH:57][CH2:56]1>>[Cl:24][C:20]1[CH:19]=[C:18]([N:17]2[C:13]([C:4]3[CH:5]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:7]=[C:2]([F:1])[CH:3]=3)=[CH:14][C:15]([C:25]([N:57]3[CH2:58][CH2:59][S:55][CH2:56]3)=[O:26])=[N:16]2)[CH:23]=[CH:22][N:21]=1
Reactant: C1CSCN1
Reactant: O=C(O)c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2ccnc(Cl)c2)n1
Agent: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Product: O=C(c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2ccnc(Cl)c2)n1)N1CCSC1

Procedure:
200 mg (0.55 mmol) of the compound of Example 35A is reacted analogously to the synthesis of the compound of Example 1 with 0.05 ml (0.60 mmol) of thiazolidine. 193 mg (80% of theory) of the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]=[C:9]([Cl:30])[C:10]=1[NH:11][C:12]1[N:22]=[C:21]2[C:15]([N:16]([CH3:29])[C:17](=[O:28])[CH2:18][CH2:19][N:20]2[CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:14][N:13]=1)[C:5](O)=[O:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:56][CH:57]1[CH2:62][CH2:61][N:60]([CH3:63])[CH2:59][CH2:58]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]=[C:9]([Cl:30])[C:10]=1[NH:11][C:12]1[N:22]=[C:21]2[C:15]([N:16]([CH3:29])[C:17](=[O:28])[CH2:18][CH2:19][N:20]2[CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:14][N:13]=1)[C:5]([NH:56][CH:57]1[CH2:62][CH2:61][N:60]([CH3:63])[CH2:59][CH2:58]1)=[O:6]
Reactant: CN1CCC(N)CC1
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Nc3c(Cl)cc(C(=O)O)c(F)c3Cl)ncc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2cc(Cl)c(Nc3ncc4c(n3)N(C3CCCC3)CCC(=O)N4C)c(Cl)c2F)CC1
Reaction time: 2 h
Yield: 65.9 %

Procedure:
3,5-dichloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-2-fluoro-benzoic acid (Intermediate 221; 85 mg, 0.18 mmol), HATU (104 mg, 0.27 mmol) and 4-amino-1-methylpiperidine (32 mg, 0.27 mmol) were stirred in DMF (3 mL) and diisopropylethylamine (95 μl, 0.54 mmol) added. The mixture was stirred for 2 hours and absorbed on to an SCX column, which was subsequently washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated and the residue purified by column chromatography (4% ammonia in methanol/DCM) to yield the title compound as a white solid (67 mg, 66%).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH:6]1([C:9](=O)[C:10](=[CH:32]OCC)[C:11]([C:13]2[C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:15][CH:14]=2)=[O:12])[CH2:8][CH2:7]1.Cl.[NH2:38][OH:39]>C(O)C.C(OCC)(=O)C>[CH:6]1([C:9]2[O:39][N:38]=[CH:32][C:10]=2[C:11]([C:13]2[C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:15][CH:14]=2)=[O:12])[CH2:8][CH2:7]1
Reactant: NO
Reactant: CCOC=C(C(=O)c1cnc(-c2ccccc2)n(-c2ccccc2)c1=O)C(=O)C1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(c1cnoc1C1CC1)c1cnc(-c2ccccc2)n(-c2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Anhydrous sodium acetate (68 mg, 0.83 mmol) was added to a solution of 1-cyclopropyl-3-(1,6-dihydro-6-oxo-1,2-diphenyl-5-pyrimidinyl)-2-(ethoxymethylene)-1,3-propanedione (i.e. the product from Example 6, Step B) (171 mg, 0.41 mmol) in ethanol (4 mL) at 0° C. Hydroxylamine hydrochloride (29 mg, 0.42 mmol) was added and the resulting suspension was stirred at 0° C. for 30 min and then at ambient temperature for 2 h. The resulting mixture was diluted with ethyl acetate (20 mL) and ethanol (20 mL), concentrated onto 0.8 g silica gel, and the residue purified by medium pressure liquid chromatography using a 12 g silica gel column and eluting with 0 to 100% ethyl acetate in hexanes to obtain 14 mg of the title compound, a compound of the present invention as a yellow glassy solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22](F)[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[CH:32]1([SH:37])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([S:37][CH:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: SC1CCCC1
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(F)cc(C(F)(F)F)c1
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(SC2CCCC2)cc(C(F)(F)F)c1
Yield: 83 %

