Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].Cl[C:16]1[C:21]([C:22]#[N:23])=[CH:20][C:19]([C:24]([F:27])([F:26])[F:25])=[CH:18][N:17]=1>O1CCCC1>[C:22]([C:21]1[C:16]([CH:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:17][CH:18]=[C:19]([C:24]([F:27])([F:25])[F:26])[CH:20]=1)#[N:23]
Reactant: N#Cc1cc(C(F)(F)F)cnc1Cl
Reactant: COC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC(C)(C)C)c1ncc(C(F)(F)F)cc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of sodium hydride (7.8 g, 200 mmol) in tetrahydrofuran (100 mL) under nitrogen was added dropwise a solution of tert-butyl methyl malonate (20 mL, 120 mmol) in anhydrous tetrahydrofuran (100 mL) via syringe. The reaction mixture was stirred for 0.5 h before a solution of the intermediate prepared in Step D above (20.1 g, 97.6 mmol) in tetrahydrofuran (200 mL) was added slowly via syringe. The reaction was stirred at room temperature overnight, then quenched with a saturated solution of ammonium chloride. The organic layer was separated and the aqueous layer was extracted with three portions of ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate and concentrated in vacuo. Flash chromatography afforded the title compound. 1H NMR (500 MHz, CDCl3) δ 9.03 (d, J=1.5 Hz, 1H), 8.25 (d, J=2.0 Hz, 1H), 5.25 (s, 1H), 3.86 (s, 3M), 1.52 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C:9]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:14][O:13][C:11](=[O:12])[C:10](=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:9]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15]
Reactant: O=Cc1cccnc1
Reactant: COC(=O)CC(=O)OC(C)(C)C
Agent: O=C(O)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Solvent: C1CCNCC1
Product: COC(=O)C(=Cc1cccnc1)C(=O)OC(C)(C)C
Yield: 48 %

Procedure:
A mixture of pyridine-3-carboxaldehyde (2.72 g), propanedioic acid, 1,1-dimethylethyl methyl ester (4.42 g), piperidine (0.173 g) and benzoic acid (0.155 g) in benzene (100 ml) was heated at reflux with removal of water to a Dean-Stark trap for 12 hours. The cooled mixture was washed with bicarbonate solution, concentrated under vacuum and the residue was purified by column chromatography, eluting with ethyl acetate-hexane (3:7) to afford racemic 2-pyridin-3-ylmethylene-malonic acid tert-butyl ester methyl ester as an oil (3.21 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH:27]1([O:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[C:35]([CH3:40])[CH:34]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][CH2:40][C:35]1[CH:34]=[C:33]([O:32][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:38]=[CH:37][C:36]=1[F:39]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(OC2CCCC2)ccc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(OC2CCCC2)cc1CBr
Temperature: 80 °C
Reaction time: 12 h
Yield: 65.7 %

Procedure:
4.81 g of N-bromosuccinimide (27 mmol) and 0.6 g of benzoyl peroxide (2 mmol) are introduced into a solution of 5 g of 4-cyclopentyloxy-1-fluoro-2-methylbenzene (25.8 mmol) in carbon tetrachloride (130 ml). The mixture is heated at 80° C. for 17 hours, a further 2.29 g of N-bromosuccinimide (12.89 mmol) and 0.3 g of benzoyl peroxide (1 mmol) are then added and heating is continued for 12 hours. The mixture is then cooled to room temperature and filtered through Celite. The mother liquor is concentrated and the black oil obtained is purified by chromatography on a column of silica (eluent: 88/12 cyclohexane/ethyl acetate). 4.63 g of an orange oil are obtained:
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].O[C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:26]2>ClCCl>[F:7][C:8]([F:21])([F:20])[S:9]([O:12][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:26]2)(=[O:11])=[O:10]
Reactant: COC(=O)CC1CCc2cc(O)ccc21
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CC1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.1 %

