Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[NH2:13].[Br:14]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:14][C:10]1[CH:9]=[C:8]([CH3:12])[C:7]([NH2:13])=[C:6]([C:2]2[NH:3][CH2:4][CH2:5][N:1]=2)[CH:11]=1
Reactant: Cc1cccc(C2=NCCN2)c1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(C2=NCCN2)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.4 %

Procedure:
To a solution of the title compound of Step B (0.38 g, 2.17 mmol) in N,N-dimethylformamide (10 mL) was added N-bromosuccinimide (0.38 g, 2.13 mmol) and the mixture was stirred at ambient temperature for 1 hour. Additional N-bromosuccinimide (0.06 g, 0.34 mmol) was added and the mixture stirred for an additional 0.5 hour before being diluted with ethyl acetate and washed three times with water. The combined aqueous fractions were extracted with ethyl acetate and the organic layer was washed with water. The combined organic fractions were dried (magnesium sulfate), concentrated and purified by flash column chromatography (silica gel, 2% then 5% methanol in dichloromethane) to give the title compound of Step C (94 mg) as a light brown oil.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[F:13])[C:3]([NH2:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[OH:21][CH2:22][C:23]1([N:26]2[CH2:31][C:30]3([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[O:29][CH2:28][C:27]2=[O:37])[CH2:25][CH2:24]1>CN(C)C=O.O>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([CH:2]([N:34]2[CH2:35][CH2:36][C:30]3([O:29][CH2:28][C:27](=[O:37])[N:26]([C:23]4([CH2:22][OH:21])[CH2:24][CH2:25]4)[CH2:31]3)[CH2:32][CH2:33]2)[C:3]([NH2:5])=[O:4])=[C:7]([F:13])[CH:8]=1
Reactant: NC(=O)C(Br)c1ccc(Br)cc1F
Reactant: O=C1COC2(CCNCC2)CN1C1(CO)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1(CO)CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-bromo-2-(4-bromo-2-fluorophenyl)acetamide (1.037 mmol) in N,N-dimethylformamide (5 mL) was treated with potassium carbonate (2.96 mmol) and the crude 4-(1-(hydroxymethyl)cyclopropyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride from Example 29a. The reaction was stirred at room temperature overnight. The reaction solution was then diluted with water (100 mL) and was extracted three times with ethyl acetate. The combined organic layers were washed three times with water, three times with brine, and was then dried over sodium sulfate, filtered and concentrated to dryness in vacuo to afford the crude title compound as a yellow oil (500 mg of 85% pure material as determined by 1H NMR, 91% yield over the two steps). MS(ES)+ m/e 470.1/472.0 [M+H]+ (bromide isotope pattern).
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[NH:11])[NH2:10])[CH2:5][CH2:4]1.[Cl:12][C:13]([SH:16])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:12][C:13]1[S:16][N:10]=[C:9]([N:6]2[CH2:7][CH2:8][CH:3]([OH:2])[CH2:4][CH2:5]2)[N:11]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)N1CCC(O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: OC1CCN(c2nsc(Cl)n2)CC1
Temperature: 25 °C
Yield: 15.9 %

Procedure:
To a solution of 4-hydroxypiperidine-1-carboximidamide hydrochloride (1.80 g, 10.0 mmol) and perchloromethyl mercaptan (2.15 ml, 20.0 mmol) in dichloromethane (50 ml) was added dropwise a solution of sodium hydroxide (3.20 g, 80.0 mmol) in water (6 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 350 mg (12.7%) of the desired product as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[N-:12]([C:15]#[N:16])[C:13]#[N:14].[Na+]>>[C:13]([N:12]=[C:15]([NH2:16])[NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][CH:3]=1)#[N:14]
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: N#C[N-]C#N
Agent: [Na+]
Product: N#CN=C(N)Nc1ccc(C(F)(F)F)nc1

