Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](OC(=O)C)(=[O:12])[CH3:11]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Cl)cc1Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Cl)cc1Br
Reaction time: 8 h
Yield: 87.2 %

Procedure:
To a stirred mixture of 2-bromo-4-chloroaniline (5 g, 24 mmol) and catalytic DMAP in CH2Cl2 (15 mL) was add acetic anhydride (2.3 mL, 24 mmol) at room temperature. The reaction mixture was stirred overnight then washed with saturated aqueous NaHCO3 solution. The CH2Cl2 layer was dried (MgSO4), filtered, concentrated in vacuo. The crude material was triturated with Hexane/Et2O and the solid filtered and dried in vacuo to give N-(2-bromo-4-chloro-phenyl)-acetamide (5.2 g, 86%). HPLC: Rt=2.26 min. m/z=248 (M+H+).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:21])[C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[F:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N+:17]([C:15]1[CH:16]=[C:11]([C:10]2[O:21][C:2]3[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=3[N:9]=2)[C:12]([F:20])=[CH:13][CH:14]=1)([O-:19])=[O:18]
Reactant: O=C(Nc1cc(F)ccc1O)c1cc([N+](=O)[O-])ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(F)ccc3o2)c1

Procedure:
Prepared by the method of Example 15b), from N-(2-hydroxy-5-fluorophenyl)-2-fluoro-5-nitrobenzamide (676 mg, 2.3 mmol) and p-toluenesulfonic acid monohydrate (961 g, 5.1 mmol) the subtitle compound was obtained (318 mg, 50%). 1H NMR (DMSO) δ 8.94(m, 1H), 8.54(m, 1H), 7.95(m, 1H), 7.81(m, 2H), 7.41(m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=1
Reactant: N#Cc1cccc(C(=O)CBr)c1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2cccc(C#N)c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-3′-cyanoacetophenone. 1H-NMR (CDCl3) δ: 8.21 (1H , d, J=1.8 Hz), 8.03 (1H, s), 7.94 (1H, m), 7.80-7.72 (1H, m), 7.63-7.52 (2H, m), 7.32 (1H, dd, J=8.4, 1.8 Hz), 6.10 (2H, brs), 3.88 (2H, q, J=7.3 Hz), 0.95 (3H, t, J=7.3 Hz).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([C:11]2[CH:16]=[C:15]([F:17])[C:14](B(O)O)=[C:13]([F:21])[CH:12]=2)=[C:6]([F:22])[CH:5]=1)[CH2:2][CH3:3].[Cl:23][C:24]1[N:29]=[CH:28][C:27](Br)=[CH:26][N:25]=1>>[CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([C:27]3[CH:26]=[N:25][C:24]([Cl:23])=[N:29][CH:28]=3)=[C:13]([F:21])[CH:12]=2)=[C:6]([F:22])[CH:5]=1)[CH2:2][CH3:3]
Reactant: Clc1ncc(Br)cn1
Reactant: CCCc1cc(F)c(-c2cc(F)c(B(O)O)c(F)c2)c(F)c1
Product: CCCc1cc(F)c(-c2cc(F)c(-c3cnc(Cl)nc3)c(F)c2)c(F)c1

Procedure:
0.25 mol of 39A is coupled to 0.29 mol of 2-chloro-5-bromopyrimidine analogously to Example 1A. The product obtained in this way is processed further without purification.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18]([CH:26]=[CH2:27])=[CH:19][N:20]=[CH:21]3)[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:28].CO>>[ClH:28].[CH:26]([C:18]1[C:17]2[C:22](=[CH:23][CH:24]=[CH:25][C:16]=2[O:15][C@H:12]2[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]2)[CH:21]=[N:20][CH:19]=1)=[CH2:27]
Reactant: C=Cc1cncc2cccc(O[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Solvent: CO
Product: C=Cc1cncc2cccc(O[C@H]3CC[C@H](N)CC3)c12

