Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=O)=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[NH:12][C:11]2=[O:17])=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:35]
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Reactant: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.6 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(3-fluoro-phenyl)2-oxo-1,2-dihydro-indol-3-ylidenemethyl]4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (26 mg, 23%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][NH:12][CH2:13][CH2:14][OH:15]>O>[CH3:11][N:12]([CH2:13][CH2:14][OH:15])[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CNCCO
Reactant: Clc1nc2ccccc2s1
Solvent: O
Product: CN(CCO)c1nc2ccccc2s1
Temperature: 120 °C

Procedure:
A mixture of 2-chlorobenzothiazole (8.5 g) and 2-methylaminoethanol (20 ml) was heated at 120° C. under pressure in a sealed, glass lined, stainless steel reaction vessel for 18 hours. After cooling, the oil was added to water (100 ml), extracted with dichloromethane (2×100 ml), the organic extracts were dried (MgSO4), filtered and evaporated to dryness. Chromatography of the residual oil on silica-gel in 21/2% methanol in dichloromethane gave the title compound which was used in Preparation 1 without further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:4]=2[S:3]1.Br[CH2:14][CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[OH:17][CH2:16][CH2:15][CH2:14][N:6]1[C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:4]=2[S:3][C:2]1=[O:1]
Reactant: O=Cc1ccc2[nH]c(=O)sc2c1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc2c(c1)sc(=O)n2CCCO
Temperature: 65 °C
Yield: 128.3 %

Procedure:
2-oxo-2,3-dihydro-1,3-benzothiazole-6-carbaldehyde (120 mg, 0.67 mmol), 3-bromopropan-1-ol (85 μL, 0.94 mmol), potassium carbonate (278 mg, 2.01 mmol) and potassium iodide (55 mg, 0.33 mmol) were suspended in acetonitrile (2 mL) and the whole mixture was heated at 65° C. for 48 h. Then, the solids were filtered off and washed with acetonitrile and the resulting filtrate was evaporated to dryness to afford the title compound as a solid (204 mg of 77% purity by HPLC, 99% yield) which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.[CH3:14][C:15]([S@@:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6](/[CH:7]=[N:20]/[S@:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19])[CH:9]=[CH:10][CH:11]=1
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
In a 50 ml round-bottomed flask, 3-(trifluoromethoxy)benzaldehyde (400 mg, 2.1 mmol) was dissolved in dichloromethane (12 ml) and (S)-2-methylpropane-2-sulfinamide (281 mg, 2.31 mmol) and anhydrous copper (II) sulfate (739 mg, 4.63 mmol) were added. The reaction mixture was stirred at room temperature overnight then filtered through a glass microfiber filter, rinsing with dichloromethane. The filtrate was concentrated and the residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-20% EtOAc) to afford 430 mg (70%) of (S)-2-methyl-propane-2-sulfinic acid 1-(3-trifluoromethoxy-phenyl)-meth-(E)-ylideneamide as a light yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:20][NH:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([OH:33])=[CH:30][CH:31]=2)[N:26]([CH3:34])[C:25]=1[CH3:35])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+].O>CCOC(C)=O>[CH3:20][NH:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([O:33][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:30][CH:31]=2)[N:26]([CH3:34])[C:25]=1[CH3:35])=[O:23]
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N5CCC(OC)C5)sc34)ccc12

Procedure:
This material was prepared by the reaction of 7-chloro-2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 4b (157 mg, 0.5 mmole) with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid methylamide 16e (150 mg, 0.7 mmole) and Cs2CO3 (673 mg, 2.1 mmole) in a manner as previously described for example 1 to give 51 mg (39%) of a crisp foam. 1H NMR (DMSO-d6) δ8.54 (1H, dd, J=5.5, 1.13 Hz), 8.05 (1H, s), 7.84 (1H, d, J=8.6 Hz), 7.61-7.55 (1H, m), 7.54 (1H, d, J=2.1 Hz), 7.03 (1H, dd, J=2.1, 8.6 Hz), 6.64 (1H, d, J=5.5 Hz), 4.12-3.51 (5H, m), 3.67 (3H, s), 3.27, 3.24 (3H, 2 s), 2.80 (3H, d, J=4.5 Hz), 2.60 (3H, s), 2.35-1.95 (2H, m). Anal. Calcd for C25H26N4O4S.0.9 H2O.0.2 EtOAc: C, 60.47; H, 5.78; N, 10.93; S, 6.26. Found: C, 60.46; H, 5.56; N, 10.81; S, 6.34.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[CH2:29]([N:3]1[CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1][CH2:2]1)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCNCC3)nc1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCN(CCc2ccccc2)CC3)nc1

