Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C@@H:11]([CH3:20])[CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH:3]=1.[Br:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([CH:33]=1)[C:27](N(OC)C)=[O:28]>>[Br:21][C:22]1[CH:33]=[C:26]([C:27]([C:2]2[C:10]3[CH:9]=[N:8][CH:7]=[N:6][C:5]=3[N:4]([C@@H:11]([CH3:20])[CH2:12][O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[CH:3]=2)=[O:28])[CH:25]=[N:24][CH:23]=1
Reactant: CON(C)C(=O)c1cncc(Br)c1
Reactant: C[C@@H](COC1CCCCO1)n1cc(I)c2cncnc21
Product: C[C@@H](COC1CCCCO1)n1cc(C(=O)c2cncc(Br)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Preparation 24 using 5-iodo-7-[(1S)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 18) and 5-bromo-N-methoxy-N-methylnicotinamide to afford the title compound as a colourless oil in 32% yield, 181 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([CH3:32])[CH:24]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: Cc1cccc(B(O)O)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cccc(-c2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)c1
Yield: 83.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), m-tolylboronic acid (0.025 g; 0.176 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) furnished 0.057 g (83%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][N:11]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH3:10][N:11]([CH:20]1[CH2:21][CH2:22][N:23]([C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH2:24][CH2:25]1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C=Nc1ccccc1
Reactant: CN(CCc1ccccc1)C1CCNCC1
Solvent: ClC(Cl)Cl
Product: CN(CCc1ccccc1)C1CCN(C(=O)Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 ml of phenyl isocyanate was added to a solution of 1.0 g of 4-[N-methyl-N-(2-phenylethyl)amino]piperidine in 15 ml of chloroform. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added diethyl ether for crystallization. The resulting crystals were collected by filtration and recrystallized from ethyl acetate to obtain 0.7 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-anilinocarbonylpiperidine as colorless prism-like crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][O:10]C)[CH:5]=[CH:4][C:3]=1[C:12]1[S:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[C:16]([C:21]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22]1)[N:15]=2.Cl>O1CCOCC1.C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[S:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[C:16]([C:21]1([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][CH2:23]1)[N:15]=2
Reactant: COC=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=CCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
2-(2-Fluoro-4-(2-methoxyvinyl)phenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (570 mg, 1.42 mmol) was dissolved in 1,4-dioxane (14 mL) before concentrated hydrochloric acid (1.18 mL, 14.16 mmol) was added and stirred at 65° C. for 1 h. The reaction mixture was diluted with 100 mL of DCM, added to a separatory funnel, partitioned with 1 N NaOH (aqueous), washed with sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to give 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)acetaldehyde after flash chromatography. MS (ESI) m/z: Calculated: 388.1; Observed: 389.0 (M++H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[N:25]=[C:24]([NH2:29])[N:23]=1>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[N:25]=[C:24]([NH:29][CH2:3][C:4]2[N:8]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]3=[N:6][C:5]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:23]=1
Reactant: Nc1nc(F)cc(F)n1
Reactant: Cc1ccc2nc(-c3ccc(F)cc3)c(CCl)n2c1
Agent: Cl
Product: Cc1ccc2nc(-c3ccc(F)cc3)c(CNc3nc(F)cc(F)n3)n2c1
Yield: 39 %

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridine hydrochloride and 4,6-difluoropyrimidin-2-amine. (0.23 g, 39% yield), M/e+ 370.1 for C19H14F3N5 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:25]3[CH:26]=[CH:27][C:28]4[C:32]([CH:33]=3)=[N:31][N:30]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:29]=4)[CH:9]=[C:10]([CH:11]3[CH2:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[ClH:41]>CO.O1CCOCC1>[ClH:41].[NH:14]1[CH2:15][CH2:16][CH2:17][CH:11]([C:10]2[N:6]3[C:7]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)=[C:8]([C:25]3[CH:26]=[CH:27][C:28]4[C:32]([CH:33]=3)=[N:31][N:30]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:29]=4)[CH:9]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ncnn2c(C3CCCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]azepane-1-carboxylate in MeOH (10 mL) was added 4M HCl in dioxane (5 mL). The mixture was stirred at rt for 5 h. The mixture was concentrated to dryness to afford 924 mg (100%) of the desired product, which contained trace impurities. LC-MS [M+H]+=438.28, RT=2.10 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1.S(=O)(=O)(O)O.[H][H]>CO.[Pd]>[NH2:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH2:1])=[O:18])=[CH:15][CH:14]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(C(=O)Nc2ccccc2N)cc1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Product: NCc1ccc(C(=O)Nc2ccccc2N)cc1
Yield: 96.2 %