Procedure:
To a solution of pyridine (820 μL, 10.1 mmol) in dichloromethane (10 mL) cooled to 0° C. trifluoromethanesulfonic anhydride (1.56 mL, 9.28 mmol) was added. The resulting mixture was stirred for 5 min, and methyl (R/S)-(5-hydroxy-indan-1-yl)acetate (1.74 g, 8.44 mmol, from Step C) was added. The reaction mixture was warmed to ambient temperature, stirred for 1 hr and diluted with dichloromethane. The organic layer was washed with H2O, brine and dried over MgSO4. The mixture was filtered and concentrated in vacuo. Purification by flash chromatography (10% EtOAc/hexanes) on SiO2 gave 2.63 g of the title compound as a pale yellow liquid: 1H NMR (CDCl3) δ 1.83-1.88 (m, 1H), 2.47-2.55 (m, 2H), 2.78 (dd, 1H, J=6.0, 15.8 Hz), 2.92-3.01 (m, 2H), 3.62-3.65 (m, 1H), 3.76 (s, 3H), 7.09 (dd, 1H, J=2.3, 8.3 Hz), 7.16 (s, 1H), 7.25 (d, 1H, J=8.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][C:18]=1[C:19]([OH:21])=O)=[C:14]([C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29])[C:13](=[O:30])[CH:12]=[CH:11]2.C(Cl)CCl.C1C=CC2N(O)N=[N:41]C=2C=1.[OH-].[NH4+]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][C:18]=1[C:19]([NH2:41])=[O:21])=[C:14]([C:22]1[C:23]([F:29])=[CH:24][CH:25]=[CH:26][C:27]=1[F:28])[C:13](=[O:30])[CH:12]=[CH:11]2
Reactant: O=C(O)c1ccc2c(-c3c(F)cccc3F)c(=O)ccn2c1-c1ccc(F)cc1F
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1ccc2c(-c3c(F)cccc3F)c(=O)ccn2c1-c1ccc(F)cc1F
Reaction time: 2 h
Yield: 81.1 %

Procedure:
To a solution of 6-(2,4-difluorophenyl)-1-(2,6-difluorophenyl)-2-oxo-2H-quinolizine-7-carboxylic acid (Example 53, 21 mg) in THF was added EDC (20 mg), HOBt (10 mg) and ammonium hydroxide (0.1 mL) at room temperature. After stirring for 2 h, the mixture was diluted with ethyl acetate and washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by silica gel (methylene chloride/methanol=20/1) to give the title compound (17 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:26][C@@H:25]4[C@H:20]([CH2:21][CH2:22][CH2:23][N:24]4[C:27](=O)[CH2:28][CH3:29])[CH2:19][C:18]=3[CH:31]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].B.O1CCCC1.Cl>O1CCCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:26][C@@H:25]4[C@H:20]([CH2:21][CH2:22][CH2:23][N:24]4[CH2:27][CH2:28][CH3:29])[CH2:19][C:18]=3[CH:31]=2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCC(=O)N1CCC[C@@H]2Cc3cc(NS(=O)(=O)c4ccc(C(C)C)cc4)ccc3C[C@H]21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCCN1CCC[C@@H]2Cc3cc(NS(=O)(=O)c4ccc(C(C)C)cc4)ccc3C[C@H]21
Yield: 13.6 %

Procedure:
0.18 mg of trans-4-isopropyl-N-(1-propionyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)-benzenesulfonamide (0.268 mmol) were dissolved in 7 ml of tetrahydrofuran. 1.4 ml of 1 M borane-tetrahydrofuran-complex in tetrahydrofurane were added and the reaction stirred under reflux for 30 min. 2 ml of 2 N aqueous hydrochloric acid were added, the reaction further stirred for 3 h under reflux, and the solvent removed under reduced pressure. Water adjusted to pH 9 with sodium hydroxide was added and the aqueous phase extracted three times with diethyl ether. The combined organic layers were dried over magnesium sulfate, filtered, and the solvent removed. The residue was purified via silica gel chromatography on chroma-bond column with cyclohexane/ethyl acetate 1:3 as eluent to yield 0.0155 g of the desired product
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([CH2:33][C@@H:34]([OH:37])[CH2:35][OH:36])=[CH:8][N:9]2[C:14]1[CH:32]=[CH:31][C:17]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:27]([F:30])([F:29])[F:28])=[C:23]([CH:26]=2)[C:24]#[N:25])=[CH:16][CH:15]=1)[CH2:3][OH:4].CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1>>[OH:1][CH:2]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([CH2:33][C@H:34]([OH:37])[CH2:35][OH:36])=[CH:8][N:9]2[C:14]1[CH:32]=[CH:31][C:17]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:27]([F:30])([F:28])[F:29])=[C:23]([CH:26]=2)[C:24]#[N:25])=[CH:16][CH:15]=1)[CH2:3][OH:4]
Reactant: N#Cc1cc(Oc2ccc(-n3cc(C[C@@H](O)CO)c4c(C(O)CO)cccc43)cc2)ccc1C(F)(F)F
Agent: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Product: N#Cc1cc(Oc2ccc(-n3cc(C[C@H](O)CO)c4c(C(O)CO)cccc43)cc2)ccc1C(F)(F)F