Procedure:
A solution of 5-amino-2-(trifluoromethyl)pyridine and sodium dicyanamide was processed as described in Example 71A to provide the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH3:14])[CH:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)#[N:2].[NH:22]1[C:30]2[C:25](=[C:26]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH3:14][CH2:13][CH2:12][N:8]1[C:9]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[C:6]([CH:15]2[CH2:20][CH2:19][CH:18]([N:34]3[CH2:35][CH2:36][N:31]([C:26]4[C:25]5[CH:24]=[CH:23][NH:22][C:30]=5[CH:29]=[CH:28][CH:27]=4)[CH2:32][CH2:33]3)[CH2:17][CH2:16]2)=[CH:7]1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: CCCn1cc(C2CCC(=O)CC2)c2cc(C#N)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCn1cc(C2CCC(N3CCN(c4cccc5[nH]ccc45)CC3)CC2)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
A solution of 4-(5-cyano-1-n-propyl-indol-3-yl)-cyclohexanone (1.68 g, 6 mmol), 1-(indol-4-yl)piperazine (1.27 g, 6.3 mmol), sodium triacetoxyborohydride (1.84 g, 8.9 mmol) and acetic acid (0.94 ml, 16 mmol) in 1,2-dichloroethane (80 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1N sodium hydroxide (20 ml), extracted with methylene chloride (3×100 ml) and washed with brine (3×100 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) afforded 0.42 g(15%) of product as a white powder.
Reaction SMILES: [OH-].[Na+].C1C(S(C2C=CC(Cl)=CC=2)(=O)=O)=CC=C(Cl)C=1.[C:20]([OH:25])(=O)[C:21](O)=O.C[C:27]1[C:32]([OH:33])=[C:31](C)[C:30](C)=[C:29]([C:36]([C:39]2C=CC(O)=C[CH:40]=2)(C)[CH3:37])[C:28]=1C>C1(C)C=CC=CC=1.O>[C:32]1([OH:33])[CH:31]=[CH:30][C:29]([C:36]2[CH:37]=[CH:21][C:20]([OH:25])=[CH:40][CH:39]=2)=[CH:28][CH:27]=1
Reactant: Cc1c(C)c(C(C)(C)c2ccc(O)cc2)c(C)c(C)c1O
Reactant: O=C(O)C(=O)O
Agent: O=S(=O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1ccc(-c2ccc(O)cc2)cc1
Temperature: 130 °C

Procedure:
This mixture was stirred and heated under a nitrogen atmosphere. To it was added over 8 minutes at 40°-49° C. aqueous sodium hydroxide (49.47%, 36.31 g, 447.8 mmole); the contents of the addition funnel were rinsed in with a total of about 6 ml of hot deionized water. Temperature was raised over 29 minutes to 109° C. and then over 1.5 hours to 122° C. while water was periodically drained from the Dean-Stark trap. Toluene was then removed over 27 minutes, the temperature rising to 160° C. A hot solution of 4,4'-dichlorodiphenylsulfone (64.62 g, 225.0 mmole) in toluene (75 ml) was then added over 25 minutes at a reactor temperature of 160° C., and the addition funnel was rinsed with about 10 ml of hot toluene. The mixture was stirred for 4 hours at 160°-162° C., becoming very viscous. To it were added in quick succession aqueous sodium hydroxide (49.47%, 0.19 g, 2.3 mmole), hot deionized water (about 1 ml), and toluene (5 ml). The added water was readily removed by distillation. The mixture was stirred about one hour longer at 160° C., then allowed to cool overnight. On the second day, chlorobenzene (195 g) was added, and the temperature was raised to 130° C. to effect complete solution. Methyl chloride was sparged in for one hour at 111°-114° C. to endcap the polymer; then oxalic acid 1.0 g (11 mmole) was added, and the mixture was stirred for 30 minutes at 109°-111° C. The solution was filtered through a layer of filter aid on a coarse porosity fritted-glass funnel. The polymer was recovered by coagulation in a Waring blender, washed thoroughly with water and methanol, and dried in a vacuum oven at about 150° C. Yield 66.98 g (63.4%), reduced viscosity (1 g/dl in N-methylpyrrolidone at 25° C.) 0.53 dl/g. The composition of the diphenol mixture used to make this copolymer was 70 mole percent tetramethylbisphenol A/30 mole percent bisphenol. Test results on the polymer containing tetramethylbisphenol A are given in Table 6.
Reaction SMILES: [C:1]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[C:1]([C:4]1([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14])(=[O:3])[CH3:2]
Reactant: ClCc1ccccc1
Reactant: CC(=O)C1CCc2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)C1(Cc2ccccc2)CCc2ccccc2C1=O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
2-Acetyl-1-tetralone (5.0 g) was added into a mixture of potassium carbonate (3.8 g) and acetonitrile (60 ml). The mixture was stirred at 60° C. for 30 minutes and benzyl chloride was added and the stirring was continued at 60° C. for 5 hours. The mixture was filtered and evaporated. The yield was 7.2 g and was used for further reactions without purification.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[O:5]=[S:6]1(=[O:32])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][N:9]([C:17]2[CH:26]=[C:25]([S:27](Cl)(=[O:29])=[O:28])[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:31])[CH:23]=3)[N:18]=2)[CH2:8][CH2:7]1>ClCCl.C(N(CC)CC)C>[NH2:3][CH2:2][CH2:1][NH:4][S:27]([C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:31])[CH:23]=2)[N:18]=[C:17]([N:9]2[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:6](=[O:32])(=[O:5])[CH2:7][CH2:8]2)[CH:26]=1)(=[O:28])=[O:29]
Reactant: NCCN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(S(=O)(=O)Cl)c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(S(=O)(=O)NCCN)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 3.1 %