Procedure:
According to the method of Example 1, Step C, deprotection was performed (room temperature, 2 hours) by using Intermediate 124 (83.9 mg) and 10% hydrogen chloride/methanol solution (2 ml). The solvent was evaporated under reduced pressure, and the residue was added with methanol (0.5 ml) and diethyl ether (1.5 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (63.3 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])[C:11]([CH3:14])=[C:10]([CH3:15])[C:9]1=[O:16].[Cl:17][CH2:18][C:19](O)=[O:20].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])[C:11]([CH3:14])=[C:10]([CH3:15])[C:9]1=[O:16])=[O:20]
Reactant: O=C(O)CCl
Reactant: CC1=C(C)C(=O)N(CCCCCCO)C1=O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC1=C(C)C(=O)N(CCCCCCOC(=O)CCl)C1=O

Procedure:
A mixture of 67.6 g (0.30 mole) of N-(6-hydroxyhexyl)dimethylmaleimide, 34.0 g (0.36 mole) of chloroacetic acid, 3.5 g of concentrated sulfuric acid and 300 ml of toluene is reacted and worked up as described in Example 1. The residue consists of 86.6 g of a colourless oil.
Reaction SMILES: [C:1]1(=[O:21])[N:5]([CH2:6][CH2:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=O)[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12.[N+:22]([CH3:25])([O-:24])=[O:23].C(O)(=O)C.C(N)CCC.C(OC)(OC)OC>CO>[C:4]1(=[O:16])[N:5]([CH2:6][CH2:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=[CH:25][N+:22]([O-:24])=[O:23])[C:1](=[O:21])[C:2]2=[CH:20][CH:19]=[CH:18][CH:17]=[C:3]12
Reactant: O=Cc1ccccc1CCN1C(=O)c2ccccc2C1=O
Reactant: C[N+](=O)[O-]
Solvent: COC(OC)OC
Solvent: CCCCN
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CCc1ccccc1C=C[N+](=O)[O-]
Temperature: 35 °C
Reaction time: 30 h

Procedure:
To a stirred suspension of 2-(2′-phthalimidoethyl) benzaldehyde (900 gm, 3.22 mol), in methanol (9.0 Lt) were added nitromethane (521 ml, 9.65 mol), acetic acid (349 ml, 6.1 mol), n-butyl amine (486 ml, 4.72 mol) and trimethyl orthoformate (499 ml, 3 mol) at room temperature. The reaction mixture was then stirred at 30-40° C. for 30 hrs. The greenish coloured solid was filtered at suction, washed with chilled methanol (700 ml) and dried at 50° C. for 8 hrs. This gave the title compound, 649 gm, (62.5%) in the form of cream coloured solid
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][C:13]#[N:14])[N:6]=1)(=[O:3])[CH3:2].[C:15](OC(=O)C)(=[O:17])[CH3:16].CO>O.N>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16])[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(CCC#N)n1
Reactant: CC(=O)OC(C)=O
Agent: N
Solvent: CO
Solvent: O
Product: CC(=O)NCCCc1cccc(NC(C)=O)n1
Temperature: 25 °C
Reaction time: 28 h

Procedure:
2-Acetylamino-6-(2-cyanoethyl)pyridine (11.5 mg, 78 μmol) was dissolved in 25% ammonia water (3.0 ml) and, after purging with nitrogen, palladium black (30 mg) was added thereto. After repurging with nitrogen, the mixture was stirred at room temperature under a hydrogen stream at 9 atmospheres for 28 hours. After nitrogen purging, the palladium black was filtered off and the filtrate was concentrated under reduced pressure. Chloroform (500 μl) was added to the residue and, the mixture was cooled with ice and, after addition of acetic anhydride (100 μl, 1.1 mmol), stirred for 10 minutes. After allowing the temperature to rise to room temperature, stirring was continued for 5 hours. After cooling with ice, methanol (1.0 ml) was added and the mixture was stirred for 1 hour and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [silica gel 10 g, chloroform-methanol (19:1)→(15:1)] to give 2-acetylamino-6-(3 -acetylaminopropyl)pyridine as a colorless solid (Yield 6 mg (51%)).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[CH2:11]([CH:13]([CH2:17][CH3:18])[C:14](Cl)=[O:15])[CH3:12].[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH2:11]([CH:13]([CH2:17][CH3:18])[C:14]([C:3]1[S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[CH3:1])=[O:15])[CH3:12]
Reactant: CCC(CC)C(=O)Cl
Reactant: Cc1csc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CCC(CC)C(=O)c1sc2ccccc2c1C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a mixture of 3-methyl-1-benzothiophene (1.00 g), 2-ethylbutyryl chloride (1.02 mL) and nitromethane (10 mL) was added aluminum chloride (1.35 g) at 0° C., and the mixture was stirred for 3 hr. Water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-10% ethyl acetate/hexane) to give the title object compound (1.65 g, 99%) as a pale-yellow oil.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[CH2:24]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH2:25][CH2:26][CH3:27]>>[CH2:24]([C:28]1[CH:29]=[CH:30][C:31]([NH:32][C:1]([C:4]23[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]2)[CH2:6][CH2:5]3)=[O:3])=[CH:33][CH:34]=1)[CH2:25][CH2:26][CH3:27]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CCCCc1ccc(N)cc1
Product: CCCCc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 40.1 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-butylaniline (51.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-butylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (28.2 mg).
Reaction SMILES: [CH2:1]([C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[NH2:14][OH:15]>CCO>[OH:15][NH:14][C:12](=[NH:13])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: NO
Reactant: CCCCCCCCCCCC#N
Solvent: CCO
Product: CCCCCCCCCCCC(=N)NO
Temperature: 70 °C
Reaction time: 48 h
Yield: 94 %