Procedure:
To a solution of N-(2-aminophenyl)-4-cyanobenzamide (237 mg, 1 mmol) in methanol (40 ml) was added sulfuric acid (196 mg, 1 mmol) and 5% palladium on charcoal (0.20 g). The mixture was stirred under an atmosphere of hydrogen at room temperature until hydrogen uptake ceased. The mixture was filtered through celite, and the filtrate was neutralized with 1 N NaOH solution in methanol (2 ml). The resulting mixture was filtered, and the filtrate was evaporated under vacuum to give the title compound (232 mg, 96% yield) as a grey solid. LC-MS (m/z) 242 (M+1).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[C:15]([N:17]2[CH2:30][CH2:29][C:20]3[NH:21][C:22]4[C:23]([OH:28])=[CH:24][CH:25]=[CH:26][C:27]=4[C:19]=3[CH2:18]2)=[O:16])=[O:8])[CH2:5][CH2:4]1)#[N:2].Br[CH2:32][CH2:33][CH3:34].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[C:15]([N:17]2[CH2:30][CH2:29][C:20]3[NH:21][C:22]4[C:23]([O:28][CH2:32][CH2:33][CH3:34])=[CH:24][CH:25]=[CH:26][C:27]=4[C:19]=3[CH2:18]2)=[O:16])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2CCCC[C@H]2C(=O)N2CCc3[nH]c4c(O)cccc4c3C2)CC1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1cccc2c3c([nH]c12)CCN(C(=O)[C@@H]1CCCC[C@H]1C(=O)NC1(C#N)CC1)C3
Yield: 60 %

Procedure:
(1R,2R)-2-(6-Hydroxy-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carbonyl)-cyclohexanecarboxylic acid (1-cyano-cyclopropyl)-amide (102 mg, 0.25 mmol), 1-bromopropane (28.0 uL, 0.30 mmol) and potassium carbonate (35.0 mg, 0.25 mmol) in acetone (5 mL) were heated to reflux for 3 h. Added further 1-bromopropane (58.0 uL, 0.60 mmol) and potassium carbonate (70.0 mg, 0.50 mmol) and heated overnight. The reaction darkened significantly and LCMS indicated 60% required product and 40% SM. The reaction was filtered and the liquors evaporated to dryness before redissolving in acetonitrile and purifying by preparative HPLC (0.5% HCOOH, CH3CN/H2O gradient) to give a brown glass (21.3 mg, 18%)
