Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:16]3[CH2:18][CH2:17]3)[C:10](=[O:15])[N:11]([CH2:13]O)[N:12]=2)=[CH:4][CH:3]=1.CN(C=O)C.S(Cl)([Cl:26])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:26][CH2:13][N:11]1[C:10](=[O:15])[N:9]([CH:16]2[CH2:18][CH2:17]2)[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:12]1
Reactant: O=S(Cl)Cl
Reactant: O=c1n(CO)nc(-c2ccc(Cl)cc2)n1C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=c1n(CCl)nc(-c2ccc(Cl)cc2)n1C1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
875 mg (3.29 mmol) of the compound from Example 121A were suspended in 3 ml of dichloromethane, and a drop of DMF and 288 μl (3.95 mmol) of thionyl chloride were added. The mixture was stirred at RT for 3 h. For work-up, 5 ml of saturated aqueous sodium bicarbonate solution were added. The mixture was extracted once with 10 ml of tert-butyl methyl ether. The organic phase was washed once with 5 ml of water, dried over sodium sulfate, filtered and concentrated under reduced pressure. Drying of the residue under high vacuum gave 803 mg (86% of theory) of the target compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[NH:34]1[CH2:39][CH:38]=[C:37]([C:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[NH:42][CH:41]=2)[CH2:36][CH2:35]1>C1COCC1.CN(C=O)C>[NH:42]1[C:43]2[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:40]([C:37]2[CH2:38][CH2:39][N:34]([CH2:12][CH:13]3[O:27][C:17]4=[C:18]5[C:23](=[CH:24][CH:25]=[C:16]4[O:15][CH2:14]3)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]5)[CH2:35][CH:36]=2)=[CH:41]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)ccc4c3O2)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CC=C(c2c[nH]c4ccccc24)CC1)O3
Temperature: 25 °C

Procedure:
To a solution of (2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl 4-methylbenzenesulfonate (7.02 g, 18.1 mmole) and potassium carbonate (5.71 g, 41.3 mmole) in 250 mL of 1:1 THF/DMF was added 10.7 g (54.5 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole. The mixture was heated at reflux under nitrogen for 6 hours. After cooling to room temperature, the mixture was concentrated to dryness under vacuum and the residue column chromatographed on silica gel using first methylene chloride to elute impurities and then 3% methanol in methylene chloride to elute the product. The product-containing fractions were concentrated in vacuum and the residue recrystallized from ethanol/ethyl acetate to give 4.45 g of the (S)-enantiomer of the title compound as a yellow solid (m.p. 210° C.).
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[N:4]=1.S(Cl)([Cl:19])=O>C(Cl)Cl>[Cl:19][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: N#CCCCn1c(CO)nc2ccccc21
Solvent: ClCCl
Product: N#CCCCn1c(CCl)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4-(2-hydroxymethyl-benzoimidazol-1-yl)-butyronitrile, 68, (22 g, 102.2 mmol) suspended in CH2Cl2 (100 mL), thionyl chloride (15.81 g, 132.9 mmol) was slowly added with ice-water bath cooling. The ice bath was removed. The solution was stirred at room temperature for 1 hour and then evaporated. The residue was triturated with EtOAc to give a nearly quantitative yield of 4-(2-chloromethyl-benzoimidazol-1-yl)-butyronitrile, 69, as light gray powder.
Reaction SMILES: Br.O=[C:3]1[CH:12]([CH2:13][C:14]([O:16]C)=O)[CH2:11][CH2:10][C:9]2[CH:8]=[N:7][CH:6]=[CH:5][C:4]1=2.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1>>[F:18][C:19]([F:28])([F:29])[C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:14](=[O:16])[CH2:13][CH:12]3[C:3]([C:4]4[CH:5]=[CH:6][N:7]=[CH:8][C:9]=4[CH2:10][CH2:11]3)=[N:27]2)=[CH:24][CH:25]=1
Reactant: NNc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CC1CCc2cnccc2C1=O
Agent: Br
Product: O=C1CC2CCc3cnccc3C2=NN1c1ccc(C(F)(F)F)cc1

Procedure:
Prepared according to the method described in Example 1 from methyl 5,6,7,8-tetrahydro-5-oxoisoquinoline-6-acetate hydrobromide and 4-trifluoromethylphenylhydrazine.