Procedure:
Take up 6-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)nicotinamide (0.0500 g, 0.176 mmol) and K2CO3 (0.0488 g, 0.353 mmol) in DMF (1.0 mL). Add 2-bromoethylbenzene (0.0265 mL, 0.194 mmol) and eat to 70° C. overnight. Remove DMF as an azeotrope with xylenes. Purify by 5 g SCX column by washing with methanol and eluting with 2.0 M NH3 in methanol. Then purify by flash chromatography, eluting with 0-10% ethyl acetate and 5% (2.0 M NH3 in methanol) in dichloroethane to give the title compound: MS ES+ 388.1 (M+H)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=1.7 min, 100% purity.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH3:6][Si:7]([CH3:22])([CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]1[CH2:15][O:14]1>C(O)C>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:15][CH:13]([OH:14])[CH2:12][O:11][CH2:10][CH2:9][CH2:8][Si:7]([CH3:22])([CH3:6])[CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH3:2]
Reactant: CCNCC
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Solvent: CCO
Product: CCN(CC)CC(O)COCCC[Si](C)(C)CC[Si](C)(C)C
Temperature: 60 °C

Procedure:
Diethylamine (2.66 g, 36.4 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 60° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 60° C. for an additional 8 hours. Ethanol and diethyl amine were stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][S:15]([C:18]1[CH:19]=[C:20]([C:30](O)=[O:31])[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:22][CH:23]=1)(=[O:17])=[O:16]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:30]([C:20]3[CH:19]=[C:18]([S:15]([CH3:14])(=[O:17])=[O:16])[CH:23]=[CH:22][C:21]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:31])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Reactant: Oc1ccc(N2CCNCC2)cc1
Product: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)N2CCN(c3ccc(O)cc3)CC2)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from ′1-(4-hydroxyphenyl)-piperazine [56621-48-8] and 4-Methanesulfonyl-biphenyl-2-carboxylic acid (Example V). MS (ISP): 437.4 MH+.
Reaction SMILES: [Cl:1][C@@:2]1([CH3:25])[C@H:7]([C:8]([OH:10])=[O:9])[N:6]2[C:11](=[O:24])[C@@H:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:5]2[S:4][CH2:3]1.[N+:26]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1)([O-:28])=[O:27].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C@@:2]1([CH3:25])[C@H:7]([C:8]([O:10][CH2:33][C:32]2[CH:35]=[CH:36][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=2)=[O:9])[N:6]2[C:11](=[O:24])[C@@H:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:5]2[S:4][CH2:3]1
Reactant: C[C@@]1(Cl)CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@]1(Cl)CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 94.3 %

Procedure:
A solution of 3β-chloro-3α-methyl-7β-phenoxyacetamidocepham-4α-carboxylic acid (2.74 g), p-nitrobenzyl bromide (1.52 g), and triethylamine (1 ml) in dimethylformamide (30 ml) is kept at room temperature for 3 hours. The reaction mixture is poured into ice water, and extracted with ethyl acetate. The extract solution is washed with water, dried, and evaporated in vacuo to give p-nitrobenzyl 3β-chloro-3α-methyl-7β-phenoxyacetamidocepham-4α-carboxylate (3.45 g). Yield: 93%.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[C:8]1([CH:14]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][N:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[NH:26][C:25]3=[O:33])[CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC1C=CC=CC=1>O>[C:5]([N:26]1[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N:24]([CH2:23][CH2:22][CH2:21][N:18]2[CH2:19][CH2:20][N:15]([CH:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:16][CH2:17]2)[C:25]1=[O:33])(=[O:7])[CH3:6]
Reactant: O=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)n1c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21

