Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=3[N:10]=[N:9]2)=[CH:5][CH:4]=1.F[C:21]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24].CC(C)([O-])C.[K+].[Cl-].[NH4+]>COCCOCCOC>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:21]=[CH:30][C:29]([F:31])=[CH:28][C:27]=1[O:17][C:16]1[C:11]2[N:10]=[N:9][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(Cn2nnc3c(O)cccc32)cc1
Reactant: COC(=O)c1ccc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: COCCOCCOC
Product: COC(=O)c1ccc(F)cc1Oc1cccc2c1nnn2Cc1ccc(OC)cc1
Temperature: 100 °C

Procedure:
To a solution of EXAMPLE 342C (990 mg) and methyl 2,4-difluorobenzoate (734 mg) in diglyme (40 mL) was added potassium tert-butoxide (1M in tetrahydrofuran, 4.07 mL). The solution was heated to 100° C. for 16 hours, cooled, added to saturated ammonium chloride, and extracted with 70% ethyl acetate in hexanes. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography on silica gel using 30% ethyl acetate in hexanes.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH:14]=[O:15])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.[CH3:18][Mg+].[Br-]>C1COCC1>[CH3:17][O:16][CH:3]([O:2][CH3:1])[C:4]1[C:13]([CH:14]([OH:15])[CH3:18])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: C[Mg+]
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1C(C)O)CCCN2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 13.5 g, 49.7 mmol) in THF (250 ml) at 0° C. was slowly added a solution of MeMgBr (3M in diethylether, 66.3 ml, 199 mmol) in THF (250 ml). The reaction mixture was allowed to warm to room temperature and stirred 3 h. Additional MeMgBr (16.6 ml, 49.7 mmol) was added at room temperature and the reaction mixture was stirred for approximately 30 minutes. The reaction mixture was quenched with saturated aqueous NH4Cl solution (150 ml) and water (100 ml) and extracted with EtOAc (2×). The combined organic phases were dried using Na2SO4, filtered and concentrated to yield the title compound as a yellow solid. (UPLC-MS 3) tR 0.44 min, ESI-MS 253.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 7.33 (s, 1H), 6.36 (s, 1H), 5.18-5.10 (m, 1H), 5.03 (s, 1H), 4.65 (d, 1H), 3.31-3.26 (m, 6H), 3.26-3.21 (m, 2H), 2.69-2.62 (m, 2H), 1.82-1.71 (m, 2H), 1.20 (d, 3H).
Reaction SMILES: C([N:8]1[C:15]2[CH:16]=[C:17]([CH2:20][C:21]3[CH:22]=[C:23]([C@H:28]4[C@H:33]([OH:34])[C@@H:32]([OH:35])[C@H:31]([OH:36])[C@@H:30]([CH2:37][OH:38])[O:29]4)[CH:24]=[CH:25][C:26]=3[Cl:27])[CH:18]=[CH:19][C:14]=2[O:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.Cl>CO.[Pd]>[Cl:27][C:26]1[CH:25]=[CH:24][C:23]([C@H:28]2[C@H:33]([OH:34])[C@@H:32]([OH:35])[C@H:31]([OH:36])[C@@H:30]([CH2:37][OH:38])[O:29]2)=[CH:22][C:21]=1[CH2:20][C:17]1[CH:18]=[CH:19][C:14]2[O:13][C:10]3([CH2:12][CH2:11]3)[CH2:9][NH:8][C:15]=2[CH:16]=1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)N(Cc3ccccc3)CC3(CC3)O4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)NCC3(CC3)O4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 2 h
Yield: 22.4 %

Procedure:
To a solution of (2S,3R,4R,5S,6R)-2-[3-[(4-benzylspiro[3H-1,4-benzoxazine-2,1′-cyclopropane]-6-yl)methyl]-4-chloro-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol (300 mg) in methanol (3 mL), was added ethyl acetate (0.5 mL), 10% palladium on charcoal (40 mg), and 0.3 mL conc. HCl. The reaction mixture was stirred under hydrogen balloon pressure for 2 h then filtered through a celite bed which was washed with methanol, and the resulting filtrate was concentrated to a residue which was purified by preparative HPLC to furnish (2S,3R,4R,5S,6R)-2-[4-chloro-3-(spiro[3,4-dihydro-1,4-benzoxazine-2,1′-cyclopropane]-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol (56 mg).
