Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]=[CH:8][CH2:7][NH:6]1)=[O:4].[Cl:11][C:12]1[C:17]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:16][C:15]([N:22]=[C:23]=[O:24])=[C:14]([F:25])[CH:13]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]=[CH:8][CH2:7][N:6]1[C:23]([NH:22][C:15]1[CH:16]=[C:17]([O:18][CH:19]([CH3:20])[CH3:21])[C:12]([Cl:11])=[CH:13][C:14]=1[F:25])=[O:24])=[O:4]
Reactant: COC(=O)C1CC=CCN1
Reactant: CC(C)Oc1cc(N=C=O)c(F)cc1Cl
Solvent: Cc1ccccc1
Product: COC(=O)C1CC=CCN1C(=O)Nc1cc(OC(C)C)c(Cl)cc1F

Procedure:
To a stirred solution of 5,65 g (0,04 moles) of 1,2,3,6-tetrahydro-2-pyridinecarboxylic acid methyl ester in 75 ml of dry toluene are added dropwise without cooling 9,2 g (0,04 moles) of 4-chloro-2-fluoro-5-isopropoxyphenyl isocyanate, dissolved in 200 ml of dry toluene.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][CH3:26])[CH:19]=2)[N:12]([CH2:27][C:28]([NH:30][CH:31]([CH3:33])[CH3:32])=[O:29])[C:11]3=[O:34])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:36][CH2:37][OH:38].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[N:12]([CH2:27][C:28]([NH:30][CH:31]([CH3:32])[CH3:33])=[O:29])[C:11](=[O:34])[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([N:1]4[CH2:7][CH2:6][CH2:5][N:4]([CH2:36][CH2:37][OH:38])[CH2:3][CH2:2]4)[CH:9]=3)[N:14]=2)=[CH:19][C:20]=1[O:25][CH3:26]
Reactant: OCCBr
Reactant: COc1cc(-c2nc3ccc(N4CCCNCC4)cc3c(=O)n2CC(=O)NC(C)C)ccc1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2nc3ccc(N4CCCN(CCO)CC4)cc3c(=O)n2CC(=O)NC(C)C)ccc1F
Temperature: 100 °C

Procedure:
2-(6-(1,4-Diazepan-1-yl)-2-(4-fluoro-3-methoxyphenyl)-4-oxoquinazolin-3(4H)-yl)-N-isopropylacetamide (EXAMPLE 1i) (28 mg, 0.06 mmol), 2-bromoethanol (30 mg, 0.017 mL, 0.24 mmol), potassium carbonate (17 mg, 0.12 mmol,) and potassium iodide (1 mg, 5.99 μmol) were combined in a microwave vial and DMF (1 mL) added. The reaction mixture was heated at 100° C. for 5 min in the microwave. LCMS indicated that the desired product was being formed. Additional 2-bromoethanol (30 mg, 0.017 mL, 0.24 mmol) was added and reaction mixture was heated at 100° C. for a further 5 min in the microwave. Product was purified by preparative LCMS to afford 2-{2-(4-fluoro-3-methoxyphenyl)-6-[4-(2-hydroxyethyl)perhydro-1,4-diazepin-1-yl]-4-oxo-4H-quinazolin-3-yl}-N-isopropylacetamide (EXAMPLE 4q) (4 mg, 7.82 μmol, 13%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:42]=[CH:41][C:13]([C:14]([C:16]3[C:17]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][C:18]=4[S:19][C:20]=3[C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:23][CH:22]=3)=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:40][CH2:39][C:36]1[CH:37]=[CH:38][C:17]2[C:16]([CH:14]([C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:42][CH:41]=3)[OH:15])=[C:20]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:25][CH:26]=3)[S:19][C:18]=2[CH:35]=1
Reactant: N#Cc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc2c(C(O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 1.35 g (2.3 mol) of 3-[4-[2-(1-piperidinyl)ethoxy]benzoyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene-6-carbonitrile (Part A) in 30 mL of anhydrous THF under a nitrogen atmosphere was added 414 mg (11.6 mmol) of lithium aluminum hydride. The reaction was stirred for 2.5 hours at room temperature and then quenched with 5 mL of ethyl acetate and 5 mL of saturated aqueous potassium sodium tartrate for 16 h. The reaction mixture was poured into 50 mL of water, saturated with sodium chloride, and extracted with three 50 mL portions of THF. The combined organic layers were washed with brine, dried with anhydrous magnesium sulfate, and concentrated to give 1.32 g (95% crude yield) of a brown foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[N:16][C:17]([CH:20]([NH:22][C:23]([C:25]3[NH:26][C:27]4[C:32]([CH:33]=3)=[CH:31][CH:30]=[CH:29][CH:28]=4)=O)[CH3:21])=[CH:18][N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[NH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[C:25]1[C:23]1[N:16]2[C:17]([CH:18]=[N:19][C:14]([NH:13][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)=[N:15]2)=[C:20]([CH3:21])[N:22]=1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cc4ccccc4[nH]3)nn2)cc(OC)c1OC
Agent: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2ncc3c(C)nc(-c4cc5ccccc5[nH]4)n3n2)cc(OC)c1OC
Yield: 60.6 %