Procedure:
To a cooled solution of ethane-1,2-diamine (320 mg, 5.4 mmol) in dichloromethane (50 mL) was added triethylamine (3 drops) followed by 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinoline-4-sulfonyl chloride (the filtrate from the above step) at 0° C. The resulting mixture was stirred at room temperature for 16 hours and concentrated in vacuo. The residue was purified by preparative HPLC to afford 56.38 mg of the desired product (yield of three steps was 3.1%). MS (ESI+) [(M+H)+] 461, 1H NMR (400 MHz, CD3OD) δ ppm 8.11 (s, 1 H), 7.99-7.97 (d, J=8.4 Hz, 1 H), 7.85-7.83 (d, J=7.6 Hz, 1 H), 7.67-7.63 (m, 3 H), 7.49-7.45 (m, 2 H), 5.25 (s, 2 H), 4.76-4.03 (m, 2 H), 3.63-3.59 (t, 2 H), 3.03-3.00 (m, 4 H), 2.46 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([OH:11])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH:39]1([CH2:42][N:43]2[C:51]3[N:50]=[C:49]([CH2:52][C:53]4[CH:58]=[CH:57][C:56]([NH:59][CH3:60])=[CH:55][CH:54]=4)[NH:48][C:47]=3[C:46](=[O:61])[N:45]([CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=3[F:69])[C:44]2=[O:70])[CH2:41][CH2:40]1.C(N(CC)CC)C>ClCCl>[CH:39]1([CH2:42][N:43]2[C:51]3[N:50]=[C:49]([CH2:52][C:53]4[CH:54]=[CH:55][C:56]([N:59]([CH3:60])[C:9]([C:3]5[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=5[Cl:1])=[O:11])=[CH:57][CH:58]=4)[NH:48][C:47]=3[C:46](=[O:61])[N:45]([CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=3[F:69])[C:44]2=[O:70])[CH2:41][CH2:40]1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: Cc1nn(C)c(Cl)c1C(=O)O
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(Cl)c1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 39.8 %