Reaction SMILES: [NH2:1][CH:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([Cl:14])[CH:7]=[CH:8][C:9]=2[NH2:13])[NH:4][CH2:3]1.ClCCl.C1C[O:21][CH2:20][CH2:19]1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:20]([NH:1][CH:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([Cl:14])[CH:7]=[CH:8][C:9]=2[NH2:13])[NH:4][CH2:3]1)(=[O:21])[CH3:19]
Reactant: C1CCOC1
Reactant: Nc1ccc(Cl)c2c1C(=O)C(N)CN2
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC1CNc2c(Cl)ccc(N)c2C1=O

Procedure:
260 mg of the compound prepared in (3) above was dissolved into a mixed solvent of 5 ml of dichloromethane and 5 ml of THF. To this solution were added 0.16 ml of pyridine and 0.13 ml of acetic anhydride while stirring under ice cooling, and the mixture was stirred for 20 minutes. The reaction product was concentrated, and after the addition of chloroform, the residue was washed with saturated sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. The product was concentrated and the residue was charged into ether and petroleum ether in to produce 287 mg powder of the title compound.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([S:11][CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[N+:13]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1B(O)O)([O-:15])=[O:14].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.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>[CH3:22][C:20]1[CH:19]=[CH:18][C:17]([C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([S:11][CH3:12])=[N:9]3)=[CH:4][CH:3]=2)=[C:16]([N+:13]([O-:15])=[O:14])[CH:21]=1
Reactant: CSc1ncc2ccc(Br)n2n1
Reactant: Cc1ccc(B(O)O)c([N+](=O)[O-])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: O
Solvent: C1COCCO1
Product: CSc1ncc2ccc(-c3ccc(C)cc3[N+](=O)[O-])n2n1
Temperature: 95 °C

Procedure:
7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (600 mg, 2 mmol), 2-nitro-4-methyl-phenylboronic acid (500 mg, 3 mmol) 1.50 M of Sodium carbonate in Water (5 mL, 8 mmol) and dioxane (10 mL) were added to a RB flask. The reaction mixture was degassed with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.1 mmol) was added and the reaction mixture was degassed again. The reaction mixture was heated at 95° C. overnight under argon. MS showed product formation. The mixture was cooled to RT, concentrated, filtered through a pad of celite, and partitioned with water and EtOAc. The organic phase was separated, washed with brine, and dried over magnesium sulfate. After solvent evaporation, the product, 7-(4-Methyl-2-nitro-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine, was obtained as a solid which was further purified by taking in ether followed by filtration and washing with ether (628 mg, 80%). LCMS (E/I+) 301 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[CH:7][C:6]=2[CH:18]=1.C([Li])CCC.[C:24](=[O:26])=[O:25].Cl>C1COCC1.CCCCCC>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH2:9][O:10][C:5]3[CH:4]=[CH:3][C:2]([C:24]([OH:26])=[O:25])=[CH:18][C:6]=3[CH:7]=2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(C2=Cc3cc(Br)ccc3OC2)cc1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C2=Cc3cc(C(=O)O)ccc3OC2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Into a solution of 6-bromo-3-(4-methylphenyl)-2H-1-benzopyran (0.5 g) in THF (15 ml) was added at −78° C. 1.6 M butyl lithium (a hexane solution) (1.14 ml) under a nitrogen atmosphere. The resulting mixture was stirred at −78° C. for one hour, was then mixed with dry ice and was stirred for additional one hour. After addition of 1 N hydrochloric acid (10 ml), the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the resulting crystals were collected by filtration, and the crystals were washed with diethyl ether and hexane to obtain 3-(4-methylphenyl)-2H-1-benzopyran-6-carboxylic acid (218 mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([OH:12])=O.