Procedure:
A mixture of 1.55 parts of acetic acid anhydride, 3 parts of 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one and 22.5 parts of methylbenzene is stirred and refluxed overnight. Water is added to the reaction mixture and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1-acetyl-3-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 124.4° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([Sn](C)(C)C)=[CH:5][CH:4]=[N:3]1.[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:18]=[C:19](I)[S:20][C:13]=12>CC1C=CC=CC=1C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:18]=[C:19]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[S:20][C:13]=12
Reactant: Cn1nccc1[Sn](C)(C)C
Reactant: Clc1ccnc2cc(I)sc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: Cn1nccc1-c1cc2nccc(Cl)c2s1

Procedure:
A mixture of 1-methyl-5-trimethylstannanyl-1H-pyrazole 10a (2.1 g, 8.5 mmole), 7-chloro-2-iodo-thieno[3,2-b]pyridine (2.5 g, 8.5 mmole), tetrakis(triphenylphosphine)palladium(0) (0.5 g, 0.4 mmole, 5 mol %) in o-xylene (85 ml was degassed, purged with nitrogen and heated to 120°, which gave an orange solution. After 14 hours the black reaction mixture was diluted with toluene (100 ml) and extracted with 1.2 M HCl (3×60 ml). The combined aqueous layers were washed with toluene (100 ml). The organic layers were discarded and the aqueous layer was treated with NaOH to pH 14. The resultant white solid was collected (1.1 g, 52%): TLC (6% methanol-dichloromethane) Rf 0.8; 1H-NMR (DMSO-d6, 400 MHz) δ 8.70 (1H, d, J=5.3 Hz), 8.00 (1H, s), 7.63 (1H,d, J=5.3 Hz), 7.56 (1H, d, J=2.0 Hz), 6.79 (1H, d, J=2.0 Hz), 4.09 (3H, s). ESIMS m/z 250 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][OH:15].Cl[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=1>C1COCC1>[CH3:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][O:15][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(C)CCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)CCOc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
Add sodium bis(trimethylsilyl)amide (3.95 mL, 7.9 mmol, 2M solution in THF) to a solution of 3,3-dimethyl-butan-1-ol (960 □L, 7.9 mmol) in anhydrous THF (10 mL). Stir for 30 min at room temperature and then add a solution of 6-chloro-nicotinonitrile (1 g, 7.2 mmol) in anhydrous THF (5 mL). Stir at room temperature overnight and then quench the reaction mixture with saturated aqueous NaHCO3 (100 mL). Extract the aqueous layer with dichloromethane (3×100 mL) and wash the organic layer with brine (100 mL). Dry the combined organic extracts over MgSO4 and concentrate in vacuo to give the desired intermediate as a yellow solid (1.4 g, 94%). GC-MS m/z: 204 (M+).
Reaction SMILES: [Cl:1][C:2]([Cl:6])=[CH:3][CH2:4]Cl.[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH:12]=[CH:11]2>>[CH3:22][CH:18]([C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH2:4][CH:3]=[C:2]([Cl:6])[Cl:1])[CH:9]=2)[CH:14]=1)[C:19]([OH:21])=[O:20]
Reactant: ClCC=C(Cl)Cl
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Product: CC(C(=O)O)c1ccc2cc(OCC=C(Cl)Cl)ccc2c1

Procedure:
The title compound is prepared according to the method of Example 7 using 3,3-dichloroallyl chloride and racemic 6-hydroxy-α-methyl-2-naphthaleneacetic acid. White crystals are obtained having a melting point of 107°-109° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1cnc(-c2ccccc2)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cnc(-c2ccccc2)nc1
Temperature: 25 °C