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([O:26][CH3:27])=[C:7]([CH:13]([N:15]3[C:19]4=[N:20][CH:21]=[N:22][C:23]([NH2:24])=[C:18]4[C:17]([CH3:25])=[N:16]3)[CH3:14])[CH:8]=[C:9]([Cl:12])[C:10]=2[Cl:11])[CH2:2]1.C([BH3-])#N.[Na+].[CH:32](=O)[CH3:33].C(O)(=O)C>CO>[Cl:11][C:10]1[C:9]([Cl:12])=[CH:8][C:7]([CH:13]([N:15]2[C:19]3=[N:20][CH:21]=[N:22][C:23]([NH2:24])=[C:18]3[C:17]([CH3:25])=[N:16]2)[CH3:14])=[C:6]([O:26][CH3:27])[C:5]=1[CH:3]1[CH2:2][N:1]([CH2:32][CH3:33])[CH2:4]1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(Cl)c1C1CNC1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCN1CC(c2c(Cl)c(Cl)cc(C(C)n3nc(C)c4c(N)ncnc43)c2OC)C1
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
A solution of 1-[1-(3-azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.098 mmol) in methanol (2.6 mL) was treated with sodium cyanoborohydride (15 mg, 0.25 mmol) followed by acetaldehyde (22 μL, 0.39 mmol) and stirred at 20° C. for 20 min. The reaction mixture was quenched with acetic acid (130 μL, 2.3 mmol), diluted with methanol, and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product as a mixture of enantiomers. This racemic mixture was separated by chiral HPLC (RT=18.6 min and 22.0 min; Phenomenex Lux Cellulose C-4 column, 21.2×250 mm, 5 micron particle size, eluting with 5% ethanol in hexanes at 18 ml/min, 2.5 mg/inj) to give the desired peak 1 isomer (11 mg, 26%). 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.45 (s, 1H), 7.33 (br s, 2H), 6.21 (q, J=6.9 Hz, 1H), 3.98-3.77 (m, 3H), 3.57 (s, 3H), 2.92-2.83 (m, 1H), 2.79-2.72 (m, 1H), 2.55 (s, 3H), 2.35-2.22 (m, 2H), 1.70 (d, J=7.1 Hz, 3H), 0.86 (t, J=7.1 Hz, 3H). LCMS for C20H25Cl2N6O (M+H)+: m/z=435.1; Found: 435.0.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH3:20][O:21][C:22]([CH:24]1[CH2:28][CH:27]([OH:29])[CH2:26][NH:25]1)=[O:23]>>[CH3:20][O:21][C:22]([CH:24]1[CH2:28][CH:27]([OH:29])[CH2:26][N:25]1[C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19])=[O:23]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: COC(=O)C1CC(O)CN1
Product: CCc1cc(-c2cncc(C(=O)N3CC(O)CC3C(=O)OC)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 4-hydroxy-pyrrolidine-2-carboxylic acid methyl ester to afford the title compound. MS: m/e=386 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[CH2:32]([O:31][C:29](=[O:30])[NH:18][CH2:17][CH:14]1[CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:16]=2[O:15]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2cccc(-c3ccccc3Cl)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3ccccc3Cl)c2O1)OCc1ccccc1
Yield: 75.5 %

