Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[C:17]([O:20][CH2:21][CH3:22])(=O)[CH3:18]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:20]1[CH:21]=[CH:22][CH:18]=[C:17]1[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(Cl)n1
Reactant: CCOC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#Cc1cccc(-c2ccco2)n1
Reaction time: 0.17 h
Yield: 87 %

Procedure:
6-Chloro-2-pyridinecarbonitrile (0.90 g, 6.5 mmol) and 2-furanboric acid (1.1 g, 9.8 mmol) were dissolved in toluene (80 ml)-ethanol (205 ml), and potassium carbonate (2.2 g, 15.9 mmol) and water (20 ml) were added thereto. The mixture was deairated under reduced pressure for 10 minutes. Tetrakis(triphenylphosphine)palladium (0) (0.36 g, 0.31 mmol) was added to the reaction mixture under argon atmosphere, and the mixture was refluxed for 13 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was separated, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (5:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (0.97 g, 87%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([N:26]1[CH:30]=[C:29]([NH2:31])[CH:28]=[N:27]1)[CH3:25]>C(O)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:31][C:29]4[CH:28]=[N:27][N:26]([CH2:24][CH3:25])[CH:30]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Reactant: CCn1cc(N)cn1
Solvent: CCCCO
Product: CCn1cc(Nc2ncnc3[nH]c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc23)cn1
Temperature: 120 °C

Procedure:
A mixture of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (110 mg, 0.33 mmol) and 1-ethyl-4-amino-1H-pyrazole (44 mg, 0.39 mmol) in 1-butanol (3 mL) was heated at 120° C. overnight, LC-MS showed the desired product and some de-Boc product. After the mixture was cooled to rt, it was diluted with methylene chloride (3 ml), then N,N-diisopropylethylamine (0.11 mL, 0.66 mmol) and di-tert-butyldicarbonate (72 mg, 0.33 mmol) were added, the resulting mixture was stirred at rt for 30 min. The mixture was diluted with EtOAc (30 mL), then washed with brine (20 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized with EtOAc to give the title compound as an off-white solid. LC-MS (ES, Pos.): 410 [MH+]. 1H NMR (CDCl3, 400 MHz): δ=1.51 (s, 9H), 1.56 (t, J=7.3 Hz, 3H), 2.50 (m, 2H), 3.66 (m, 2H), 4.16 (m, 2H), 4.22 (q, J=7.3 Hz, 2H), 6.04 (s, 1H), 6.17 (s, 1H), 6.57 (s, 1H), 7.56 (s, 1H), 7.95 (s, 1H), 8.38 (s, 1H), 10.96 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[Cl:11][C:12]1[N:13]=[C:14](Cl)[C:15]2[CH:21]=[CH:20][CH:19]=[N:18][C:16]=2[N:17]=1.C(N(CC)C(C)C)(C)C>ClCCCl.O>[Cl:11][C:12]1[N:13]=[C:14]([NH:5][CH2:4][C:3]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=2[Cl:1])[C:15]2[CH:21]=[CH:20][CH:19]=[N:18][C:16]=2[N:17]=1
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: Clc1nc(Cl)c2cccnc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCCl
Product: Clc1ccc(CNc2nc(Cl)nc3ncccc23)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.5 %

Procedure:
2,4-Dichlorobenzylamine (211 mg, 1.2 mmol) was added to the stirred solution of 2,4 dichloro-pyrido[2,3-d]pyrimidine(200 mg, 1 mmol) and N,N-diisopropylethylamine (266 μL, 1.5 mmol) in 1,2-dichloroethane (5 mL). The reaction mixture was stirred at room temperature for 12 h and then diluted with water (10 mL). The aqueous layer was extracted with CH2Cl2 and the combined organic layer was washed with water (2×10 mL), dried (Na2SO4) and concentrated in vaccuo to give (2-Chloro-pyrido[2,3-d]pyrimidin-4-yl)-(2,4-dichloro-benzyl)-amine as a yellow oil (185 mg) and was used as such in the next reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:24][C:25]1[CH:26]=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1)[CH3:23]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:31][C:28]3[N:29]=[CH:30][C:25]([O:24][CH2:22][CH3:23])=[CH:26][N:27]=3)=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cnc(N)nc1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Br)c(F)c2)C1
Solvent: C1COCCO1
Product: CCOc1cnc(Nc2ccc(C3CN(C(=O)OC(C)(C)C)CCO3)cc2F)nc1
Temperature: 120 °C
Yield: 18.4 %