Procedure:
A suspension of 5-methyl-2-phenyl-pyrimidine (3.0 g, 17.6 mmol), N-bromosuccinimide (2.0 g, 11.2 mmol) and a,a'-azobis(isobutyronitrile) (0.10 g, 0.61 mmol) in dry carbon tetrachloride (150 mL) is refluxed for 0.5 hours. After cooling to room temperature, the mixture is filtered and the filtrate is concentrated in vacuo, giving 5-bromomethyl-2-phenyl-pyrimidine as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[CH3:20])=[CH:15][CH:14]=1.S([O-])([O-])(=O)=O.[Mg+2].C(O)(=O)C>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:18]=[CH:17][C:16](/[C:19](=[N:1]/[C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][O:5][C:6]3=[O:11])/[CH3:20])=[CH:15][CH:14]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: Nc1cccc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C/C(=N\c1cccc2c1COC2=O)c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 36 h
Yield: 87.6 %

Procedure:
To a solution of 4-aminoisobenzofuran-1(3H)-one (1 g, 6.7 mmol) and 1-(4-fluorophenyl)ethanone (1.4 g, 10.1 mmol) in toluene (35 mL) was added anhydrous magnesium sulfate (8.8 g, 73.7 mmol) and acetic acid (0.2 mL) at room temperature under N2. The reaction mixture was then stirred at 120° C. for 36 hr. The reaction mixture was cooled to 90° C. and filtered. After filter cake was washed with acetonitrile, the filtrates were combined and evaporated to dryness to obtain yellow solid, which was washed by petroleum ether to obtain the title compound as a white solid (1.58 g, yield 88%). LC-MS (ESI) m/z: 270(M+1)+H-NMR (400 MHz, CDCl3) δ (ppm): 2.30 (s, 3H), 5.16 (s, 2H), 7.00-7.02 (d, J=7.6 Hz, 1H), 7.13-7.18 (m, 2H), 7.51-7.56 (t, J=7.6 Hz, 1H), 7.66-7.69 (d, J=7.6 Hz, 1H), 7.99-8.03 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:2].[NH2:18][OH:19]>CCO>[NH2:2][C:1](=[N:18][OH:19])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: NO
Reactant: CCOC(=O)CCCOc1cccc(C#N)c1
Solvent: CCO
Product: CCOC(=O)CCCOc1cccc(C(N)=NO)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.1 %

Procedure:
Ethyl 4-(3-cyanophenoxy)butanoate (3.79 g; 16.25 mmol; 1 eq.) was suspended in EtOH (75.80 mL). Hydroxylamine (2.40 mL; 81.24 mmol; 5 eq.) was added in one portion and the reaction mixture was stirred at RT for 24 hours. The reaction mixture was concentrated affording the title compound as a white solid (4.29 g, 99%). 1H NMR (DMSO-d6, 300 MHz) δ 9.61 (br s, 1H), 7.27-7.20 (m, 3H), 6.94-6.90 (m, 1H), 5.79 (br s, 2H), 4.11-3.98 (m, 4H), 2.48-2.44 (t, J=7.15 Hz, 2H), 2.01-1.93 (m, 2H), 1.20-1.15 (t, J=7.03 Hz, 3H). LC/MS (Method A): 266.8 (M+H)+. HPLC (Method A) Rt 2.62 min (Purity: 98.8%).
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][CH2:4][N:3]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2]1.[C:22]1([S:28]([CH2:30][CH2:31]Cl)=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[H-].[Na+]>CN(C=O)C>[C:22]1([S:28]([CH2:30][CH2:31][N:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]3[CH2:1][CH2:2][N:3]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4][CH2:5][C:6]2=3)=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(CCCl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccccc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCS(=O)c3ccccc3)c3ccccc23)CC1
Reaction time: 3 h