Procedure:
Starting with {(R)-4-[(3-fluoro-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (1st step intermediate of example 8-1) and cyclopentanethiol using the method analogous to the method analogous to the one described for the 1st step of example 7-1, {(R)-4-[(3-Cyclopentylsulfanyl-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (20.2 mg, 83%) was obtained. MS cald. for C24H30F3N3O4S2 545, obsd. (ESI+) [(M+H)+] 546.
Reaction SMILES: [C:1]([Cl:4])(=O)C.[CH:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH2:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1>CO>[CH3:1][O:13][C:12]([C@@H:11]([NH2:15])[C:8]1[CH:7]=[CH:6][CH:5]=[CH:10][CH:9]=1)=[O:14].[ClH:4]
Reactant: N[C@@H](C(=O)O)c1ccccc1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)[C@@H](N)c1ccccc1
Product: Cl
Reaction time: 24 h

Procedure:
Acetyl chloride (4 ml) was added cautiously and dropwise to methanol (20 ml) at 0° C. over 2 minutes. When the addition was completed, D-phenylglycine (1 g, 5.9 mmol, Aldrich) was introduced in a single portion. The mixture was stirred until dissolved then allowed to stand at RT for 24 hours. The solvent was evaporated then coevaporated twice from toluene to afford the title compound as a white crystalline solid in quantitative yield. The title compound was obtained as a white crystalline solid in quantitative yield with an identical n.m.r. spectrum to the L-isomer.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][C:15]([C@H:44]([N:46]2[CH2:51][CH2:50][N:49]([S:52]([CH3:55])(=[O:54])=[O:53])[CH2:48][CH2:47]2)[CH3:45])=[CH:14][N:13]=1.[F:56][C:57]1[CH:58]=[C:59]([NH2:65])[CH:60]=[N:61][C:62]=1[O:63][CH3:64]>C1COCC1>[F:56][C:57]1[CH:58]=[C:59]([NH:65][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=4)[CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[N:19]=3)=[CH:16][C:15]([C@H:44]([N:46]3[CH2:47][CH2:48][N:49]([S:52]([CH3:55])(=[O:53])=[O:54])[CH2:50][CH2:51]3)[CH3:45])=[CH:14][N:13]=2)[CH:60]=[N:61][C:62]=1[O:63][CH3:64]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Reactant: COc1ncc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 M in hexane; 31.9 mL, 31.9 mmol) was added (dropwise over 10 min) to a mixture of (R)-4-(2-fluoro-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 146, Step 6; 6.75 g, 10.62 mmol) and 5-fluoro-6-methoxypyridin-3-amine (Anichem, North Brunswick, N.J.; 2.264 g, 15.93 mmol) in THF (100 mL) at 0° C., and the resulting solution was stirred at 0° C. for 1 h. Excess LiHMDS was then quenched with saturated aqueous NH4Cl (140 mL) and the reaction mixture was partitioned between EtOAc (500 mL) and half-saturated aqueous NH4Cl (200 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×200 mL). The combined organic extracts were sequentially washed with brine (300 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 100% EtOAc/hexanes) furnished (R)-4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (7.25 g, 90% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.88 (1H, s), 8.72 (1H, d, J=2.0 Hz), 8.25 (1H, d, J=2.2 Hz), 8.06 (1H, dd, J=12.3, 1.6 Hz), 7.96 (1H, d, J=2.0 Hz), 7.21 (4H, t, J=8.2 Hz), 6.86 (4H, dd, J=14.1, 8.4 Hz), 4.70-4.96 (4H, m), 4.01 (3H, s), 3.81 (3H, s), 3.78 (3H, s), 3.55 (1H, q, J=6.7 Hz), 3.15 (4H, br s), 2.68 (3H, s), 2.59 (3H, s), 2.48-2.57 (4H, m), 1.38 (3H, d, J=6.7 Hz). 19F NMR (376 MHz, CDCl3) δ −139.13 (1F, d, J=13.0 Hz). m/z (ESI, +ve) 758.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[C:16]#[N:17].[CH3:18][O:19][C:20]([NH:22][NH2:23])=[O:21]>CO>[NH2:17][C:16]1[N:22]([C:20]([O:19][CH3:18])=[O:21])[N:23]=[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=12
Reactant: COC(=O)NN
Reactant: CCCn1c(=O)c(C#N)c(Cl)c2ccccc21
Solvent: CO
Product: CCCn1c(=O)c2c(N)n(C(=O)OC)nc2c2ccccc21
Yield: 54.3 %