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[CH:20]=[C:21]([C@@H:25]([NH2:27])[CH3:26])[CH:22]=[CH:23][CH:24]=2)[CH:14]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:27][C@H:25]([C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[CH:20]=1)[CH3:26])=[O:12]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: C[C@H](N)c1cccc(-c2cccnc2)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)C=Cc1ccccc1F)c1cccc(-c2cccnc2)c1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
A mixture of 3-(2-fluoro-phenyl)-acrylic acid (0.083 mmol), (S)-1-(3-pyridin-3-yl-phenyl)ethylamine (12.7 mg, 0.064 mmol), EDC (18.4 mg, 0.096 mmol), HOBT (13 mg, 0.096 mmol), DMF (2 mL) and diisopropylethylamine (33 μL, 0.192 mmol) was stirred at 23° C., 18 hours. The residue was purified by preparative HPLC (Primeshere C18-HC 21.2×100 mm; (5 mM NH4OAc) 0-100% gradient over 5 minutes 20 mL/min flow rate) to afford the title product.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH2:32][CH3:33])(=[O:29])=[O:28])[CH:21]=4)[CH2:16][CH2:15][NH:14]3)[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:34](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.[OH-].[Na+]>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH2:32][CH3:33])(=[O:28])=[O:29])[CH:21]=4)[CH2:16][CH2:15][N:14]3[CH3:34])[CH2:10][CH2:11][CH2:12]2)=[CH:5][CH:4]=1
Reactant: CCCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)NCC2
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CI
Product: CCCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)N(C)CC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
Butane-1-sulfonic acid (2-{1-[1-(4-chloro-phenyl)-cyclobutyl]-1,2,3,4-tetrahydro-isoquinolin-7-yloxy}-ethyl)-amide hydrochloride (example 16, 50.0 mg, 0.10 mmol) is dissolved in acetone (3 ml) and potassium carbonate (29.0 mg, 0.21 mmol) and methyl iodide (16.4 mg, 0.12 mmol) were added. The mixture was stirred at RT for 14 h. The solvent was reduced, the reaction mixture was diluted with 1 N sodium hydroxid solution and extracted with dichloromethane. The combined organic layers were washed with saturated sodium chloride solution and dried with potassium sulphate. The residue was purified by HPLC with . . . to give the product (50.0 mg, 0.10 mmol, 13%).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[C:14]([NH2:18])=[C:13]1[C:8]([CH2:9][CH2:10][CH2:11][CH2:12]1)=[N:7]2.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>CS(C)=O>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:18][C:14]1[C:15]2[C:6]([N:7]=[C:8]3[C:13]=1[CH2:12][CH2:11][CH2:10][CH2:9]3)=[CH:5][C:4]([Cl:3])=[CH:17][CH:16]=2
Reactant: BrCCCCCCCBr
Reactant: Nc1c2c(nc3cc(Cl)ccc13)CCCC2
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Clc1ccc2c(NCCCCCCCBr)c3c(nc2c1)CCCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
Potassium hydroxide (95 mg, 1.7 mmoL) was added to a solution of 6-chloro-1,2,3,4-tetrahydro-acridin-9-ylamine (395 mg, 1.7 mmoL) in dimethylsulfoxide (15 ml) and the mixture was stirred vigorously under nitrogen at room temperature for 2 h. 1,7-Dibromoheptane (438 mg, 1.7 mmoL) was added, and the reaction was continued to stir at room temperature for 12 h. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The combined ethyl acetate extract was dried, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel using hexane/ethyl acetate/triethyl amine (8/2/1) to provide the desired product (244 mg, 0.60 mmoL) in 35% yield.