Procedure:
To a solution of undecyl cyanide (1.810 g, 9.98 mmol) in EtOH (20 mL) was added a 50% aqueous solution of hydroxylamine (1 mL) and the resulting reaction mixture was stirred at 70° C. for 48 h. The solvents were evaporated and the resulting white solid was dissolved in EtOAc (100 mL) and washed with H2O (2×20 mL), dried over MgSO4, filtered and the solvents evaporated under vacuum to give the title compound as a white solid (2.001 g, 94%). 1H NMR (CDCl3, 300 MHz) δ 6.21-4.99 (br s, 1H), 4.49 (br s, 2H), 2.07 (t, J=7.6 Hz, 2H), 1.55-1.40 (m, 2H), 1.34-1.09 (m, 16H), 0.81 (t, J=7.0 Hz, 3H)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[C@@H:23]2[CH2:27][C@H:26]([N:28]3[CH:32]=[C:31]([CH2:33][OH:34])[CH:30]=[N:29]3)[C@@H:25]([OH:35])[C@H:24]2[OH:36])=[C:16]([NH:37][CH2:38][CH:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:15]=1)=[O:13].FC(F)(F)C(O)=O.O[C@@H]1[C@H](O)[C@@H](N2C=C(C)C=N2)C[C@H]1N1C=NC2C1=NC(NC1CCC(N[C:104]([NH:106][CH:107]3[CH2:112][CH2:111][N:110]([C:113]4[CH:118]=[CH:117][CH:116]=[CH:115][N:114]=4)[CH2:109]C3)=[O:105])CC1)=NC=2NCC(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1N1CC[C@H](NC(N2C=CN=C2)=O)C1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:114]1[CH:115]=[CH:116][CH:117]=[CH:118][C:113]=1[N:110]1[CH2:111][CH2:112][C@H:107]([NH:106][C:104](=[O:105])[NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([N:28]4[CH:32]=[C:31]([CH2:33][OH:34])[CH:30]=[N:29]4)[C@@H:25]([OH:35])[C@H:24]3[OH:36])=[C:16]([NH:37][CH2:38][CH:39]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:15]=2)=[O:13])[CH2:109]1
Reactant: Cc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NC5CCC(NC(=O)NC6CCN(c7ccccn7)CC6)CC5)nc43)[C@H](O)[C@@H]2O)c1
Reactant: NCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1
Agent: O=C(N[C@H]1CCN(c2ccccn2)C1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1)N[C@H]1CCN(c2ccccn2)C1

Procedure:
This compound is prepared from 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (2-amino-ethyl)-amide trifluoroacetate (Example 80, first step a) using a procedure analogous to that of 1-{4-[9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-methyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-ylamino]-cyclohexyl}-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-urea trifluoroacetate (Example 42) replacing N-[1-(2-pyridinyl)-4-piperidinyl]-1H-imidazole-1-carboxamide with imidazole-1-carboxylic acid ((S)-1-pyridin-2-yl-pyrrolidin-3-yl)-amide. MS (ES+) m/e 394 (MH+/2).
Reaction SMILES: Br[CH2:2][C:3]1[C:10]([CH2:11]Br)=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[C:13]1([C:19]([NH2:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:19]([N:32]1[CH2:2][C:3]2[C:4]([C:5]#[N:6])=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:11]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1cccc(CBr)c1CBr
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: N#Cc1cccc2c1CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2