Procedure:
Compound 141 (white solid) was prepared following the procedure described for preparing compound 139 using Ad-mix-α instead of Ad-mix-β: 1H-NMR (400 MHz, CD3OD): δ 7.82 (d, 1H, 8.8 Hz), 7.53-7.57 (m, 3H), 7.34-7.39 (m, 2H), 7.31 (s, 1H), 7.23-7.27 (m, 3H), 7.1-7.14 (m, 1H), 5.44-5.51 (m, 1H), 3.89-3.95 (m, 1H), 3.72-3.76 (m, 1H), 3.47-3.63 (m, 3H), 3.12-3.18 (m, 1H), 2.86-2.97 (m, 1H); LC/MS: m/z=535.2 [M+Na]+ (Calc: 512.5).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])N)=[CH:6][C:5]=1[N+:16]([O-:18])=[O:17].N([O-])=O.[Na+]>C(OCC)(=O)C>[Cl:1][C@@H:9]([CH2:8][C:7]1[CH:14]=[CH:15][C:4]([O:3][CH3:2])=[C:5]([N+:16]([O-:18])=[O:17])[CH:6]=1)[C:11]([OH:13])=[O:12]
Reactant: COc1ccc(C[C@H](N)C(=O)O)cc1[N+](=O)[O-]
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(C[C@H](Cl)C(=O)O)cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 96.4 %

Procedure:
To suspension solution of O-methyl-3-nitro-L-tyrosine.hydrochloride(4.93 g) in 6N aqueous hydrochloric acidwas added under ice-cooling, sodium nitrite (1.97 g) and was stirredat the same temperature for 1 and 1/2 hour and further at roomtemperature for 3 hours. The resultant suspension solution wasextracted with ethyl acetate (50 ml×3). After the ethyl acetate layerwas washed with saturated brine, dried over anhydrous sodiumsulfate. The solvent was evaporated in vacuo to give (S)-2-chloro-3-(4-methoxy-3-nitrophenyl)propionicacid (4.46 g).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O.[F:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[C@@H:35]1[CH2:45][CH2:44][C@@H:43]([OH:46])[C:38]2=[N:39][CH:40]=[CH:41][CH:42]=[C:37]2[C@H:36]1[NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51].[OH-].[Li+]>O.O1CCCC1>[F:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[C@@H:35]1[CH2:45][CH2:44][C@H:43]([OH:46])[C:38]2=[N:39][CH:40]=[CH:41][CH:42]=[C:37]2[C@H:36]1[NH:47][C:48](=[O:54])[O:49][C:50]([CH3:52])([CH3:51])[CH3:53]
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2[C@H](O)CC[C@H]1c1cccc(F)c1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2[C@@H](O)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DIAD (0.356 mL, 1.833 mmol) was added to a tetrahydrofuran (5 mL) solution of 4-nitrobenzoic acid (0.306 g, 1.833 mmol), tert-butyl (5S,6S,9R)-6-(2,3-difluorophenyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ylcarbamate (0.3578 g, 0.916 mmol) at 0° C. The reaction was stirred overnight while it was gradually warmed up to room temperature. Lithium hydroxide (0.110 g, 4.58 mmol) in 10 mL water was added to the reaction mixture. The reaction was stirred at room temperature for 5 h. Volatile components were removed via vacuum and the crude residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed two more times by water before dried (sodium sulfate), filtered and concentrated. The crude was purified by flash chromatography eluting with ethyl acetate in hexane from 0 to 100%. The product was contaminated with some triphenyl phosphine oxide but was carried on to the next step without further purification: MS(ESI)[M+H+]=391.15.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14](=O)[C:13]=34)[N:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:24]>P(Cl)(Cl)(Cl)=O>[Cl:24][C:14]1[C:13]2[N:12]([CH:11]=[N:10][C:9]=2[C:6]2[N:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[O:8][N:7]=2)[C:21]2[C:16]([N:15]=1)=[CH:17][CH:18]=[CH:19][CH:20]=2