Reaction SMILES: [OH:1][C@H:2]1[C@H:11]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:22]3[C:23](=[O:31])[C:24](=[O:30])[C:25]=3OC(C)C)[CH:9]=2)[O:4][C:3]1([CH3:33])[CH3:32].[CH2:34]([CH2:36][NH2:37])[OH:35]>CC#N.O>[OH:1][C@H:2]1[C@H:11]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:22]3[C:23](=[O:31])[C:24](=[O:30])[C:25]=3[NH:37][CH2:36][CH2:34][OH:35])[CH:9]=2)[O:4][C:3]1([CH3:32])[CH3:33]
Reactant: NCCO
Reactant: CC(C)Oc1c(-c2ccc3c(c2)[C@@H](N2Cc4ccccc4C2=O)[C@H](O)C(C)(C)O3)c(=O)c1=O
Solvent: CC#N
Solvent: O
Product: CC1(C)Oc2ccc(-c3c(NCCO)c(=O)c3=O)cc2[C@@H](N2Cc3ccccc3C2=O)[C@@H]1O
Temperature: 50 °C
Yield: 23.4 %

Procedure:
A solution of 529 mg(1.18 mmol) of 3-[trans-3-hydroxy-2,2-dimethyl-4-(1-oxo-1,3-dihydroisoindol-2-yl)-chroman-6-yl]-4-isopropoxy-cyclobut-3-ene- 1,2-dione as prepared in Example 3 in CH3CN (20 mL) and ethanolamine (716 μL; 11.8 mmol) was stirred at room temperature for 4 days. The reaction mixture was heated at 50° C. for 1 h, cooled to room temperature, diluted with H2O, and extracted into 20% THF/CH2Cl2. The organic extracts were dried over MgSO4 and purified by flash chromatography (CH2Cl2 : MeOH :NH4OH (93.25; 4.5; 2.25)) followed by trituration from MeOH/ether to give 124 mg of the title compound as a tan solid, mp 205°-215° C.: 1H-NMR (DMSO-d6 ; 400 MHz) δ8.93 (t, 1 H), 7.79 (dd, 1 H), 7.74 (s, 1 H), 7.69 (dd, 1 H), 7.5-7.64 (m, 3 H), 7.00 (d, 1 H), 5.75 (d, 1 H), 5.2-5.5 (br, 1 H), 4.86 (t, 1 H), 4.4-4.5 (br d, 1 H), 3.67 (m, 2 H), 3.53 (q, 3 H), and 1.27 ppm (s, 3 H); IR (KBr) 1780, 1710, 1660, and 1600 cm-1 ; mass spectrum (+FAB), m/e 449 (M +H), and 471 (M+Na). Anal. Calcd. for C25H24N2O6. 1 H2O C, 64.37; H, 5.62; N, 6.01 Found: C, 64.32; H, 5.83; N, 6.18.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[F:6][C:7]([F:27])([F:26])[O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][C:17]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:16]2=[O:25])=[CH:11][CH:10]=1.CCN(CC)CC>C(Cl)(Cl)Cl>[O:25]=[C:16]1[C:17]2([CH2:24][CH2:23][N:22]([S:1]([Cl:5])(=[O:3])=[O:2])[CH2:21][CH2:20]2)[CH2:18][CH2:19][N:15]1[C:12]1[CH:11]=[CH:10][C:9]([O:8][C:7]([F:27])([F:6])[F:26])=[CH:14][CH:13]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=S(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 405 mg (2.91 mmol) sulfuryl chloride in 15 mL anhydrous CHCl3 at 0° C. was slowly added a mixture of 915 mg (2.91 mmol) 2-(4-(trifluoromethoxy)phenyl)-2,8-diazaspiro[4.5]decan-1-one and 295 mg (2.91 mmol) NEt3 over a period of 30 min and stirred at 0° C. for 1 h. the mixture was allowed to warm to room temperature stirred for 1 h and 405 mg (2.91 mmol) sulfuryl chloride was added. The mixture was stirred for 5 h at room temperature, evaporated to dryness and used without further purification in the consecutive step. MS (ESI): 315.2 (M-SO2Cl)H+.