Procedure:
To a 10 ml glass vial was added (RS)-2-(4-bromo-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (70 mg, Example 96(e)) and 5-ethoxy-2-pyrimidinamine (40.6 mg, CAS 39268-74-1) in dioxane (2 ml). The reaction mixture was purged with argon for 5 min. 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (13.6 mg), tris(dibenzylideneacetone)dipalladium(0) (7.12 mg) and sodium tert-butoxide (21.0 mg) were then added. The vial was capped and heated at 120° C. for 16 h. The reaction mixture was then filtered through sintered glass and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in hexanes) to afford (RS)-2-[4-(5-ethoxy-pyrimidin-2-ylamino)-3-fluoro-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (15 mg, 18%) as a yellow gum. MS (ISP): 441.4 ([M+Na]+), 419.3 ([M+H]+).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([CH3:31])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][N:57]1[CH2:62][CH2:61][CH:60]([NH2:63])[CH2:59][CH2:58]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:63][CH:60]5[CH2:61][CH2:62][N:57]([CH3:56])[CH2:58][CH2:59]5)=[O:27])=[C:24]([CH3:31])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)ccc1C(=O)O
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1cc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)ccc1C(=O)NC1CCN(C)CC1

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-methylbenzoic acid as described in the general procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36-1.77 (m, 11H) 1.98 (m, 4H) 2.16 (s, 3H) 2.31 (s, 3H) 2.75 (d, J=11 Hz, 2H) 3.17 (br. s., 2H) 3.67 (d, J=7 Hz, 1H) 4.03 (t, J=14 Hz, 3H) 4.81 (m, 1H) 7.22 (d, J=8 Hz, 1H) 7.46 (d, J=8 Hz, 1H) 7.68 (br. s., 1H) 7.99 (d, J=8 Hz, 1H) 8.25 (s, 1H) 9.51 (br. s., 1H). [M+H] calc'd for C27H35F2N7O2, 528. found 528.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH:13]=[C:12]([C:14]([OH:16])=O)[N:11]=[CH:10]2)[CH:4]=1.[NH:19]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[F:17][C:2]([F:1])([F:18])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH:13]=[C:12]([C:14]([N:19]3[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:20]3)=[O:16])[N:11]=[CH:10]2)[CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=C(O)c1cn(-c2cc(C(F)(F)F)ccn2)cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)c2cn(-c3cc(C(F)(F)F)ccn3)cn2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[4-(trifluoromethyl)pyridin-2-yl]-1H-imidazole-4-carboxylic acid (120 mg, 0.47 mmol) and tert-butyl (3S)-pyrrolidin-3-ylcarbamate (87 mg, 0.47 mmol) in DMF (3 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (210 mg, 0.47 mmol) followed by triethylamine (0.20 mL, 1.4 mmol). The reaction was stirred at room temperature overnight and purified by HPLC to give the title compound. MS (M+H) 426.3.
Reaction SMILES: [CH3:1][N:2]([CH3:11])P(N(C)C)(N(C)C)=O.CN([CH:15]([CH3:20])[C:16]([O:18][CH3:19])=[O:17])C.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:21]([CH:15]([CH2:20][N:2]([CH3:11])[CH3:1])[C:16]([O:18][CH3:19])=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)C(C)N(C)C
Reactant: BrCc1ccccc1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccccc1)CN(C)C
Reaction time: 0.5 h

Procedure:
The reaction mixture is stirred for 1/2 hour at the same temperature, a solution of 179 g of hexamethylphosphoramide in 200 ml of tetrahydrofuran is added and stirring is continued for 1/2 hour at -78°. At the same temperature a solution of 125 g of methyl N,N-dimethylaminopropionate in 200 ml of tetrahydrofuran is then added dropwise and stirring is continued for 20 minutes. A solution of 171 g of benzyl bromide in 300 ml of tetrahydrofuran is then added, again at -78°. The solution is stirred at this temperature for 2 hours and then quenched, first with 250 ml of saturated aqueous ammonium chloride and then 250 ml of saturated aqueous sodium chloride solution. To this is added 1500 ml of ether. The layers are separated and the aqueous layer is extracted with 4×200 ml of ether. The ether extract is dried over magnesium sulfate and evaporated to dryness. The resulting oil is redissolved in 300 L ml of ether, the ether solution is washed with 100 ml of water and the aqueous layer is reextracted with 3×100 ml ether. The combined ether solutions are dried over magnesium sulfate and evaporated to dryness in yield an oil which is purified by fractional distillation to yield pure methyl 2-benzyl-3-dimethylaminopropionate, b.p. 104°/0.2-0.4 mm Hg.
Reaction SMILES: [CH2:1]([N:3]1CCCCC1)[CH3:2].[CH2:9]([O:16][C:17]([NH:19][C@H:20]([C:22]([OH:24])=O)[CH3:21])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.ClC(OC(CC)C)=O.C(N)C>O1CCCC1>[CH2:1]([NH:3][C:22](=[O:24])[C@H:20]([CH3:21])[NH:19][C:17]([O:16][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:18])[CH3:2]
Reactant: CCN1CCCCC1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCC(C)OC(=O)Cl
Agent: CCN
Solvent: C1CCOC1
Product: CCNC(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: -6 °C
Reaction time: 0.13 h