Procedure:
In a similar manner as described for Example 9, N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-1H-indole-2-carboxamide (Intermediate 33) (219 mg, 0.491 mmol), and 1,2,4-triazole (210 mg, 3.0 mmol) in pyridine (10 mL) and phosphorous oxychloride (0.14 mL, 1.5 mmol) gave 7-(1H-indol-2-yl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (128 mg, 61%) as a yellow solid: 1H NMR (DMSO-d6): δ11.85 (s, 1H), 9.67 (s, 1H), 9.26 (s, 1H) 7.55 (s, 1H), 7.52 (d, J=8.24 Hz, 1H), 7.46 (d, J=8.24 Hz, 1H), 7.21 (s, 2H), 7.15 (t, J=7.51, 1H), 7.04 (t, J=7.51 Hz, 1H), 3.82 (s, 6H), 3.68 (s, 3H), 2.58 (s, 3H). MS m/z 430 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].CC1(C)COC2=CC3OCC4(C=3C=C12)C1C(=CC=CC=1)NC4=O.Br[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[O:53][C:54]([F:57])([F:56])[F:55].BrCC1OC(C(F)(F)F)=CC=1>>[F:55][C:54]([F:56])([F:57])[O:53][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[CH2:46][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: FC(F)(F)Oc1ccccc1CBr
Agent: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2ccccc2OC(F)(F)F)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.21, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 1-(bromomethyl)-2-(trifluoromethoxy)benzene to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (77%) as a white solid: mp 130-135° C.; MS (ES+) m/z 456.3 (M+1).
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[N:8]([C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[CH2:7]1)=[O:5].[CH3:23][Mg]Br>C1COCC1>[C:4]([C@H:6]1[CH2:7][N:8]([C@@H:12]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9](=[O:11])[CH2:10]1)(=[O:5])[CH3:23]
Reactant: C[Mg]Br
Reactant: COc1ccc([C@@H](C)N2C[C@H](C(=O)N(C)OC)CC2=O)cc1
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C[C@H](C(C)=O)CC2=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (R)-N-methoxy-1-((R)-1-(4-methoxyphenyl)ethyl)-N-methyl-5-oxopyrrolidine-3-carboxamide 1.02 (6.87 g, 22.4 mmol) in THF (70 mL) was cooled to an internal temperature of 19° C. under Ar. Methylmagnesium bromide (3 M in Et2O, 14.9 mL, 44.7 mmol) was added in portions over ca. 10 min to keep the internal temperature below 10° C. The resulting mixture was stirred for 1 h, by which time the internal temperature had reached −12° C., and was then warmed in an ice bath to 0° C. After an additional 50 min, the reaction was quenched with saturated aqueous NH4Cl (150 mL) and was diluted with EtOAc (150 mL) and water to dissolve solids. The phases were separated, and the aqueous phase was extracted with EtOAc (100 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated onto 25 g silica gel. The product was purified by silica gel chromatography (15% to 45% acetone in hexanes) to afford (R)-4-acetyl-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.03.
Reaction SMILES: C[C:2]1[C:3]([NH:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:10](O)=[O:11])[NH:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[H-].C([Al+]CC(C)C)C(C)C.C(OCC)C.N>C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][NH:4][C:3]([NH:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:10]=[O:11])[CH:2]=1
Reactant: COC1=C(C)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)(C(=O)O)NC=C1
Agent: CC(C)C[Al+]CC(C)C
Agent: N
Agent: [H-]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC1=CC(C=O)(NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC=C1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
1.19 g of methyl 4-methoxy-2-(trityl-amino)-picolinic acid (compound B12) are dissolved in 41 ml of toluene. Subsequently, the solution is cooled to −70° C. and 3.36 ml of diisobutylaluminium hydride in toluene (strength 1.5 M) are added dropwise. After 30 min, 6.0 ml of diethyl ether and 3.5 ml of aqueous acetic acid (20% strength) are added. After further 30 min, the mixture is allowed to warm up to room temperature. Subsequently, 34 ml of aqueous ammonia (25% strength) is added and the mixture is filtered through a celite pad. The filter cake is rinsed with 50 ml of toluene. The filtrate is extracted three times each with 70 ml of sat sodium chloride solution. The organic layer is dried using sodium sulphate, filtered with suction and concentrated in vacuum. The crude product (1.36 g) is purified by chromatography (eluent: toluene/ethyl acetate 10:1) to yield 898 mg of the title compound as an amorphous solid. M.p. 172° C. TSP-MS: 395.2 [MH+]. TLC: Rf=0.40 (toluene/ethyl acetate 10:1).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[CH2:10]([O:12][C:13](=[O:23])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[CH3:11]>>[CH2:10]([O:12][C:13](=[O:23])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:7]([C:5]2[N:6]=[C:2]([Cl:1])[S:3][CH:4]=2)=[O:9])[CH:17]=1)[CH3:11]
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1csc(Cl)n1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2csc(Cl)n2)c1