Procedure:
In 60 ml of methanol were refluxed 2.00 g (8.1 mmol) of Compound b prepared in Example 2 and 1.10 g (12.2 mmol) of methoxycarbonylhydrazine for 6 hours. The reaction mixture was cooled to obtain 1.32 g (54%) of the titled compound as a colorless crystal.
Reaction SMILES: [C:1]([Si:5]([CH3:12])([CH3:11])[O:6][CH2:7][C@@H:8]1[CH2:10][O:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:13][C:14]1[CH:15]=[CH:16][C:17]2[O:22][CH2:21][C:20](=[O:23])[NH:19][C:18]=2[CH:24]=1>CC#N>[C:1]([Si:5]([CH3:12])([CH3:11])[O:6][CH2:7][C@@H:8]([OH:9])[CH2:10][NH:13][C:14]1[CH:15]=[CH:16][C:17]2[O:22][CH2:21][C:20](=[O:23])[NH:19][C:18]=2[CH:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CO1
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OC[C@@H](O)CNc1ccc2c(c1)NC(=O)CO2
Temperature: 50 °C
Reaction time: 6 h
Yield: 66.1 %

Procedure:
LiClO4 (7.20 g, 3 eq.) was added to a solution of tert-butyl-dimethyl-((S)-1-oxiranylmethoxy)-silane (commercial; 4.25 g, 22.6 mmol) in MeCN (70 mL). 6-amino-4H-benzo[1,4]oxazin-3-one (commercial; 3.70 g, 1 eq.) was then added and the mixture was stirred at 50° C. for 6 h. The solvent was removed under reduced pressure and the residue was purified by CC (DCM/MeOH/NH4OH 1000/25/2) to afford the title intermediate as a pale brown foam (5.25 g, 66% yield).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[C:14]([CH:17]=O)[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19]/[C:20](/[CH3:24])=[CH:21]\[C:22]#[N:23].Cl.[C:26]([CH2:29][C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])(=N)[NH2:27].C([O-])(=O)C.[Na+]>C(O)(C)C>[NH2:27][C:26]1[NH:19][C:20]([CH3:24])=[C:21]([C:22]#[N:23])[CH:17]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:15]=2[CH:16]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[N:9]3)[C:29]=1[C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31]
Reactant: CC(C)OC(=O)CC(=N)N
Reactant: O=Cc1cccc2ncc(-c3ccccc3)cc12
Reactant: C/C(N)=C/C#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2cccc3ncc(-c4ccccc4)cc23)C(C(=O)OC(C)C)=C(N)N1

Procedure:
4.66 g (20 mmol) of 3-phenyl-quinoline-5-aldehyde are boiled in 40 ml of isopropanol with 1.64 g (20 mmol) of 3-aminocrotononitrile, 3.6 g (20 mmol) of isopropyl amidinoacetate hydrochloride and 1.64 g (20 mmol) of sodium acetate for 20 hours. The mixture is concentrated, the residue is taken up in ethyl acetate/water and the phases are separated. The organic phase is washed twice with water, dried and concentrated. The reaction mixture is separated over a silica gel column using methylene chloride/ethyl acetate mixtures. The desired fractions are collected and concentrated. The resulting evaporation residue is crystallised with acetonitrile and filtered off with suction. 635 mg of colourless crystals of melting point 227=20 -229° C. are obtained.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1)[CH3:9])(C)(C)C.Br[C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].N1C=CC=CC=1>[Cu](I)I.CCOC(C)=O.C(Cl)Cl>[N:21]1[CH:20]=[C:19]([O:16][C:12]2[CH:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[CH:15]=[CH:14][CH:13]=2)[CH:24]=[N:23][CH:22]=1
Reactant: Brc1cncnc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(O)c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](N)c1cccc(Oc2cncnc2)c1
Temperature: 115 °C
Yield: 89.6 %