Reaction SMILES: C1(B(O)O)CCCCC1.Br[C:11]1[CH:46]=[CH:45][CH:44]=[CH:43][C:12]=1[CH2:13][N:14]1[C:19](=[O:20])[C:18]([C:21]([NH:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[O:22])=[C:17]([OH:32])[C:16]2[CH2:33][N:34]([C:36]([C:38]3[N:39]=[CH:40][S:41][CH:42]=3)=[O:37])[CH2:35][C:15]1=2>>[CH2:13]([N:14]1[C:19](=[O:20])[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:22])=[C:17]([OH:32])[C:16]2[CH2:33][N:34]([C:36]([C:38]3[N:39]=[CH:40][S:41][CH:42]=3)=[O:37])[CH2:35][C:15]1=2)[C:12]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:11]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1c(O)c2c(n(Cc3ccccc3Br)c1=O)CN(C(=O)c1cscn1)C2
Agent: OB(O)C1CCCCC1
Product: O=C(O)CNC(=O)c1c(O)c2c(n(Cc3ccccc3)c1=O)CN(C(=O)c1cscn1)C2

Procedure:
In a failed attempt to couple cyclohexyl boronic acid with tert-butyl N-{[1-(2-bromobenzyl)-4-hydroxy-2-oxo-6-(1,3-thiazol-4-ylcarbonyl)-2,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridin-3-yl]carbonyl}glycinate (prepared in similar fashion to Intermediate 5), and using a similar procedure to that described in Example 49 Step A, the above side product, compound E54-1 obtained. HPLC/MS: 454.9 (M+1); Rt=2.67 min.
Reaction SMILES: OC1C=C(C=CC=1OC)C(OC)=O.[Cl:14]C1C=C(CCO)C=CC=1.[CH3:24][O:25][C:26](=[O:45])[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=2)[CH:28]=1.ClN1C(=O)CCC1=O>C(Cl)Cl.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[CH3:24][O:25][C:26](=[O:45])[C:27]1[CH:28]=[C:29]([O:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=2)[C:30]([O:33][CH3:34])=[CH:31][C:32]=1[Cl:14]
Reactant: OCCc1cccc(Cl)c1
Reactant: COC(=O)c1ccc(OC)c(OCCc2cccc(Cl)c2)c1
Agent: [Zr+4]
Agent: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: COC(=O)c1cc(OCCc2cccc(Cl)c2)c(OC)cc1Cl

Procedure:
Methyl 3-hydroxy-4-methoxybenzoate and 2-(3-chlorophenyl)-ethanol were reacted in analogy to step 1 of example 1. The obtained 3-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoic acid methyl ester (300 mg, 0.935 mmol), N-chloro-succinimide (381 mg, 2.81 mmol), and zirconium tetrachloride (129 mg, 0.57 mmol) were suspended in DCM (4 ml) and the mixture was stirred under reflux for 5 h until the starting material was used up. The mixture was partitioned between EA and a saturated aqueous sodium hydrogencarbonate solution, the aqueous phase extracted with EA, and the combined organic extracts were dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by silica chromatography (HEP/EA gradient) to give 118 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:13])[CH2:11][CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([NH:13][C@H:10]([C:8]2[N:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]3[CH:20]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH2:11][CH3:12])[N:25]=[CH:24][N:23]=1
Reactant: CC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 90 °C
Yield: 78.6 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)propylamine (62 mg, 0.23 mmol), 4-amino-6-chloro-5-cyanopyrimidine (36 mg, 0.23 mmol) and DIPEA (0.08 mL, 0.46 mmol) in IPA (2 mL) was heated for 6 h at 90° C. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si—PPC, gradient 0-5% 2M NH3/MeOH in EtOAc) to afford 358 as a white solid (70 mg, 79%). LCMS (Method K): RT 4.10 min [M+H]+ 388.1. 1H NMR (DMSO-d6, 400 MHz): δ 7.81 (1H, s), 7.68 (1H, dd, J=8.8, 4.9 Hz), 7.56-7.44 (6H, m), 7.16 (2H, br s), 7.07 (1H, ddd, J=9.8, 8.8, 2.5), 6.79 (1H, dd, J=8.9, 2.5), 5.29 (1H, dt, J=7.7, 6.2), 1.97 (1H, dqd, J=14.9, 7.5, 6.2), 1.87 (1H, dqd, J=14.9, 7.5, 6.2), 0.75 (3H, t, J=7.5)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7]C)=[O:6].[CH:12]([C:15]1[NH:16][CH:17]=[CH:18][N:19]=1)([CH3:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.[Cu]I>[CH:12]([C:15]1[N:16]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([OH:7])=[O:6])[CH:17]=[CH:18][N:19]=1)([CH3:14])[CH3:13]