Procedure:
Carboxylic acid (79) (220 mg, 1.34 mmol) was coupled to aniline (60) (257 mg, 1.34 mmol) using Method C to give the title compound.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:10]1[S:14][C:13]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[N:12][CH:11]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[C:1]1([C:7]#[C:8][C:10]2[S:14][C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)=[N:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: Ic1cnc(-c2cccs2)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C(#Cc1cnc(-c2cccs2)s1)c1ccccc1
Yield: 71.4 %

Procedure:
In a manner similar to Step D of Example 1, the reaction of 1.3 gram (0.013 mole) of phenylacetylene, 50 ml of triethylamine, 3.2 grams (0.011 mole) of 5-iodo-2-(thien-2-yl)thiazole, 0.080 gram (1.1×10-4 mole) of dichlorobis(triphenylphosphine)palladium (II), and 0.022 gram (1.1×10-4 mole) of copper(I) iodide produced 2.1 grams of 1-phenyl-2-[2-(thien-2-yl)thiazol-5-yl]ethyne as a solid, m.p. 94°-96° C., Compound 22 of Table 1.
Reaction SMILES: [C:1]1([S:7][C:8]2[NH:9][C:10](=O)[C:11]3[NH:12][CH:13]=[N:14][C:15]=3[N:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:29])=O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[C:1]1([S:7][C:8]2[N:16]=[C:15]3[C:11]([NH:12][CH:13]=[N:14]3)=[C:10]([Cl:29])[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(Sc2ccccc2)nc2nc[nH]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: Clc1nc(Sc2ccccc2)nc2nc[nH]c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
To a flame-dried round bottom flask (200 mL) was added 2-Phenylsulfenylhypoxanthine 2 (1.22 g, 5.0 mmol), tetrabutyl-ammonium chloride (anhydrous, 2.78 g, 10.0 mmol) and N,N-dimethylaniline (0.63 mL, 5.0 mmol), followed by dissolving them in acetonitrile (anhydrous, 50 mL). To the solution phosphorus oxychloride (2.8 mL, 30.0 mmol) was added dropwise. The reaction was refluxed under argon. After 2 hours, the reaction was cooled to 0° C. on an ice bath and quenched by addition of saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (4×100 mL). The combined organic layers were dried over sodium sulfate, and were concentrated on the rotary evaporator. The crude product was further purified by re-crystallization from methanol to afford desired product 3 as white solid (0.94 g, 72%). 1H NMR (400 MHz, (CD3)2SO) 7.50 (m, 3H), δ 7.65 (m, 2H), 8.53 (s, 1H); MS (ES) calculated for C11H7ClN4S [MH+] 263.02, found: 263.00.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH2:21]1[C:23]2([CH2:27][CH2:26][CH2:25][NH:24]2)[CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:22]1[C:23]2([CH2:27][CH2:26][CH2:25][N:24]2[C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:21]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: C1CNC2(C1)CC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CCCC12CC2