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccccc2n2cnc(-c3noc(C4CC4)n3)c12
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nc2ccccc2n2cnc(-c3noc(C4CC4)n3)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
A ground mixture of 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydro-4-oxo-imidazo[1,5-a]quinoxaline (3.76 g, 13 mmol) and phosphorus pentachloride (2.67 g, 13 mmol) in phosphorus oxychloride (10 ml) was stirred for 2 h at 150°-160° C. The resulting solution while still warm was poured into 200 ml of ice and stirred for 1 h. The precipitate was collected by filtration, rinsed with water and dried to give 3.4 g of the title compound, m.p. 140°-150° C. (dec.). The crude product obtained in this way was processed without further purification. (Compound 1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=2[CH3:28])=[CH:16][C:15]=1[Cl:29])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-:32].[K+].[K+].OO.CCCCCCC>CS(C)=O.O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:30])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:32])[NH2:27])=[CH:22][C:21]=2[CH3:28])=[CH:16][C:15]=1[Cl:29])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C#N)ccc1-c1ccc(CN(CCC(C)C)C(=O)OC(C)(C)C)c(Cl)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C(N)=O)ccc1-c1ccc(CN(CCC(C)C)C(=O)OC(C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(3-Chloro-4′-cyano-2′-methyl-biphenyl-4-ylmethyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-3d) was dissolved in 100 mL dimethyl sulfoxide (DMSO) and to which was added potassium carbonate and 4.0 mL of 30% hydrogen peroxide in water. The reaction was stirred at room temperature for 2 hours. The reaction was quenched with water and extracted using ethyl acetate (2 times). The combined organic layers were washed with water (5 times), brine, dried over sodium sulfate, filtered and concentrated. The product (I-3e) was isolated by dissolving the crude product in ethyl acetate and addition of heptane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:14]1[N:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1>C1COCC1>[Br:20][C:17]1[CH:16]=[N:15][C:14]([O:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:19][CH:18]=1
Reactant: Brc1cnc(Br)nc1
Reactant: OCCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(CCOc2ncc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
To a solution of 2-(4-fluorophenyl)ethanol (0.566 g) in THF (10 mL) was added NaH (0.269 g). The mixture was stirred at room temperature for 2 hours, before 2,5-dibromopyrimidine (0.8 g) was added. The mixture was stirred at room temperature for 16 h. The reaction was quenched with water and extracted with EtOAc (2×20 mL). The organic layers were combined, dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel column (Hex/EtOAc=100:5) to give 5-bromo-2-(4-fluorophenethoxy)pyrimidine (0.7 g). LCMS (M+H)=297.0.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16](Cl)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]([NH2:47])=[N:39][CH:38]=2)O1>>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([C:37]2[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:40]([NH2:47])=[N:39][CH:38]=2)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2cnc(N)c3ccccc23)OC1(C)C
Reactant: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(-c3cnc(N)c4ccccc34)nc21