Procedure:
A mixture of (S)-[1-(3-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (1 g, 4.2 mmol), 5-bromo-pyrimidine (0.8 g, 5.1 mmol), potassium carbonate (powder, 1.4 g, 10.1 mmol), copper iodide (325 mesh powder, 0.6 g, 3.2 mmol) and pyridine (5 mL) was heated at 115° C. for 24 h. CH2Cl2 (100 mL) was added, the reaction mixture was filtered through celite, rinsed with CH2Cl2 (2×50 mL), and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 1:1/Hexane:EtOAc to give the title product (0.81 g, 61% yield).
Reaction SMILES: O.O.[NH2:3][C:4]1[S:5][CH:6]=[C:7](/[C:9](=[N:13]/[O:14][C:15](=[O:17])[CH3:16])/[C:10]([OH:12])=[O:11])[N:8]=1.N12CCN(CC1)CC2.[P:26](Cl)([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[S:27]>CC(N(C)C)=O>[CH2:29]([O:28][P:26]([O:11][C:10](=[O:12])/[C:9](/[C:7]1[N:8]=[C:4]([NH2:3])[S:5][CH:6]=1)=[N:13]\[O:14][C:15](=[O:17])[CH3:16])([O:31][CH2:32][CH3:33])=[S:27])[CH3:30]
Reactant: CC(=O)O/N=C(\C(=O)O)c1csc(N)n1
Reactant: CCOP(=S)(Cl)OCC
Agent: C1CN2CCN1CC2
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOP(=S)(OCC)OC(=O)/C(=N\OC(C)=O)c1csc(N)n1
Temperature: -20 °C
Reaction time: 3.5 h
Yield: 86 %

Procedure:
To a stirred solution of 134.9 g (Z)-(2-aminothiazol-4-yl)-acetoxyiminoacetic acid dihydrate (508.6 mmol) and 570 mg 1,4-diazabicyclo[2.2.2]octane (DABCO) (5.09 mmol) in 1500 ml dimethylacetamide was added under argon 158 ml tributylamine (661 mmol). The yellowish solution was cooled to -20° C. and over 30 min was added dropwise 104 ml diethyl chlorothiophosphate (661 mmol). Stirring was continued at -20° C. for 3.5 h. The reaction was followed by HPLC. After 3 h, all starting material was consumed. The reaction mixture was allowed to warm up to 0° C. and over 1.0 h was added dropwise 2200 ml water. The precipitated product was filtered, washed with water and dissolved in 800 ml dichloromethane. The aqueous layer was back-extracted with 300 ml dichloromethane. The combined organic layers were dried over 70 g sodium sulfate and concentrated under reduced pressure until the product started to crystallize. The residual solution was cooled to 2° C. and 1200 ml n-hexane was added dropwise over 1 h. The resulting suspension was stirred for 1 h at 2° C. and then filtered. The crystalline product was washed with n-hexane and dried to constant weight. (Z)-(2-aminothiazol-4-yl)-acetoxyiminoacetic acid diethoxythiophosphoryl ester was obtained as a white solid (166.9 g, yield=86%, mp 128°-130° C. and was stored under argon at -20° C. No further purification was necessary and the product was used as isolated for the next step.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)=[CH:10]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.O>[C:6]([CH2:8][N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=2)=[CH:10]1)([OH:7])=[O:5]
Reactant: CCOC(=O)c1ccc(-c2ccc(=O)n(CC(=O)OC(C)(C)C)c2)cc1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(-c2ccc(=O)n(CC(=O)O)c2)cc1
Yield: 93.9 %