Procedure:
Prepared in analogy to Example A2(b) from 2,3-Bis-bromomethyl-benzonitrile (CAS: 66126-18-9) and triphenylmethylamine. Yellow foam.
Reaction SMILES: Cl.C(O)C.[NH2:5][C:6]([NH2:33])=[N:7][C:8]([C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:23][CH2:24][O:25]CC3C=CC=CC=3)[C:12]=2[CH:11]=1)=[O:9]>[C].[Pd].C1COCC1>[NH2:33][C:6]([NH2:5])=[N:7][C:8]([C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:23][CH2:24][OH:25])[C:12]=2[CH:11]=1)=[O:9]
Reactant: NC(N)=NC(=O)c1ccc2c3ccccc3n(CCOCc3ccccc3)c2c1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: NC(N)=NC(=O)c1ccc2c3ccccc3n(CCO)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.5 %

Procedure:
A 1.0 ml portion of 1 M hydrochloric acid and 40 mg of 10% palladium-carbon were added to an ethanol 9 ml-THF 3 ml solution of 393 mg N-(diaminomethylene)-9-[2-(benzyloxy)ethyl]-9H-carbazole-2-carboxamide, followed by stirring at room temperature for 3 days under an atmosphere of hydrogen gas. After carrying out celite filtration by adding 1 M sodium hydroxide aqueous solution, the organic solvent was evaporated and the water layer was extracted with chloroform, followed by washing with saturated brine and drying with anhydrous magnesium sulfate. By evaporating the solvent, 140 mg of N-(diaminomethylene)-9-(2-hydroxyethyl)-9H-carbazole-2-carboxamide was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[NH2:23][C:24]1[CH:40]=[CH:39][C:27]([O:28][C:29]2[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)=[CH:26][CH:25]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:23][C:24]2[CH:40]=[CH:39][C:27]([O:28][C:29]3[CH:34]=[CH:33][C:32]([S:35](=[O:37])(=[O:36])[NH2:38])=[CH:31][CH:30]=3)=[CH:26][CH:25]=2)=[O:21])=[CH:18][CH:19]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: Nc1ccc(Oc2ccc(S(N)(=O)=O)cc2)cc1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Nc4ccc(Oc5ccc(S(N)(=O)=O)cc5)cc4)cc3)c2)o1

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-[4-(4-sulphamoylphenoxy)phenyl-]1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-(4-aminophenoxy)phenylsulphonamide using method I. LCMS; retention time 3.38 min, MH+ 541.
Reaction SMILES: I[CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[N-:9]=[N+:10]=[N-:11].[Na+]>CS(C)=O.C(OCC)C>[N:9]([CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)=[N+:10]=[N-:11]
Reactant: ICC1CCOCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: [N-]=[N+]=NCC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Iodomethyl)tetrahydro-2H-pyran (4.76 g, 21.1 mmol) was dissolved in dimethyl sulfoxide (25 mL). Sodium azide (2.70 g, 41.5 mmol) was added and the mixture was stirred at ambient temperature overnight. The resulting slurry was diluted with diethyl ether and washed with water. The organic layer was concentrated under reduced pressure to afford the title compound. The product was used directly in subsequent reactions without characterization.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15]([NH2:18])(=[O:17])=[O:16].S([O-])(O)(=O)=O.[Na+]>CN(C)C=O>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15]([N:18]=[CH:3][N:4]([CH3:6])[CH3:5])(=[O:17])=[O:16]
Reactant: COC(OC)N(C)C
Reactant: NS(=O)(=O)CCCCCCl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C=NS(=O)(=O)CCCCCCl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.29 ml of N,N-dimethylformamide-dimethyl acetal were added dropwise at ambient temperature under an inert gas atmosphere to a solution of 1.5 g of the product of Step A in 8 ml of dimethylformamide. The solution was stirred at ambient temperature for 3 hours, then poured into a 1% aqueous solution of sodium hydrogen sulfate, extracted with ethyl acetate, washed with water, then with a saturated aqueous solution of sodium chloride, dried and evaporated to dryness under reduced pressure to obtain 1.809 g of the expected product.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([CH2:12][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[C:21]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])[N:20]=[C:19]2[N:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:33])=O)C.O.[OH-].[Na+]>C1COCC1>[OH:9][CH2:10][CH2:12][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[C:21]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])[N:20]=[C:19]2[N:32]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH3:33]
Reactant: CCOC(=O)COc1cccc2c(N(C)c3ccccc3)nc(Nc3ccccc3C)nc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1Nc1nc(N(C)c2ccccc2)c2cccc(OCCO)c2n1