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 4-azaspiro[2.4]heptane (95442-76-5) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=364.5 [MH+].
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C:4]([F:7])([F:6])[F:5].Cl.[NH2:10][OH:11]>C(Cl)(Cl)Cl.O>[Br:1][CH2:2][C:3](=[N:10][OH:11])[C:4]([F:7])([F:6])[F:5]
Reactant: NO
Reactant: O=C(CBr)C(F)(F)F
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: ON=C(CBr)C(F)(F)F
Reaction time: 24 h
Yield: 54.6 %

Procedure:
To a solution of 10.5 mL (102.3 mmol) of 1-bromo-3,3,3-trifluoropropan-2-one in 100 mL of chloroform (passed through a pad of basic Al2O3) was added a solution of 10.4 g (149.7 mmol) of hydroxylamine hydrochloride in 20 mL of water and the mixture was warmed at reflux. After 24 hours, the mixture was cooled and the organic phase was separated. The aqueous layer was extracted with three 30 mL portions of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 11.5 g (55.7%) of 3-bromo-1,1,1-trifluoropropan-2-one oxime as a mixture (3:2) of geometric isomers.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH2:16][C:17]1[S:18][C:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[C:20]([OH:22])[N:21]=1.P(Cl)(Cl)Cl>O>[Br:1][C:2]1[CH:11]=[C:10]([C:12]([NH:16][C:17]2[S:18][CH:19]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C:20](=[O:22])[N:21]=2)=[O:14])[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1nc(O)c(-c2ccc(Cl)cc2)s1
Reactant: O=C(O)c1cc(Br)c2cccnc2c1O
Solvent: O
Solvent: ClP(Cl)Cl
Product: O=C(NC1=NC(=O)C(c2ccc(Cl)cc2)S1)c1cc(Br)c2cccnc2c1O
Reaction time: 8 h
Yield: 11.5 %

Procedure:
A solution of 5-bromo-8-hydroxyquinoline-7-carboxylic acid (0.268 g) of Preparation 2 and 2-amino-5-(4-chlorophenyl)-4-hydroxy-1,3-thiazole (0.227 g) in 50 mL xylenes is heated to reflux. To this is added dropwise PCl3 (0.069 g). Refluxing is continued overnight. The reaction is then cooled and water is added to destroy excess PCl3. The resulting solid is collected, washed with water and dried. The crude product is recrystallized from HOAc to yield 0.055 g of the title product as an orange solid.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH2:5]([NH:10][C:11]1[C:15]2[CH:16]=[C:17]([C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[CH:23]=O)[CH:18]=[CH:19][C:14]=2[O:13][N:12]=1)[C:6]([CH3:9])([CH3:8])[CH3:7].[H-].C(B)#N.[Na+].C(=O)([O-])O.[Na+]>C1COCC1>[CH:1]1([NH:4][CH2:23][C:22]2[CH:21]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]4[O:13][N:12]=[C:11]([NH:10][CH2:5][C:6]([CH3:8])([CH3:7])[CH3:9])[C:15]=4[CH:16]=3)[CH:27]=[CH:26][CH:25]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)CNc1noc2ccc(-c3cccc(C=O)c3)cc12
Reactant: NC1CC1
Agent: BC#N
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)CNc1noc2ccc(-c3cccc(CNC4CC4)c3)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.6 %