Procedure:
14 ml. of N-ethyl piperidine was added to a solution of 23.3 grams of benzyloxycarbonyl alanine in 100 ml. of tetrahydrofuran and, after cooling to -10 degrees C., 14 ml. of sec. butyl chlorformate was added. Next, the mixture was stirred for 8 minutes and cooled to -6 degrees C. Then 30 ml. of a 4.1 solution of ethylamine in tetrahydrofuran was added. After 30 minutes of stirring at 0 degrees C. and 2 hours of stirring at room temperature, the reaction solution was evaporated, gradually shaken with a 5% solution of sodium hydrogen carbonate, with water, dried with anhydrous sodium carbonate, and evaporated. The evaporation residue was crystallized from ethyl acetate (30 ml.) and petroleum ether. 18.1 g of a product having a melting point of 116 to 117 degrees C. was obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:32]([NH:34][C@H:35]([C:38]([NH:40][C@H:41]([C:46]([NH:48][C@H:49]([C:62]([NH:64][C@H:65]([C:71]([NH:73][C@H:74]([C:79]([NH:81][C@H:82]([C:92]([NH:94][C@H:95]([C:100]([NH:102][C@H:103]([C:116]([NH:118][C@H:119]([C:141]([NH:143][C@H:144]([C:149]([O:151]C(C)(C)C)=[O:150])[CH2:145][C:146](=[O:148])[NH2:147])=[O:142])[CH2:120][S:121]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:117])[CH2:104][C:105]1[CH:110]=[CH:109][C:108]([O:111]C(C)(C)C)=[CH:107][CH:106]=1)=[O:101])[CH2:96][C:97](=[O:99])[NH2:98])=[O:93])[CH2:83][CH2:84][C:85](=[O:91])[O:86]C(C)(C)C)=[O:80])[CH2:75][CH:76]([CH3:78])[CH3:77])=[O:72])[CH2:66][CH2:67][C:68](=[O:70])[NH2:69])=[O:63])[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57]C(C)(C)C)=[CH:53][CH:52]=1)=[O:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39])[CH2:36][OH:37])=[O:33])[CH2:11][S:12]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].FC(C(O)=O)(F)F.O>C(S)C.FC(F)(F)C(O)=O>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:32]([NH:34][C@H:35]([C:38]([NH:40][C@H:41]([C:46]([NH:48][C@H:49]([C:62]([NH:64][C@H:65]([C:71]([NH:73][C@H:74]([C:79]([NH:81][C@H:82]([C:92]([NH:94][C@H:95]([C:100]([NH:102][C@H:103]([C:116]([NH:118][C@H:119]([C:141]([NH:143][C@H:144]([C:149]([OH:151])=[O:150])[CH2:145][C:146](=[O:148])[NH2:147])=[O:142])[CH2:120][SH:121])=[O:117])[CH2:104][C:105]1[CH:106]=[CH:107][C:108]([OH:111])=[CH:109][CH:110]=1)=[O:101])[CH2:96][C:97](=[O:99])[NH2:98])=[O:93])[CH2:83][CH2:84][C:85](=[O:86])[OH:91])=[O:80])[CH2:75][CH:76]([CH3:77])[CH3:78])=[O:72])[CH2:66][CH2:67][C:68](=[O:70])[NH2:69])=[O:63])[CH2:50][C:51]1[CH:52]=[CH:53][C:54]([OH:57])=[CH:55][CH:56]=1)=[O:47])[CH2:42][CH:43]([CH3:44])[CH3:45])=[O:39])[CH2:36][OH:37])=[O:33])[CH2:11][SH:12])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](N)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CC(N)=O)C(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCS
Product: CC[C@H](C)[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3.429 g (1.5 mmoles) of H-Ile-Cys(Trt)-Ser-Leu-Tyr(But)-Gln-Leu-Glu(OBut)-Asn-Tyr(But)-Cys(Trt)-Asn-OBut trifluoroacetate are dissolved in a mixture of 19 ml of ethylmercaptan and 19 ml of trifluoroacetic acid. The reaction mixture is stirred for 4 hours at room temperature and is then poured into 250 ml of water, while stirring. The precipitate is filtered off, washed with ether and dried. It is then triturated with ether, filtered off and dried. Yield 1.964 g. This substance is then deblocked once more as described above. Yield 1.6 g (61%). In total, a further 330 mg of substance was obtainable from the filtrates after extraction with ether and freeze-drying.
Reaction SMILES: [C:1]([Li])#[C:2][CH3:3].[F:5][C:6]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9]>O=[Mn]=O>[F:5][C:6]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:7]=1[C:8](=[O:9])[C:1]#[C:2][CH3:3]
Reactant: [Li]C#CC
Reactant: O=Cc1cccc(F)c1F
Agent: O=[Mn]=O
Product: CC#CC(=O)c1cccc(F)c1F