Procedure:
A mixture of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid (40 mg, 0.231 mmol) in dichloromethane (2.0 mL) at 25° C. was treated with triphenylphosphine (72 mg, 0.28 mmol). The reaction was cooled to 0° C. and then was treated with N-chlorosuccinimide (37 mg, 0.28 mmol). This mixture was stirred at 0° C. for 5 min and then was warmed to 25° C. for 15 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (100 mg, 0.23 mmol) and triethylamine (0.04 mL, 0.28 mmol). This mixture was stirred at 25° C. for 24 h. At this time, the reaction was diluted with dichloromethane (50 mL) and then was washed with a IN aqueous hydrochloric acid solution (1×50 mL) and a saturated aqueous sodium bicarbonate solution (1×50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1:99 methanol/dichloromethane) afforded 5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (54 mg, 48%) as a white solid: LR-MS for C30H29ClFN7O3 (M+H)+ at m/z=590.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11](OCC)(=[O:17])[C:12](OCC)=[O:13]>>[OH:13][C:12]1[C:11]([OH:17])=[N:10][C:4]2[C:5](=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[N:9]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: CCOC(=O)C(=O)OCC
Product: Oc1nc2cc(F)c(F)cc2nc1O
Temperature: 25 °C

Procedure:
A mixture consisting of 11.3 g. (0.0784 mole) of 4,5-difluoro-o-phenylenediamine (U.S. Pat. No. 4,264,600) and 80 ml. (0.589 mole) of diethyl oxalate was refluxed for a period of four hours to give a thick precipitate of product. The spent reaction mixture was then cooled to room temperature (~20° C.) overnight, filtered and the solid product so obtained was thereafter washed several times with diethyl ether and air-dried to constant weight to ultimately afford 15.5 g of pure 2,3-dihydroxy-6,7-difluoroquinoxaline, m.p. >310° C. Mass Spectrum: m/e, 198 (P+).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].C(N(CC)CC)C.[NH2:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[Cl:24])=[CH:21][CH:20]=[CH:19][CH:18]=2>ClCCl>[Cl:24][C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[NH:13][C:1](=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: Nc1cnc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1cnc2ccccc2c1Cl
Reaction time: 8 h

Procedure:
Propionyl chloride (6.32 mL, 1.3 eq) and triethylamine (11.69 mL, 1.5 eq) were added sequentially to a solution of 3-amino-4-chloroquinoline (10.0 g, 1.0 eq) in dichloromethane (200 mL). The reaction mixture was stirred overnight and then quenched with aqueous saturated sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 2% methanol in dichloromethane) to provide 5.8 g of N-(4-chloroquinolin-3-yl)propionamide.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.C(N(CC)CC)C.[CH2:16]([N:20]1[C:25]([NH:26][N:27]=[CH:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=2)=[CH:24][C:23](=[O:39])[N:22]([CH3:40])[C:21]1=[O:41])[CH:17]([CH3:19])[CH3:18]>CN(C)C=O>[CH2:16]([N:20]1[C:25]2=[N:26][N:27]([CH2:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)[C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[CH3:1])=[C:24]2[C:23](=[O:39])[N:22]([CH3:40])[C:21]1=[O:41])[CH:17]([CH3:19])[CH3:18]
Reactant: Cc1ccsc1C=O
Reactant: CC(C)Cn1c(NN=Cc2cccc3ccccc23)cc(=O)n(C)c1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccsc1-c1c2c(=O)n(C)c(=O)n(CC(C)C)c2nn1Cc1cccc2ccccc12
Temperature: 90 °C
Yield: 62.9 %

Procedure:
3-methyl-2-thiophenecarbaldehyde (0.063 g) and triethylamine (0.1 ml) was added to a solution of 1-naphthaldehyde (3-isobutyl-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)hydrazone (0.0875 g) in dimethylformamide (1.5 ml). The solution was heated at 90° C. for 24 hours. Reaction cooled to room temperature and purified on preparative HPLC to give the title compound (0.072 g). Mass: 458.87 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.Cl.[OH:10][CH:11]1[CH2:14][NH:13][CH2:12]1.[OH-].[Na+]>O>[Cl:8][C:6]1[N:7]=[CH:2][N:3]=[C:4]([N:13]2[CH2:14][CH:11]([OH:10])[CH2:12]2)[CH:5]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OC1CNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC1CN(c2cc(Cl)ncn2)C1
Yield: 115.1 %