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:13]1(=[O:20])[NH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C1CCCCC1.N1C=CC=CC=1>[C:1]([N:19]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:20])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:19]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]2=[O:20])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CCCCCN1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Solvent: C1CCCCC1
Solvent: c1ccncc1
Product: O=C1CCCCCN1C(=O)c1ccc(C(=O)N2CCCCCC2=O)cc1

Procedure:
Terephthaloyl chloride (51 g, 0.25 mol) is added in the course of 30 minutes to a solution of ε-caprolactam (56.6 g, 0.5 mol) in 400 ml of cyclohexane and 117 ml of pyridine at room temperature. The mixture is then refluxed for 4 h. After cooling, the resulting light yellow precipitate is filtered off by suction, washed with water and dried. Yield 81 g (91%).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].C(N(CC)CC)C.[C:16](Cl)(=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH:6][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:2]
Reactant: CCN(CC)CCN
Reactant: CCCCCCCC(=O)Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNCCN(CC)CC
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.3 %

Procedure:
A mixture of N,N-diethylethylenediamine (9.6 g, 0.0826 mol) and 8.4 g (0.0826 mol) of triethylamine in 40 ml of chloroform was added dropwise to the ice cold chloroform solution (40 ml) of octanoyl chloride (13.4 g, 0.0826 mol). After addition, the ice bath was removed and the solution was stirred for 5 hours at room temperature. The reaction mixture was stirred with aqueous sodium bicarbonate for one hour. The organic layer was then dried over magnesium sulfate leaving a yellow liquid which was concentrated in vacuo. The yellow liquid was subject to high vacuum distillation to yield 9.65 g (0.040 mol, 48.3%, b.p.0.05mm =115° C.). The above amide (9.65 g, 0.040 mol) was reduced with lithium aluminum hydride (1.7 g, 0.045 mol) to yield 6.94 g (0.030 mol, 76.1%) of the product after vacuum distillation: (b.p.0.05mm =77° C.). NMR (CDCl3) δ 2.7-2.4 (m, 10H, NCH2 and NHCH2), 1.6 (s, 1H, NH), 1.5 (m, 2H, NHCH2CH2), 1.28 (s, 10H, NHCH2CH2 (CH2)5), 1.01 (t, 6H, NCH2CH3), 0.88 (t, 3H, CH3). Elemental Analysis: Caled. for C14H32N2 (228.41): C, 73.61; H, 14.12; N, 12.26. Found: C, 73.68; H, 14.76; N, 12.12.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][O:11][CH3:12])[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:16])[N:3]=1.[CH2:17]([CH:19]([NH2:22])[CH2:20][CH3:21])[CH3:18]>C1(C)C=CC=CC=1>[CH2:17]([CH:19]([NH:22][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][O:11][CH3:12])[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:16])[N:3]=1)[CH2:20][CH3:21])[CH3:18]
Reactant: CCC(N)CC
Reactant: COCc1c(C#N)c(Cl)nc(C)c1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: CCC(CC)Nc1nc(C)c([N+](=O)[O-])c(COC)c1C#N
Temperature: 50 °C

Procedure:
2-Chloro-3-cyano-4-methoxymethyl-5-nitro-6-methylpyridine (4.8 grams, 0.02 mole), 1-ethylpropylamine (3.6 grams, 0.04 mole) and 100 ml of toluene were charged into a glass reaction vessel fitted with a stirrer, thermometer and condenser. The reaction mixture was stirred and heated to 50° C. for 34 hours. It was then filtered and the solvent stripped off under reduced pressure to yield the desired product 2-(1-ethylpropylamino)-3-cyano-4-methoxymethyl-5-nitro-6-methylpyridine as a brown solid having a melting point of 74°-76° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11](=[O:23])[C:12]2[N:13]([N:15]=[C:16]([C:18]([O:20]CC)=[O:19])[CH:17]=2)[CH:14]=1.[OH-].[Na+].O.Cl>COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11](=[O:23])[C:12]2[N:13]([N:15]=[C:16]([C:18]([OH:20])=[O:19])[CH:17]=2)[CH:14]=1
Reactant: CCOC(=O)c1cc2c(=O)[nH]c(-c3ccc(Cl)cc3Cl)cn2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: O=C(O)c1cc2c(=O)[nH]c(-c3ccc(Cl)cc3Cl)cn2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
500 mg (1.42 mmol) of ethyl 6-(2,4-dichlorophenyl)-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazine-2-carboxylate (Example 11A) were suspended in 60 ml of 1,2-dimethoxyethane, 1M aqueous sodium hydroxide (5.7 ml, 5.7 mmol) was added and the mixture was stirred at RT for 3 h. The reaction mixture was poured into water and acidified to pH 2 using 2M aqueous hydrochloric acid. The precipitate was filtered off and washed with water. Drying gave 430 mg (93% of theory) of the product as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)([CH3:7])[CH3:6])[CH3:2].[OH-].[K+].CS(C)=O.Br[CH2:26][CH2:27][CH2:28][Cl:29]>O>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH2:26][CH2:27][CH2:28][Cl:29])([CH3:7])[CH3:6])[CH3:2]
Reactant: ClCCCBr
Reactant: CCOC(=O)C(C)(C)Oc1cccc2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1cccc2c1ccn2CCCCl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
2-(1H-Indol-4-yloxy)-2-methylpropionic acid ethyl ester (0.100 g, 0.40 mmol, 1.0 eq), powdered potassium hydroxide (0.034 g, 0.61 mmol, 1.5 eq), and DMSO (3 mL) were mixed and stirred at room temperature for 10 minutes. 1-Bromo-3-chloropropane (0.12 mL, 0.191 g, 1.21 mmol, 3.0 eq) was then added to the above mixture. The reaction mixture was stirred at room temperature for another 1.5 hours before 15 mL of water was added. The mixture was extracted with ethyl acetate (2×30 mL). The organic layer was collected, combined, washed with water (6×25 mL) and brine (2×20 mL), and dried over anhydrous Na2SO4. The solvent was removed in vacuo to afford 2-[1-(3-chloropropyl)-1H-indol-4-yloxy]-2-methylpropionic acid ethyl ester (0.127 g, yield: 97%) as a dense oily liquid, which was used for the next step without further purification.
Reaction SMILES: [C:1]([NH:4][CH:5](Br)[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2].[NH2:17][OH:18]>C1COCC1>[C:1]([NH:4][CH:5]([NH:17][OH:18])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: NO
Reactant: CC(=O)NC(Br)C(=O)NCc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)NC(NO)C(=O)NCc1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
2-Acetamido-N-benzyl-2-bromoacetamide (prepared from 2-acetamido-N-benzyl-2-ethoxyacetamide (3.00 g, 12.0 mmol) and BBr3 (1M in CH2Cl2, 17.2 mL, 17.2 rental)) was dissolved in THF (250 mL), cooled (-10° C.), and then added dropwise (30 min) to a suspension of NH2OH (5-6 equiv) in THF (50 mL) at -10° C. The reaction mixture was stirred (30 min) at this temperature and then allowed to warm to room temperature (1 h). The insoluble materials were filtered and the filtrate was concentrated in vacuo. The residue was separated into two components by flash column chromatography on SiO2 gel (7.5% MeOH/CHCl3).