Procedure:
Treatment of (±)-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.743 g 2.52 mmol) with diisopropylethylamine (0.488 g, 3.77 mmol) and benzyl chloroformate (0.472 g, 2.77 mmol) generally according to the procedure described for Intermediate 12 afforded 0.749 g (76%) (±)-benzyl[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a white solid. mp 155-157° C.; Anal. calcd. for C23H20ClNO3: C, 70.14; H, 5.12; N, 3.56. Found: C, 70.1; H, 5.15; N, 3.37. Chiral HPLC separation of (±)-benzyl[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, hexane:ethanol 1:1) provided two fractions. Fraction 1 (Rt=9.655 min, Chiralcel OJ, hexane:ethanol 1:1); Fraction 2 (Rt=16.300 min, Chiralcel OJ, hexane:ethanol 1:1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](Cl)(=[O:30])[C:27]([Cl:29])=[O:28]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[CH:13]=[C:12]2[C:26](=[O:30])[C:27]([Cl:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cn2ccc3cc(OCc4ccccc4)ccc32)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: O=C(Cl)C(=O)c1cn(Cc2ccc(F)cc2)c2ccc(OCc3ccccc3)cc12

Procedure:
A solution of 5-benzyloxy-1-(4-fluorobenzyl)indole in 200 ml of THF is cooled under a N2 atmosphere to 0° C. While stirring and cooling further, a solution of oxalyl chloride in 100 ml of THF is added dropwise in such a way that the internal temperature does not exceed 10° C. The reaction mixture is then boiled under reflux for 2 hours. The solvent is distilled out as completely as possible in vacuo at a bath temperature of 50–60° C. The crude product remains as residue and crystallizes on cooling. It is employed without further working up in the next reaction stage.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N+:11]([O-])=O)[CH:3]=1.Cl.[CH3:15][O:16][C:17](=[O:29])[CH:18]([NH2:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1.O>O=S(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:15][O:16][C:17](=[O:29])[C@@H:18]([NH:28][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][C:4]=1[NH2:11])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1
Reactant: COC(=O)C(N)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(I)cc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(Cl)c(Cl)c1)NC(=O)c1ccc(I)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
A solution of 4-iodo-2-nitrobenzoic acid (0.35 g, 1.20 mmol) dissolved in SOCl2 (5 mL) was heated at reflux for 2 h. The mixture was concentrated and the resulting liquid was dissolved in DMF (5 mL). DMAP (161 mg, 1.32 mmol) and 2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride (0.37 g, 1.32 mmol) were added and the solution was stirred overnight at rt. The mixture was poured into water and extracted with EtOAc (3×). The organic layers were combined, dried (MgSO4), and concentrated to provide the crude product as a yellow oil. The oil was purified by flash chromatography (hexanes/EtOAc) to provide the product as a colorless oil (50%, 313 mg). 1H NMR (400 MHz, CDCl3): 7.59 (d, J=8.1, 2H), 7.37 (d, J=8.2, 1H), 7.28 (d, J=2.0, 1H), 7.18 (d, J=8.0, 1H), 7.04 (dd, J=8.2, 2.0, 1H), 6.49 (d, J=7.4, 1H), 5.10-5.04 (m, 1H), 3.81 (s, 3H), 3.33-3.17 (m, 2H).
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([C:14]2[C:15]([C:21]([O:23]C)=O)=[C:16]([CH3:20])[NH:17][C:18]=2[CH3:19])=O)[CH:8]=[CH:9][CH:10]=1>C(O)(=O)C>[Br:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH2:11][C:12]1[C:14]2[C:15](=[C:16]([CH3:20])[NH:17][C:18]=2[CH3:19])[C:21](=[O:23])[NH:2][N:3]=1
Reactant: NN
Reactant: COC(=O)c1c(C)[nH]c(C)c1C(=O)Cc1cccc(Br)c1
Solvent: CC(=O)O
Solvent: O
Product: Cc1[nH]c(C)c2c(=O)[nH]nc(Cc3cccc(Br)c3)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.8 %

Procedure:
Hydrazine hydrate (0.110 mL, 1.48 mmol) was added to methyl 4-(2-(3-bromophenyl)acetyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (49) (0.470 g, 1.34 mmol) in acetic acid (20 mL). The resulting solution was stirred at room temperature for 2 days. The reaction mixture was evaporated to dryness and redissolved in EtOAc (200 mL), and washed sequentially with 2M NaOH (100 mL) and saturated brine (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the desired material as a beige solid (0.253 g, 56.7% yield); 1H NMR (400.132 MHz, MeOD) δ 2.18 (3H, s), 2.50 (3H, s), 4.03 (2H, s), 7.04-7.11 (2H, m), 7.25 (2H, m); m/z (LC-MS, ESI+), RT=1.84 min (M+H=333.97).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14](=[O:15])[CH2:13][CH2:12][O:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[C:16](Cl)([N:18]=[C:19]=[O:20])=[O:17]>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[O:15][C:19](=[O:20])[NH:18][C:16](=[O:17])[C:13]=3[CH2:12][O:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C=NC(=O)Cl
Reactant: O=C1CCOCC1c1cc(F)cc(F)c1
Product: O=c1[nH]c(=O)c2c(o1)C(c1cc(F)cc(F)c1)COC2
Temperature: 55 °C
Reaction time: 2 h
Yield: 21.7 %