Reactant: COC(=O)c1ccnc(Br)c1
Reactant: CC(C)c1ncc[nH]1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)c1nccn1-c1cc(C(=O)O)ccn1
Temperature: 120 °C
Yield: 54.9 %

Procedure:
A mixture of methyl 2-bromoisonicotinate (2.00 g, 9.26 mmol), 2-isopropyl-1H-imidazole (1.12 g, 10.2 mmol), cesium carbonate (6.03 g, 18.5 mmol) and copper (1) Iodide (176 mg, 926 umol) in DMSO was heated to 120° C. for eighteen hours, under nitrogen. The crude material was filtered, purified by preparative HPLC (10-90% CH3CN in water). The pure fractions were collected and concentrated to give 2-(2-isopropyl-1H-imidazol-1-yl)isonicotinic acid as a white sticky solid (1.176 g, 55% yield). MS 232 (MH+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].C1COCC1.Cl[C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[NH:19][CH:20]=[N:21]2>C(O)(=O)C>[C:1]1([CH2:7][CH2:8][O:9][C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[NH:19][CH:20]=[N:21]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: OCCc1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: c1ccc(CCOc2ncnc3nc[nH]c23)cc1
Temperature: 60 °C
Yield: 62 %

Procedure:
2-Phenylethanol (13 ml) was stirred under nitrogen and sodium (0.75 g, 32.36 mmol) was added. The reaction was heated to 60° C. When no sodium remained, anhydrous THF (18 ml) and 6-chloropurine (1.0 g, 6.47 mmol) were added. After refluxing under nitrogen for 5 h, the reaction mixture was allowed cool to room temperature and neutralised with glacial acetic acid. The THF was removed and the remaining alcohol was removed in vacuo. The product was recrystallised from ethanol and isolated as a white crystalline solid (962 mg, 62%), m.p. 209-210° C.; (Found: C, 64.57; H, 5.12; N, 23.54. Calc. for C13H12N4O: C, 64.99; H, 5.03; N, 23.34%); νmax (cm−1) 3135,3063, 3031, 2948, 2897, 2797, 2672, 2583 (NH, C—H); δH (200 MHz, d6-DMSO) 8.483 (1H, s, C(2)H or C(8)H), 8.365 (1H, s, C(2)H or C(8)H), 7.366-7.194 (5H, m, Ph), 4.741 (2H, t, J=7.0 Hz, OCH2), 3.134 (2H, t, J=7.0 Hz, CH2Ph); m/z 240 (M+, 11%), 149 ([M—Bn]+, 11%), 136 ([M—CH2CH2Ph]+, 87%), 119 ([M—OCH2CH2Ph]+, 40%), 104 ([CH2CH2Ph]+, 100%), 91 (BN+, 37%), 77 (Ph+, 55%), 69 (48), 65 (15), 51 (26).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH2:6])=[O:5].[Cl:12][C:13]1[CH:14]=[C:15]([N:20]=[C:21]=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19].[Na].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:6][C:21]([NH:20][C:15]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([Cl:12])[CH:14]=1)=[O:22])=[O:5]
Reactant: NC(=O)c1c(Cl)cccc1Cl
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na]
Solvent: c1ccncc1
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(Cl)c(Cl)c1
Temperature: 100 °C

Procedure:
9.5 g of 2,6-dichlorobenzamide and 10.34 g of 3,4-dichlorophenylisocyanate in 25 ml of pyridine to which 1 g of sodium has been added are heated on a steam bath (100° C.+) for 24 hours. The reaction mixture is poured on ice which contains concentrated hydrochlorid acid and the solid precipitate is thoroughly washed with successively water and alcohol. The substance is recristallized from acetonitrile. Melting point 232° C.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=1[S:20](=[O:23])(=[O:22])[NH2:21])=O)C.Cl>[OH-].[Na+]>[CH3:19][S:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]2[NH:8][C:6]([CH2:5][C:4]([OH:3])=[O:24])=[N:21][S:20](=[O:23])(=[O:22])[C:10]=2[CH:11]=1)(=[O:18])=[O:17]
Reactant: CCOC(=O)CC(=O)Nc1ccc(NS(C)(=O)=O)cc1S(N)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
N-(4-Methanesulfonylamino-2-sulfamoyl-phenyl)-malonamic acid ethyl ester (9.55 g, 26.16 mmol) was dissolved in 8% aqueous sodium hydroxide solution (262 mL) and heated at 100° C. for 1.5 h. The reaction mixture was cooled to 0° C. and the solution was acidified by slowly adding 12.0 M aqueous hydrochloric acid solution until pH 1-2 was reached. A precipitate started to form and the suspension was allowed to stir for 30 min at 0° C. The precipitate was collected by vacuum filtration, washed with cold water, and dried under high vacuum to afford (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (7.20 g, 21.621 mmol, 82.6%) as a pinkish solid. 1H NMR (400 MHz, DMSO-d6) δ: 3.03 (3H, s), 3.56 (2H, s), 7.33 (1H, d, J=9.1 Hz), 7.52-7.54 (2H, m), 10.09 (1H, s), 12.24 (1H, s), 13.02 (1H, bs). LC-MS (ESI) calcd for C10H11N3O6S2 333.01, found 334.1 [M+H+].
Reaction SMILES: Cl.Cl.Cl.[CH3:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1.CCN(C(C)C)C(C)C.Cl.[CH3:40][N:41]1[CH2:46][CH2:45][N:44]([C:47](Cl)=[O:48])[CH2:43][CH2:42]1.O>CN(C=O)C>[CH3:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][N:27]([C:47]([N:44]6[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]6)=[O:48])[CH2:28][CH:29]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: Cn1ncc2cc(Nc3ncnc4[nH]c(C5=CCNCC5)cc34)ccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN1CCN(C(=O)N2CC=C(c3cc4c(Nc5ccc6c(cnn6C)c5)ncnc4[nH]3)CC2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of (1-methyl-1H-indazol-5-yl)-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine tris-hydrochloride (78.1 mg, 0.172 mmol, 1 eq) in DMF (5 mL), DiPEA (180 μL, 1.0 mmol, 6 eq) was added. After cooling the suspension to 0° C., 4-methyl-1-piperazinecarbonyl chloride hydrochloride (28.6 mg, 0.170 mmol, 1 eq) in DMF (1.5 mL) was added and the reaction was stirred at 0° C. for 2 h. An additional 0.2 eq of 4-methyl-1-piperazinecarbonyl chloride hydrochloride (6.1 mg, 0.036 mmol) in DMF (1 mL) was added and the suspension was stirred again at 0° C. for 3 h. Still additional acid chloride was needed and 4-methyl-1-piperazinecarbonyl chloride hydrochloride (6.1 mg, 0.036 mmol, 0.2 eq) in DMF (1 mL) was added. After 5 h, the reaction was quenched/worked up as follows: reaction solution was added dropwise into water, filtered (M frit), washed with water and then EtOAc, and dried, giving the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ=2.19 (s, 3H), 2.31 (s, br, 4H), 2.44-2.55 (m, 2H), 3.17 (s, br, 4H), 3.40 (t, J=5.2 Hz, 2H), 3.92 (s, br, 2H), 4.03 (s, 3H), 6.38 (s, br, 1H), 6.75 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 8.25 (s, 1H), 8.38 (s, br, 1H), 9.33 (s, —NH), 11.89 (s, —NH). MS (ES+): m/z 472.14 (9) [MH+]. HPLC: tR=1.68 min (ZQ2000, polar—5 min).