Procedure:
Cyclopropylamine (1.04 mL, 14.92 mmol, 5 equiv.) was added to a solution of 3-(3-(neopentylamino)benzo[d]isoxazol-5-yl)benzaldehyde (exemplary compound 52) (0.92 g, 2.98 mmol, 1 equiv.) in THF (50 mL) and sodium cyanoboran hydride (3.16 g, 14.92 mmol, 5 equiv.) was subsequently added to the mixture. The suspension was stirred for 3 days at RT, subsequently hydrolysed by the addition of sat. aq. sodium hydrogen carbonate sol. (approx. 5 mL) and the solvent removed in a vacuum. The residue was absorbed in EtOAc (10 mL) and extracted with sat. aq. sodium hydrogen carbonate sol. (2×15 mL) and sat. aq. NaCl solution (1×15 mL), dried (MgSO4) and the solvent removed in a vacuum. After column-chromatographic purification (EtOAc/MeOH; 20:1), the desired product (0.85 g, 82%) is obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:7][C:6]([C:8]2[C:9](=[O:15])[NH:10][CH:11]=[CH:12][C:13]=2[I:14])=[N:5][C:4]=1[CH3:16].[CH3:17]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)(=O)C>ClCCl>[I:14][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([O:15][CH3:17])[C:8]=1[C:6]1[NH:7][C:3]([CH:2]=[O:1])=[C:4]([CH3:16])[N:5]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: Cc1nc(-c2c(I)cc[nH]c2=O)[nH]c1CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1nccc(I)c1-c1nc(C)c(C=O)[nH]1
Reaction time: 0.08 h
Yield: 45.3 %

Procedure:
To a stirred suspension of 3-(5-(hydroxymethyl)-4-methyl-1H-imidazol-2-yl)-4-iodopyridin-2(1H)-one (0.020 g, 0.0579 mmol) in dichloromethane (2 mL) was added the Dess-Martin reagent (0.049 g, 0.1158 mmol) at room temperature. The reaction became clear after 5 minutes of stirring. Ethyl acetate was added and the reaction was washed with 5% aqueous Na2S2O3.5H2O, saturated aqueous sodium bicarbonate and brine. The organic layer was driede over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified on silica gel chromatography (ethyl acetate) to give the title material (0.009 g, 45%). 1H NMR (400 MHz, Acetone-d6) δ (ppm): 2.47 (s, 3H) 3.72 (s, 3H) 7.42-7.50 (m, 1H) 7.78 (s, 1H) 9.81 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15].[CH2:16]([O:18][C:19]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:20])[CH3:17]>O1CCCC1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:21][C:19]([O:18][CH2:16][CH3:17])=[O:20])=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COCCCOc1cc(C=O)ccc1O
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccc(O)c(OCCCOC)c1
Reaction time: 8 h
Yield: 80.1 %

Procedure:
4-hydroxy-3-(3-methoxypropoxy)benzaldehyde (15 g, 71.3 mmol) was dissolved in tetrahydrofuran (142 mL) and (ethoxycarbonylmethylene)triphenylphosphorane (24.8 g, 71.3 mmol) was added at room temperature portionwise. The mixture was then stirred overnight. The solvents were evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 8/2) to yield 16 g (80%) of the desired product as a yellow oil of a mixture of E and Z isomers.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:32]>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:32])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CC(C)COC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OCC(C)C)C3)cc1

Procedure:
Compound er was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with isobutyl chloroformate. LC-MS: m/z=+497 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:23])[CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=2)[OH:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:23][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH:11]([O:12][S:32]([CH3:31])(=[O:34])=[O:33])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)(=[O:34])=[O:33]
Reactant: O=[N+]([O-])c1cc(C(O)CCC(O)c2ccc(Br)cc2)ccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
The product from Example 191B (3.14 g, 7.84 mmole) was dissolved in 70 mL CH2Cl2 and cooled in an ice-acetone bath to −10° C. Triethylamine (3.82 mL, 27.4 mmole) was added dropwise to the cold solution, followed by dropwise addition of methanesulfonyl chloride (1.53 mL, 19.59 mmole) in 20 mL CH2Cl2 over 10 minutes. The resulting clear solution was stirred in the cold for 90 min. The reaction was deemed complete by LC-MS analysis and the solvent was removed in vacuo leaving a light yellow solid as the title compound, (4.36 g, 100%), that was used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH:13]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)=[O:14]>>[Cl:1][C:2]1[N:3]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:13]=[O:14])[CH:20]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: O=Cc1cccc(B(O)O)c1
Product: O=Cc1cccc(-n2c(Cl)c(C=O)c3ccccc32)c1
Yield: 99 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 3-formylphenylboronic acid as described in Step 1 of Example 29 to afford 2-chloro-1-(3-formylphenyl)-1H-indole-3-carboxaldehyde (99% yield) as a white solid. ESI/MS 284 (M+H); RT 3.37 min; NMR 10.15 (1H, s); 10.12 (1H, s); 8.23 (3H, m); 7.98 (2H, m); 7.41 (2H, m); 7.18 (1H, d, J=9 Hz).