Procedure:
Intermediate 40 was prepared (as described above for intermediate 36) from 1-propynyllithium, 500 mg of 2,3-difluorobenzaldehyde, and 1.5 g of MnO2 to yield 440 mg of the title compound homogeneous by TLC (Rf=0.5, 2/1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ7.82-7.86 (m, 1H), 7.43-7.35 (m 1H), 7.22-7.15 (m, 1H), 2.15 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]4[CH:17]([C:7]=3[C:6]=2[CH:5]=[C:4]([CH3:18])[CH:3]=1)[CH2:16][CH2:15][CH2:14]4.[H-].[Na+].[O:21]1[CH2:23][CH:22]1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH3:1][C:2]1[C:10]2[N:9]([CH2:23][CH:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[OH:21])[C:8]3[CH2:11][CH2:12][N:13]4[CH:17]([C:7]=3[C:6]=2[CH:5]=[C:4]([CH3:18])[CH:3]=1)[CH2:16][CH2:15][CH2:14]4
Reactant: c1cc(C2CO2)ccn1
Reactant: Cc1cc(C)c2[nH]c3c(c2c1)C1CCCN1CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c2c(c1)c1c(n2CC(O)c2ccncc2)CCN2CCCC12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 18.9 %

Procedure:
8,10-Dimethyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (700 mg, 2.92 mmol) in DMF (20 mL) was stirred at 0° C. for 5 min. NaH (580 mg, 14.60 mmol) was added slowly at 0° C. After 10 min. stirring, 4-(oxiran-2-yl)pyridine (710 mg, 5.87 mmol) was added and the reaction mixture was stirred at RT for 15 h. The reaction mixture was poured in ice-cold water (150 mL) and extracted with EtOAc (3×200 mL). The combined organic layer was washed with water (6×300 mL), dried over anhydrous sodium sulfate and concentrated to obtain semi-solid residue that was washed with hexane (3×20 mL). The residue was suspended in ether (30 mL) stirred for 1 h. The suspension was filtered to give 200 mg of 2-(8,10-dimethyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)-1-(pyridin-4-yl)ethanol. 1H NMR (CD3OD, HCl salt) δ (ppm): 8.79 (d, 2H), 8.03 (d, 2H), 7.13 (s, 1H), 6.82 (s, 1H), 5.22 (dd, 1H), 5.01 (t, 1H), 4.67 (dd, 1H), 4.48 (dd, 1H), 4.79 (m, 1H), 3.64 (t, 2H), 3.4 (m, 3H), 2.9 (m, 1H), 2.73 (s, 3H), 2.37 (s, 3H), 2.22 (m, 3H). Separation by chiral HPLC provided diastereomers II-125a-b.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[CH:21]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.B(Br)(Br)[Br:29].O>C(Cl)Cl>[Br:29][CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:17][CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: BrB(Br)Br
Reactant: COc1cccc(CCNc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Solvent: O
Solvent: ClCCl
Product: Oc1cccc(CCNc2nc(Nc3cccc(CBr)c3)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of {3-[(5-chloro-4-{[2-(3-methoxyphenyl)ethyl]amino}pyrimidin-2-yl)amino]phenyl}methanol (0.30 g, 0.78 mmol) in methylene chloride (5.0 mL) was added slowly a solution of boron tribromide in methylene chloride (2.3 mL, 2.3 mmol, 1.0 M) at 0° C. The mixture was allowed to warm up to rt and stirred overnight. The resultant mixture was cooled in a dry ice bath when water was added. The mixture was allowed to warm up to rt. Both aqueous layer (no product in it) and organic layer (containing small amounts of product, plus byproducts) were checked and discarded. The remaining solid residue was triturated with cold EtOAc and then filtered. The cake was washed with cold EtOAc and then H2O to give the desired product as a white powder (0.30 g, 89%). LCMS for C19H19BrClN4O (M+H)+: m/z=433.0, 435.0, 437.0. 1H NMR (400 MHz, CD3OD): δ 7.94 (s, 1H), 7.60 (s, 1H), 7.40 (m, 2H), 7.32 (m, 1H), 7.05 (m, 1H), 6.60 (m, 3H), 4.54 (s, 2H), 3.76 (t, J=6.4 Hz, 2H), 2.85 (t, J=7.6 Hz, 2H).
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][N:11]=[C:10]([NH2:14])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:16]>C(Cl)Cl>[N:14]([C:10]1[CH:9]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:13]=[CH:12][N:11]=1)=[C:15]=[S:16]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Nc1cc(Oc2ccccc2)ncn1
Solvent: ClCCl
Product: S=C=Nc1cc(Oc2ccccc2)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 192.5 %