Procedure:
7.2 g (48.7 mmol) 2,4-dichloropyrimidine are initially introduced into 140 ml water. 5.3 g (48.7 mmol) 3-hydroxyazetidine hydrochloride and 48.7 ml 1 N sodium hydroxide solution are added and the mixture is heated at 90° C. for 72 h (the 2,4-dichloropyrimidine being detectably volatile and precipitating in crystalline form on the condenser). The solvent is removed in vacuo and the residue is dried to give 10.4 g of the crude product, which is reacted without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:11]=1[Cl:12].[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(N(CC)CC)C>C(O)C>[Cl:12][C:11]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH2:2][S:20][C:18]1[N:17]=[C:16]([OH:21])[CH:15]=[C:14]([CH3:13])[N:19]=1
Reactant: Clc1c(CBr)nc2ccccn12
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2nc3ccccn3c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-(bromomethyl)-3-chloroimidazo[1,2-a]pyridine (1.07 g, 5.87 mmol) and 6-methyl-2-sulfanylpyrimidin-4-ol (0.539 g, 3.82 mmol) in anhydrous ethanol (30 mL) at 0° C. was added triethylamine (2.08 g, 2.86 mL, 20.57 mmol), and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated to dryness, and water was added to precipitate the product. The crude product was purified by column chromatography using dichloromethane and methanol (0-10%) to provide 2-[({3-chloroimidazo[1,2-a]pyridin-2-yl}methyl)sulfanyl]-6-methylpyrimidin-4-ol; 1H NMR (400 MHz, DMSO-d6): δ 2.18 (s, 3H), 4.52 (s, 2H), 6.03 (bs, 1H), 7.07 (t, 1H), 7.35 (t, 1H), 7.59 (d, 1H), 8.30 (d, 1H); M+1 279.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH:22]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36](Br)[N:35]=3)[CH2:23][C:24]3[CH:25]=[C:26]4[C:30](=[C:31]([CH3:33])[CH:32]=3)[NH:29][N:28]=[CH:27]4)=[O:20])[CH2:15][CH2:14]1)[CH2:7]2.[Br-].[CH2:42]([Zn+])[CH:43]([CH3:45])[CH3:44]>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>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH:22]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([CH2:42][CH:43]([CH3:45])[CH3:44])[N:35]=3)[CH2:23][C:24]3[CH:25]=[C:26]4[C:30](=[C:31]([CH3:33])[CH:32]=3)[NH:29][N:28]=[CH:27]4)=[O:20])[CH2:15][CH2:14]1)[CH2:7]2
Reactant: Cc1cc(CC(OC(=O)N2CCC(N3Cc4cccc(F)c4NC3=O)CC2)c2cccc(Br)n2)cc2cn[nH]c12
Reactant: CC(C)C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: Cc1cc(CC(OC(=O)N2CCC(N3Cc4cccc(F)c4NC3=O)CC2)c2cccc(CC(C)C)n2)cc2cn[nH]c12
Temperature: 110 °C
Yield: 73.2 %