Procedure:
To a solution of ethyl 4-(1-tert-butoxycarbonylmethyl-6-oxo-1,6-dihydropyridin-3-yl)benzoate [1.03 g, 2.88 mmol, reference example 85b] in CH2Cl2 [10 ml] and H2O [0.125 ml] is added trifluoroacetic acid [2.5 ml]. After 18 hours removed solvent in vacuo and triturated the resulting solid with methylene chloride to give 0.815 g of the product as a white solid in 93.9% yield. 1H NMR (1:1 CD3OD:CDCl3): δ 1.43 (3H, t, J=7 Hz), 4.40 (2H, q, J=7 Hz), 4.81 (2H, s), 6.73 (1H, d, J=9 Hz), 7.60 (2H, d, J=8 Hz), 7.60 (1H, s), 7.88 (1H, d, J=9.0 Hz), 8.09 (2H, d, J=8 Hz). MS (ion spray) m/z 302 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[C:14]2[C@@H:13]3[CH2:15][C@@H:12]3[CH2:11][C:10]=2[C:9]([C:16]([OH:18])=O)=[N:8]1.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([NH:23][C:16]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:15][C@H:13]3[C:14]=2[N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[N:8]=1)=[O:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(O)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G using Intermediate 2 and tert-butyl amine. LCMS m/z=298.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.47 (td, J=4.6 and 3.3 Hz, 1H), 1.22-1.27 (m, 1H), 1.48 (s, 9H), 2.25-2.32 (m, 1H), 2.71-2.76 (m, 1H), 2.93 (d, J=16.7 Hz, 1H), 3.02 (dd, J=16.6 and 6.2 Hz, 1H), 6.79 (s, 1H), 8.42 (br, 1H), 8.49 (d, J=2.0 Hz, 1H), 9.25 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[N:10]=[C:9]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[O:13])[CH:8]=[CH:7][N:6]=1.Br[CH2:25][C:26]([O:28][CH3:29])=[O:27].C(=O)(O)[O-].[Na+]>CS(C)=O.O>[CH3:29][O:28][C:26](=[O:27])[CH2:25][CH:11]([C:9]1[CH:8]=[CH:7][N:6]=[C:5]([S:4][CH3:3])[N:10]=1)[C:12](=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=1
Reactant: CSc1nccc(CC(=O)c2cccc(C(F)(F)F)c2)n1
Reactant: COC(=O)CBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CC(C(=O)c1cccc(C(F)(F)F)c1)c1ccnc(SC)n1
Reaction time: 0.5 h

Procedure:
Sodium hydride (95%, 1.78 g, 83 mmol) and dimethyl sulfoxide (DMSO) (150 mL) were combined under argon in a 3-neck 1L round bottom flask. A solution of Compound 3 in DMSO (50 mL) was added dropwise over 0.75 h using an addition funnel. After stirring an additional 0.5 h, methyl bromoacetate (7.9 mL, 83 mmol) in DMSO (50 mL) was added dropwise. After 18 h, the contents of the reaction flask were poured into water. Saturated sodium bicarbonate was added and the resulting solution was extracted several times with ethyl acetate. The combined organic extracts were washed successively with water and brine. The organic layer was dried with anhydrous sodium sulfate then concentrated in vacuo to give an oil. Purification by flash column chromatography (hexane:ethyl acetate 70:30) afforded Compound 4 as an oil: 24.6 g (64 mmol, 100%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]2[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]2)[CH2:20][CH2:19]1.[Cl:31][C:32]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[C:34]([F:47])[C:33]=1[OH:48]>>[Cl:31][C:32]1[CH:37]=[C:36]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]3[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]3)[CH2:20][CH2:19]2)[CH:35]=[C:34]([F:47])[C:33]=1[OH:48]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: O=C(c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN2CCC(O)C2)CC1)C1CC1
Product: O=C(c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN2CCC(O)C2)CC1)C1CC1

Procedure:
Following general procedure M, (6-bromo-4-((trans-4-((3-hydroxypyrrolidin-1-yl)methyl)cyclohexyl)amino)quinolin-3-yl)(cyclopropyl)methanone (25 mg, 0.053 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (27 mg, 0.10 mmol) to afford the desired product (17 mg, 60%) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 9.11 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 7.97 (dd, J=8.7, 2.0 Hz, 1H), 7.88 (d, J=8.7 Hz, 1H), 7.48 (s, 1H), 7.38 (d, J=11.8, 1H), 4.46-4.38 (m, 1H), 4.18-4.10 (m, 1H), 3.08-3.01 (m, 2H), 2.93-2.78 (m, 3H), 2.70-2.64 (m, 2H), 2.331 (d, J=12.9 Hz, 2H), 2.23-2.12 (m, 1H), 2.01 (t, J=13.6 Hz, 2H), 1.87-1.80 (m, 1H), 1.75-1.71 (m, 1H), 1.56 (q, J=12.4 Hz, 2H), 1.27-1.05 (m, 6H). ESI MS m/z 538 [C30H33ClFN3O3+H]+; HPLC>99% (AUC), tR=10.78 min.