Procedure:
The mixture of 3-(3,5-difluorophenyl)dihydro-2H-pyran-4(3H)-one (Preparation X2) (800 mg, 3.77 mmol) and carbonisocyanatidic chloride (557 mg, 5.28 mmol) was heated in a sealed bottle at 55° C. for 1 h and then at 130° C. for 2 h. The mixture was cooled to RT. Partition between EtOAc and saturated NaHCO3 solution. Extracted with EtOAc(×3 times). The combined organic layers was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel to give 8-(3,5-difluorophenyl)-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione (230 mg, 0.818 mmol, 21.69% yield). LC-MS (M+H)+=282.0. 1H NMR (500 MHz, CDCl3) δ ppm 8.94 (br, s., 1H) 6.85-7.01 (m, 2H) 6.81 (tt, J=8.81, 2.17 Hz, 1H) 4.70 (d, J=15.56 Hz, 1H) 4.49 (dd, J=15.56, 2.14 Hz, 1H) 4.03-4.12 (m, 2H) 3.68 (br. s., 1H)
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)[O:8][C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:5])C.[H][H].CCO.[OH-].[Na+].Cl>>[NH2:17][C:13]1[N:12]=[C:11]([C:9]2[O:8][C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=2)[CH:16]=[CH:15][N:14]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(-c2ccnc(N)n2)oc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nccc(-c2cc(C(=O)O)c(-c3ccccc3)o2)n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of ester 59 (221 mg, 0.71 mmol) in 1:1 H2/EtOH (9 mL), 4M aq NaOH (10 eq) was added and the reaction mixture was stirred at 100° C. for 1 h. After cooling to rt, the solution was acidified with 2M HCl yielding 5-(2-amino-pyrimidin-4-yl)-2-phenyl-furan-3-carboxylic acid as a white solid which was filtered, washed with water and dried under reduced pressure (quant.).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[CH3:17].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH3:17])=[C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][CH3:18])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1=[O:14])[CH3:13]
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(Br)cc21
Reactant: COc1ccccc1B(O)O
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3ccccc3OC)cc21

Procedure:
Compound 39A was prepared from Compound 1A using a procedure similar to that described in Example 1B, except using 2-methoxy phenylboronic acid as the starting material. MS (electrospray): mass calculated for C21H25NO2, 323.19; m/z found 324.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:12]=[C:11]([CH2:13][C:14](=O)[CH2:15][CH2:16][OH:17])[C:10]2[C:5](=[C:6]([C:19]([F:22])([F:21])[F:20])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[BH4-].[Na+].CC[OH:29]>O>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:12]=[C:11]([CH:13]([OH:29])[CH2:14][CH2:15][CH2:16][OH:17])[C:10]2[C:5](=[C:6]([C:19]([F:21])([F:22])[F:20])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: O=C(CCO)Cc1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: OCCCC(O)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of 1-(2,8-bis(trifluoromethyl)-4-quinolinyl)-4-hydroxybutanone (748 mg, 2.13 mmol) in EtOH (4 mL) at 0° C. was treated with a solution of NaBH4 (81 mg, 2.13 mmol) in water (0.2 mL), stirred at 0° C. for 30 min, poured into water (15 mL), extracted with EtOAc (2×10 mL),dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; EtOAc-heptane (2:1)] to give the title compound (618 mg, 82%) as a colourless oil; IR νmax (Nujol)/cm−1 3600-3200, 2938, 2885, 1604,1588, 1430, 1310, 1189, 1144 and 1110; NMR δH (400 MHz, CDCl3) 1.81-1.91 (3H, m), 2.08-2.17 (1H, m), 2.45-2.70 (2H, br s),3.75-3.78 (1H, m), 3.80-3.88 (1H, m), 5.52 (1H, d, J 8.0 Hz), 7.71 (1H, t, J 7.9 Hz), 8.08 (1H, s), 8.15 (1H, d, J 7.2 Hz) and 8.23 (1H, d, J 8.7 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:26]1[C:27](=[O:43])[N:28]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[CH:31]=1>CCCCCC>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:26]1[C:27](=[O:43])[N:28]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:41])([CH3:40])[CH3:42])[CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Reactant: C[Si](C)(C)CCOCn1cc([N+](=O)[O-])cc(I)c1=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)n1c(-c2cc([N+](=O)[O-])cn(COCC[Si](C)(C)C)c2=O)cc2cc(O[Si](C)(C)C(C)(C)C)ccc21

Procedure:
The title compound was prepared by the route outlined in Scheme 11 and using the experimental from Example 37, Step 3, with intermediate 5-(tert-butyl-dimethyl-silanyloxy)-indole-1-carboxylic acid tert-butyl ester (11a) (2.90 g, 8.3 mmol) and (6a), 3-iodo-5-nitro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyridin-2-one (3 g, 7.6 mmol). The resultant crude product was purified by flash chromatography on SiO2 with hexane—20% ethyl acetate/hexane (gradient) to afford after trituration using hexane, the title compound as a pale yellow solid, 3.67 g, 79%.