Procedure:
A mixture of 6-phenoxypyrimidin-4-amine (0.288 g, 1.538 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (0.357 g, 1.538 mmol) in DCM was stirred at rt for 18 h. The pale orange mixture was purified by silica gel chromatography (5-35% ethyl acetate-hexanes) to afford 4-isothiocyanato-6-phenoxypyrimidine (0.55 g, 2.96 mmol, 85% yield) a yellow oil. LCMS R.T.=2.78; [M+H]+=229.94.
Reaction SMILES: Cl[O-].[C-:3]#[N:4].[Na+].[C-]#N.[Cl:8]/[C:9](/[C:19]([F:22])([F:21])[F:20])=[CH:10]\[C@@H:11]1[C@H:13]([C:14](Cl)=[O:15])[C:12]1([CH3:18])[CH3:17].[O:23]([C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O.CCCCCC.C(Cl)Cl>[CH3:17][C:12]1([CH3:18])[CH:13]([C:14]([O:34][CH:33]([C:32]2[CH:35]=[CH:36][CH:37]=[C:30]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:31]=2)[C:3]#[N:4])=[O:15])[CH:11]1/[CH:10]=[C:9](\[Cl:8])/[C:19]([F:22])([F:21])[F:20]
Reactant: [C-]#N
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCCCCC
Solvent: O
Solvent: ClCCl
Product: CC1(C)C(/C=C(\Cl)C(F)(F)F)C1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 97.8 %

Procedure:
A 2 liter jacketed non-baffled split-neck reaction flask was equipped with an overhead stirrer (turbine), thermometer, condenser, two syringe pumps and was vented to a caustic/hypochlorite scrubber. To the reactor was charged sodium cyanide (29.4 g, 0.59 mol) in water (101 ml) and the reaction was agitated (100 rpm) for 10 min to ensure complete dissolution of the cyanide. Hexane (79 ml) was added to the reactor, then the reaction mass was cooled to 10° C. and the agitation rate adjusted to 235 rpm. 1R cis-Z 3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethyl cyclopropanecarboxylic acid chloride (133.2 g, 0.50 mol) and 3-phenoxybenzaldehyde (99 g, 0.50 mol) were added simultaneously to the reactor over 3 hr. Once the addition was complete the reaction was agitated for a further 17 hr at 10° C. GC analysis indicated the presence of un-reacted 3-phenoxybenzaldehyde, so a further charge of 1R cis-Z 3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethyl cyclopropanecarboxylic acid chloride was made (3.6 g, 0.014 mol) and the reaction agitated for a further 2 hr. The reaction mass was diluted with hexane (156 ml), and the aqueous layer allowed to settle before separation. Residual cyanide in the organic phase was destroyed with sodium hypochlorite liquor to a positive show on starch/iodide paper. The positive show for hypochlorite was removed with sodium bisulphite and the aqueous phase again settled and separated. The product oil weighed 228 g giving a yield of 97.8%. The composition of the product was—1R cis-Z-α-S diastereomer 45.5% and 1R cis-Z-α-R diastereomer 45.9%. GCMS (both diastereomers); 449 (M+), 349, 225, 208, 197, 181, 141 [α]D20: +29.8° (c=0.0104, DCM)
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:32])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[C@H:28]([CH2:29][OH:30])[CH2:27][O:26][C:25]5=[O:31])=[N:22][CH:23]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:33]I>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH3:32])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[C@H:28]([CH2:29][O:30][CH3:33])[CH2:27][O:26][C:25]5=[O:31])=[N:22][CH:23]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CI
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3CO)nc2)CC1
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)cn1

Procedure:
By reaction and treatment in the same manner as in Example 73 and using (R)-3-{5-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-4-hydroxymethyloxazolidin-2-one (144 mg) described in Example 245 and methyl iodide (38 μL), the title compound (85 mg) was obtained.