Procedure:
A microwave tube was charged with (±)-1-(6-bromopyridin-2-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl 4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxylate (13.9 mg, 0.0229 mmol, 1.0 equiv) and Pd(PPh3)4 (ca. 2 mg). Isobutylzinc bromide (0.5 M in tetrahydrofuran, 0.46 mL, 0.23 mmol, 10 equiv) was then added via syringe under nitrogen. The vial was sealed and heated by microwave at 110° C. for 4 h. Tetrahydrofuran was removed in vacuo and the residue was partitioned between ethyl acetate and 0.5 N sodium hydroxide solution. The organic layer was separated and washed with brine, dried and concentrated. Flash column chromatography 10% methanol/methylene chloride) afforded the desired product (9.8 mg, 73.3%) as a glassy solid. MS (ESI) [M+H]+=585. 1H-NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.60-7.28 (m, 2H), 7.15-6.68 (m, 7H), 6.01 (br., 1H), 4.60-4.40 (m, 1H), 4.40-4.15 (m, 2H), 4.15-3.90 (m, 1H), 3.85-3.15 (m, 2H), 3.03-2.60 (m, 4H), 2.70 (s, 3H), 2.20-2.02 (m, 1H), 1.82-1.40 (m, 4H), 1.40-1.12 (m, 2H), 1.00-0.90 (m, 6H). HPLC tR=1.44 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[CH:18]=[C:19]([NH:23][C:24]([NH:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[O:33][CH3:34])=[O:25])[CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:10]=[CH:9]2)[CH:3]=1.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>N1C=CC=CC=1>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[NH:26][C:24](=[O:25])[NH:23][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[CH:9][N:8]3[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:1][C:38]([CH:35]4[CH2:37][CH2:36]4)=[O:39])[CH:3]=3)=[CH:12][CH:13]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccccc1NC(=O)Nc1cccc(-c2ccc3ccn(-c4cc(N)ncn4)c3c2)c1
Solvent: c1ccncc1
Product: COc1ccccc1NC(=O)Nc1cccc(-c2ccc3ccn(-c4cc(NC(=O)C5CC5)ncn4)c3c2)c1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Pyridine was added to 1-(3-(1-(6-aminopyrimidin-4-yl)-1H-indol-6-yl)phenyl)-3-(2-methoxyphenyl)urea (13 mg, 0.029 mmol). At room temperature, cyclopropylcarbonyl chloride (17 μL, 0.29 mmol) was added. The reaction solution was stirred at 50° C. for 1.5 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel; EA:Hx=1:4→DCM:MeOH=20:1) yielded N-(6-(6-(3-(3-(2-methoxyphenyl)ureido)phenyl)-1H-indol-1-yl)pyrimidin-4-yl)cyclopropanecarboxamide as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)=[O:21]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([O:17][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)=[O:21])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: O=C(CBr)c1cccc(Cl)c1
Product: CC(C)(C)OC(=O)N1CCCCC1CC(=O)OCC(=O)c1cccc(Cl)c1
Yield: 81.4 %

Procedure:
The title compound (2.65 g) was prepared from (RS)-2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (2.0 g) and 2-bromo-3′chloroacetophenone (1.92 g) according to the method of description 36.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:12][C:13]([C@H:15]([CH2:22][CH:23]([CH3:25])[CH3:24])[C@H:16]([OH:21])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[CH:10]=[CH2:11].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)C.[Ag-]=O>[CH2:9]([O:12][C:13]([C@H:15]([CH2:22][CH:23]([CH3:25])[CH3:24])[C@H:16]([O:21][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:17]([O:19][CH3:20])=[O:18])=[O:14])[CH:10]=[CH2:11]
Reactant: BrCc1ccccc1
Reactant: C=CCOC(=O)[C@H](CC(C)C)[C@H](O)C(=O)OC
Agent: O=[Ag-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCOC(=O)[C@H](CC(C)C)[C@H](OCc1ccccc1)C(=O)OC
Reaction time: 24 h

Procedure:
0.51 g of silver(I) oxide and 0.33 ml of benzyl bromide were added to a solution of 0.27 g of methyl 3(R)-(allyloxycarbonyl)-2(S)-hydroxy-5-methylhexanoate in 5 ml of dimethylformamide. After stirring the mixture for 24 hours, 0.36 g of cesium carbonate were added and stirring was continued for 3 hours. The mixture was diluted with diethyl ether and filtered. The filtrate was then washed in succession with 5% aqueous citric acid, water, 5% aqueous sodium hydrogen carbonate, water and brine. The diethyl ether phase was dried over anhydrous magnesium sulphate and the solvent was evaporated. The residue was purified by flash column chromatography on silica gel using ethyl acetate/hexane (1:19) for the elution. There was obtained 0.16 g of methyl 3(R)-(allyloxycarbonyl)-2(S)-benzyloxy-5-methylhexanoate in the form of a clear oil.