Procedure:
Following General Procedure A for Suzuki coupling, 4-(8-((4-tert-butylpiperazin-1-yl)methyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-amine were reacted to give 510. LCMS: M+H+=519.3
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[N:6]=2)[CH2:2]1.C(N(CC)CC)C.[CH3:23][C:24]1[N:25]=[C:26]2[N:31]=[C:30]([C:32]3[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=3)[C:29]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:28][N:27]2[CH:46]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C>[CH3:23][C:24]1[N:25]=[C:26]2[N:31]=[C:30]([C:32]3[CH:33]=[CH:34][C:35]([CH2:36][N:1]4[CH2:4][CH:3]([C:5]5[N:6]=[C:7]([C:10]6[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=6)[NH:8][N:9]=5)[CH2:2]4)=[CH:38][CH:39]=3)[C:29]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:28][N:27]2[CH:46]=1
Reactant: c1ccc(-c2n[nH]c(C3CNC3)n2)nc1
Reactant: Cc1cn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1cn2cc(-c3ccccc3)c(-c3ccc(CN4CC(c5n[nH]c(-c6ccccn6)n5)C4)cc3)nc2n1
Reaction time: 1 h
Yield: 26.5 %

Procedure:
418.6 mg (1.53 mmol) 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-pyridine×2HCl are dissolved in 12 mL NMP. After addition of 0.43 mL (3.05 mmol) triethylamine the reaction mixture is stirred for one hour. 435 mg (1.38 mmol) 4-(2-Methyl-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-benzaldehyde and 0.19 mL acetic acid are added. The reaction mixture is stirred over night at room temperature. 706.1 mg (3.33 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature over the weekend. The reaction mixture is treated with saturated NaHCO3 and stirred for two hours. The precipitate is filtered off, washed with water, dried and purified by chromatography (silicagel, eluents: dichloromethane/methanol) yielding 182.1 mg (24%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[C:4]([C:13]#[N:14])=[CH:5][NH:6]2.[CH2:15]([O:17][C:18](=[O:38])[CH:19]=[C:20](C1C=CC=C2C=1C(C#N)=CN2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:16]>>[CH2:15]([O:17][C:18](=[O:38])[CH:19]=[C:20]([C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[C:4]([C:13]#[N:14])=[CH:5][NH:6]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:16]
Reactant: COc1cc(Br)c2c(C#N)c[nH]c2c1
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CCOC(=O)C=C(c1ccccc1)c1cc(OC)cc2[nH]cc(C#N)c12
Yield: 54 %

Procedure:
3-(3-Cyano-6-methoxy-1H-indol-4-yl)-3-phenyl-acrylic acid ethyl ester CXXIX (0.81 g, 54% yield) was prepared from 4-bromo-6-methoxy-1H-indole-3-carbonitrile using the procedure described above for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: C([SiH](CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH3:16])=[C:11]([OH:18])[CH:10]=1>C(O)(C(F)(F)F)=O>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([F:8])=[CH:10][C:11]=1[OH:18])[CH3:16]
Reactant: CC(=O)c1ccc(F)cc1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(F)cc1O
Temperature: 25 °C
Yield: 65.9 %

Procedure:
Triethylsilane (3.1 mL, 19.5 mmol) was added dropwise to a solution of 1-(4-fluoro-2-hydroxyphenyl)ethanone (1 g, 6.5 mmol) in TFA (13 mL). The mixture was stirred at ambient temperature and concentrated. Purification by flash chromatography (19:1, hexanes/EtOAc) afforded 600 mg of 2-ethyl-5-fluorophenol as a clear oil. Et3N (1.2 mL, 8.6 mmol) and TBSCl (715 mg, 4.7 mmol) were added to a solution of intermediate 386.2 (600 mg, 4.3 mmol) in CH2Cl2 and the solution was stirred overnight. Water was added to the mixture and it was extracted with CH2Cl2. The organics were combined, washed with brine, dried (Na2SO4) and concentrated. Purification by flash chromatography (hexanes) yielded 768 mg of Intermediate 386.3 as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.23 (s, 6H) 1.01 (s, 9H) 1.15 (t, J=7.46 Hz, 3H) 2.55 (q, J=7.58 Hz, 2H) 6.49 (dd, J=10.52, 2.45 Hz, 1H) 6.59 (dt, J=8.38, 2.57 Hz, 1H) 7.01-7.08 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](O)=O)[CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[NH2:18].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]2[NH:18][C:17]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:11]=2)[N:7]=1
Reactant: Nc1ccncc1N
Reactant: O=C(O)c1cccc(Cl)n1
Agent: CN(C)C(On1nnc2ccccc21)=[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: Clc1cccc(-c2nc3cnccc3[nH]2)n1
Temperature: 120 °C
Reaction time: 48 h
Yield: 18.2 %

Procedure:
6-Chloropyridine-2-carboxylic acid (2.00 g, 12.7 mmol), 3,4-diaminopyridine (1.52 g, 14.0 mmol) and DIPEA (2.43 mL, 14.0 mmol) were dissolved in DMF (20 mL) and HBTU (5.29 g, 14.0 mmol) was added. The reaction mixture was stirred for 48 h and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with 1 M aq Na2CO3 (2×100 mL), water (100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography, dissolved in AcOH and heated at 120° C. for 50 min. The solvent was removed in vacuo and the residue was suspended in 1 M aq Na2CO3 (50 mL) and extracted with EtOAc (5×50 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography and recrystallisation from MeOH to give the title compound (534 mg, 37%) as a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[N:11]=[C:10]([CH3:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][C:15]=2[O:22][CH3:23])=[C:8]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:7]=1>C(Cl)Cl>[Cl:3][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:9]2[C:8]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[N:7][C:6]([NH2:5])=[N:11][C:10]=2[CH3:12])=[C:15]([O:22][CH3:23])[CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CO)cc1OC
Solvent: ClCCl
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CCl)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (0.239 mL) was added portionwise to a solution of the product from step (v) (0.94 g) in DCM (20 mL) under nitrogen. The resulting solution was stirred at rt for 1 h. The solvent was evaporated under reduced pressure to give the subtitle compound as a colourless gum 0.99 g that was used without purification.