Procedure:
tert-Butyl 1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.170 g, 0.594 mmol) and 2-chloroethyl phenyl sulfoxide (0.225 g, 1.20 mmol, 2.0 equiv.) was dissolved in DMF (10 mL) at rt. NaH (0.100 mg, 2.5 mmol, 4.21 equiv., 60% dispersion) was added, then the reaction mixture was stirred for 3 h. The reaction was quenched with a saturated aqueous NH4Cl solution and partitioned between water and CH2Cl2. The aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were concentrated and the residue was dissolved in EtOAc, dried over MgSO4, filtered, and concentrated. The crude product was chromatographed (Biotage 12 m SiO2 column, eluted with a 20% to 30% EtOAc in hexane gradient) to give tert-butyl 6-[2-(phenylsulfinyl)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate.
Reaction SMILES: [CH3:1][NH:2][CH:3]([C:5]1[CH:19]=[CH:18][C:8]2[N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH:10]=[N:11][C:7]=2[CH:6]=1)[CH3:4].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[NH:32][N:31]=[C:30]([CH:33]3[CH2:35][CH2:34]3)[CH:29]=2)[CH:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:33]1([C:30]2[NH:31][N:32]=[C:28]([NH:27][C:25]3[CH:24]=[CH:23][N:22]=[C:21]([N:2]([CH3:1])[CH:3]([C:5]4[CH:19]=[CH:18][C:8]5[N:9]([CH:12]6[CH2:17][CH2:16][CH2:15][CH2:14][O:13]6)[CH:10]=[N:11][C:7]=5[CH:6]=4)[CH3:4])[N:26]=3)[CH:29]=2)[CH2:35][CH2:34]1
Reactant: CNC(C)c1ccc2c(c1)ncn2C1CCCCO1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccc2c(c1)ncn2C1CCCCO1)N(C)c1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
A tube was charged with mixture of 84 (200 mg, 0.77 mmol), 53 (181 mg, 0.77 mmol) and DIPEA (200 mg, 1.5 mmol) in IPA (5 mL), sealed and stirred at 120° C. overnight. The reaction mixture was cooled to RT and concentrated under reduced pressure. The crude residue was purified by SiO2 chromatography eluting with a MeOH/DCM gradient (5% to 15% MeOH) to afford 68 mg (19%) of (±)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-methyl-N2-(1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)ethyl)pyrimidine-2,4-diamine (86) as white solid: MS (ESI) m/z=459.2 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:19]=3[NH2:28])[CH2:12][CH2:11]2)=[N:2]1.[C:29]1([CH3:38])[C:30]([N:35]=[C:36]=[O:37])=[CH:31][CH:32]=[CH:33][CH:34]=1>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:19]=3[NH:28][C:36]([NH:35][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH3:38])=[O:37])[CH2:14][CH2:15]2)=[N:2]1
Reactant: Cc1ccccc1N=C=O
Reactant: COc1cc(N)c(CCN2CCN(c3nsc4ccccc34)CC2)cc1OC
Solvent: ClCCl
Product: COc1cc(CCN2CCN(c3nsc4ccccc34)CC2)c(NC(=O)Nc2ccccc2C)cc1OC
Temperature: 40 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
2-[2-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-4,5-dimethoxy-phenylamine (160 mg, 0.4 mmol) was dissolved in 4 mL methylene chloride and 2-tolyl isocyanate (49 μL, 0.4 mmol) was added. The reaction mixtures were stirred at 40° C. overnight. Methylene chloride was added to the vial and the reaction mixture was washed with water. The product was recrystallized in isopropyl alcohol. 1-{2-[2-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-4,5-dimethoxy-phenyl}-3-o-tolyl-urea (168 mg) was isolated in 100% purity @ 254 nm; LCMS (APCI): 532 [M+H]+; mp 200° C.; 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.87 (d, J=8 Hz, 1H), 7.80 (m, 2H), 7.47 (t, 1H), 7.33 (t, 1H), 7.18 (t, 1H), 7.11 (m, 2H), 7.02 (t, 1H), 6.74 (s, 1H), 6.35 (s, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.61 (t, 4H), 2.77 (m, 2H), 2.73 (m, 4H), 2.67 (m, 2H), 2.12 (s, 3H).