Reaction SMILES: [BrH:1].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11](O)[C:12]([OH:14])=[O:13])=[CH:10][C:5]=2[O:4][CH2:3]1>C1(C)C=CC=CC=1.ClCCl>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]([Br:1])[C:12]([OH:14])=[O:13])=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: Br
Reactant: O=C(O)C(O)c1ccc2c(c1)OCO2
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(O)C(Br)c1ccc2c(c1)OCO2
Reaction time: 4 h

Procedure:
62% Aqueous hydrobromic acid (220 ml) was added slowly to a stirred suspension of 2-(1,3-benzodioxol-5-yl)-2-hydroxyacetic acid (see J Org Chem, 50(23), 4523-6, 1985; 82.4 g) in a mixture of toluene (500 ml) and dichloromethane (1 liter). The mixture was stirred vigorously for 4 h. The aqueous layer was separated and removed and the organics were dried (MgSO4) and concentrated to give a brown oil. The oil crystallised over a 24 h period to give 105.3 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:5]([C:6]2[N:10]=[CH:9][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:7]=2)[CH2:4][C@H:3]1[NH2:17].Cl[C:20]1[C:25]([C:26]#[N:27])=[CH:24][N:23]=[C:22]([S:28][CH3:29])[N:21]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[CH3:1][C:2]1([CH3:18])[C@@H:5]([C:6]2[N:10]=[CH:9][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:7]=2)[CH2:4][C@H:3]1[NH:17][C:20]1[C:25]([C:26]#[N:27])=[CH:24][N:23]=[C:22]([S:28][CH3:29])[N:21]=1
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: CC1(C)[C@H](N)C[C@@H]1c1ncn(C2CCCCO2)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C#N)c(N[C@@H]2C[C@H](c3ncn(C4CCCCO4)n3)C2(C)C)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
A mixture of (1R,3S)-2,2-dimethyl-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)cyclobutanamine (340 mg, crude) and 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (210 mg, 1.14 mmol) and DIEA (450 mg, 3.50 mmol) in isopropanol (5 mL) was stirred at 90° C. for 1 h. After removal of the solvent, the residue was purified by silica gel column chromatography (10%-30% ethyl acetate in petroleum ether) to afford the title compound (290 mg, 0.727 mmol, 65% yield for two steps). MS (ESI) m/z 400.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH2:14][CH2:15][OH:16])=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1)N>>[F:17][C:18]1[CH:19]=[C:20]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([O:13][CH2:14][CH2:15][OH:16])[C:3]=23)[CH:22]=[CH:23][C:24]=1[O:25][C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1
Reactant: CN(C)C=Nc1[nH]nc(OCCO)c1C#N
Reactant: Cc1ccc(Oc2ccc(N)cc2F)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCO)c34)cc2F)cn1
Yield: 50.1 %

Procedure:
The procedure described in Example 1 was repeated using N′-[4-cyano-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide (900 mg, 4.03 mmol) and 3-fluoro-4-[(6-methylpyridin-3-yl)oxy]aniline (967 mg, 4.43 mmol) to give the title compound as a white solid (800 mg, 50%); NMR Spectrum: 2.44 (s, 3H), 3.81 (br t, 2H), 4.34 (t, 2H), 5.13 (br s, 1H), 7.24-7.31 (m, 3H), 7.55 (dd, 1H), 7.98 (dd, 1H) 8.24 (d, 1H), 8.35 (s, 1H), 8.61 (br s, 1H); Mass Spectrum: 397 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[Br:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:17]=[CH:18][C:19](O)=O>>[Br:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[CH:17]=[CH:18]/[C:19]1[NH:1][C:2]2[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: COc1ccc(C=CC(=O)O)cc1Br
Product: COc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(C)c(=O)n3C)cc1Br
Yield: 43.3 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.00 g (11.8 mmol) of 5,6-diamino-1,3-dimethyluracil and 3.32 g (12.9 mmol) of 3-bromo-4-methoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylformamide to give 2.00 g (yield 43%) of Compound 120 as a pale yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:37]5[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=5)[CH:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)c4)cc3)cc2)CC1
Reactant: OB(O)c1cccnc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccnc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(3-bromo-phenylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and pyridine-3-boronic acid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[NH2:9][CH2:10][C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[N:20][C:19]3[N:22]([CH2:25][CH3:26])[N:23]=[CH:24][C:18]=3[C:17]=2[NH:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[O:13][N:12]=1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:9][CH2:10][C:11]1[N:15]=[C:14]([C:16]2[C:17]([NH:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[C:18]3[CH:24]=[N:23][N:22]([CH2:25][CH3:26])[C:19]3=[N:20][CH:21]=2)[O:13][N:12]=1)=[O:7]
Reactant: O=C(Cl)CCCCCl
Reactant: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CN)no3)cnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CNC(=O)CCCCCl)no3)cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
5-chloropentanoyl chloride (0.12 mmol) was added to a stirred solution of Intermediate 118 (0.1 mmol) and diisopropylethylamine (0.3 mmol) in chloroform (1 ml) at room temperature. After stirring at room temperature for 16 h, the reaction mixture was applied to a SPE cartridge (aminopropyl, 2 g) and the cartridge was eluted sequentially with chlororm, ethyl acetate and methanol. Fractions containing the desired product were combined and blown down under nitrogen. The resulting residue was further purified on a SPE cartidge (silica, 1 g) eluting with a gradient of 30-100% ethyl acetate in petroleum ether to afford Intermediate 120 as a white solid (46 mg). LCMS showed MH+=462, TRET=2.86 min.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:37])[CH2:8][CH2:9][N:10]([CH3:36])[C:11]1[C:12]([NH2:35])=[CH:13][C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:28][CH:27]=3)[CH:23]=[CH:22][N:21]=2)=[C:15]([O:17][CH3:18])[CH:16]=1>C(Cl)Cl>[CH3:37][N:7]([CH3:6])[CH2:8][CH2:9][N:10]([CH3:36])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:28][CH:27]=3)[CH:23]=[CH:22][N:21]=2)=[CH:13][C:12]=1[NH:35][C:1](=[O:4])[CH:2]=[CH2:3]
Reactant: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3c[nH]c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
Temperature: -5 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
A solution of acryloyl chloride (0.584 mL, 1M in CH2Cl2, 0.58 mmol) was added dropwise to N1-(2-dimethylaminoethyl)-N4-[4-(1H-indol-3-yl)pyrimidin-2-yl]-5-methoxy-N1-methylbenzene-1,2,4-triamine (Intermediate 168, 252 mg, 0.58 mmol) in CH2Cl2 (10 mL) and the mixture was then stirred at −5° C. for 1 h. The mixture was then diluted with CH2Cl2 (100 mL), and the resulting solution was washed with sat. NaHCO3 (25 mL), water (25 mL), and then sat. brine (25 mL), and was then concentrated in vacuo. Purification by FCC, eluting with 0-30% CH3OH in CH2Cl2 gave the title compound (76 mg, 27%) as a white solid; 1H NMR (CDCl3) 2.25 (6H, s), 2.27-2.34 (3H, m), 2.69 (3H, s), 2.84-2.94 (2H, m), 3.87 (3H, s), 5.68 (1H, dd), 6.40 (1H, d), 6.48 (1H, dd), 6.78 (1H, s), 7.03 (1H, d), 7.08-7.20 (2H, m), 7.33 (1H, dd), 7.65 (1H, s), 8.12 (1H, d), 8.26 (1H, d), 8.59 (1H, s), 9.74 (1H, s), 9.97 (1H, s), 10.24 (1H, s); m/z: ES+ MH+ 486.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.[C:12](N1C=CN=C1)([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[S:13]>C(#N)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:9][C:12]([N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)=[S:13])[S:8][C:4]=2[CH:3]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc2nc(N)sc2c1
Solvent: CC#N
Product: Cc1ccc2nc(NC(=S)n3ccnc3)sc2c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 62.3 %

Procedure:
To 6-methylbenzo[d]thiazol-2-amine (1. g, 6.2 mmol) in acetonitrile (30 mL) was added 1,1′-thiocarbonyldiimidazole (1.44 g, 8.1 mmol). The reaction was stirred at 50° C. for 18 hours. The reaction was cooled to room temperature and the precipitate was filtered and washed with acetonitrile (2×50 mL). The yellow powder was dried in a vacuum oven (40° C.) for 1 hour to yield N-(6-methylbenzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide (1.06 g, 3.86 mmol, 62% yield) and then used in the next step without any further purification or characterization.