Procedure:
Lithium aluminium hydride (0.27 g, 7.1 mmol) was added to dry distilled THF (50 ml) and the mixture stirred in an ice-bath under dry nitrogen. A solution of 8-(ethoxycarbonylmethoxy)-4-(N-methylphenylamino)-2-[(2-methylphenyl)amino]quinazoline (2.4 g, 5.43 mmol) in dry THF (30 ml) was added dropwise at such a rate as to keep the reaction temperature below 5°. The mixture was then allowed to freely reach room temperature and stirred for three hours. Water was carefully added followed by a little 40% NaOH. Two layers were produced and this mixture was extracted (×2) with ethyl acetate. The combined organic extracts were worked with water (×3) and brine, dried (Na2SO4) and evaporated to give an oil which crystallised on scratching to a yellow solid (1.9 g).
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1.[SH:15][CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+].O>C(O)C>[CH:12]([C:11]1[C:3]([CH2:2][S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1)([CH3:14])[CH3:13]
Reactant: CC(C)c1cc2c(cc1CCl)OCO2
Reactant: O=C(O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1cc2c(cc1CSCC(=O)O)OCO2
Yield: 58.8 %

Procedure:
A suspension of 3.3 g of 5-chloromethyl-6-isopropyl-1,3-benzodioxole (crude oil) in 10 ml of ethanol was added to a liquid mixture comprising 2.1 g of mercaptoacetic acid, 3 g of sodium hydroxide, 25 ml of ethanol and 25 ml of water to carry out the reaction at 80° C. for 40 minutes. The reaction mixture was concentrated, followed by the addition of water. The obtained mixture was washed with ethyl acetate. Concentrated hydrochloric acid was added to the mixture to acidify the aqueous layer, followed by the extraction with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The residue was purified by column chromatography to obtain 2.45 g of the title compound as a colorless prismatic crystal.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[CH3:19])=[C:8]([Cl:20])[CH:7]=1.[CH3:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][C:39]=1B1OC(C)(C)C(C)(C)O1)[C:33]([O:35][CH3:36])=[O:34].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:20][C:8]1[CH:7]=[C:6]([NH:5][CH2:4][C:3]2[CH:21]=[CH:22][C:23]([C:25]([F:28])([F:27])[F:26])=[CH:24][C:2]=2[C:39]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][C:30]=2[CH3:29])[CH:11]=[CH:10][C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[CH3:19]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: Cc1cc(Cl)ccc1-c1ccc(NCc2ccc(C(F)(F)F)cc2Br)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(-c3ccc(Cl)cc3C)c(Cl)c2)c(C)c1
Temperature: 25 °C

Procedure:
N-(2-bromo-4-(trifluoromethyl)benzyl)-2,4′-dichloro-2′-methyl-[1,1′-biphenyl]-4-amine, prepared as described in Example 1, (500 mg, 1.0 mmol), methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (339 mg, 1.2 mmol), Pd(dppf)Cl2 (84 mg, 0.1 mmol), and K2CO3 (283 mg, 2.0 mmol) were dissolved in 1,4-dioxane (8 mL) and water (2 mL) and the resulting mixture was heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[NH:12][C:11](=O)[N:10]3[CH:14]=[CH:15][N:16]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:28].CO.CCN(C(C)C)C(C)C.CCOC(C)=O>C(Cl)Cl>[Cl:28][C:11]1[N:10]2[CH:14]=[CH:15][N:16]=[C:9]2[CH:8]=[C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1cc(-c2cc3nccn3c(=O)[nH]2)cn1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cn1cc(-c2cc3nccn3c(Cl)n2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.2 %

Procedure:
To a suspension of 7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5(6H)-one (Preparation I; 9.60 g, 44.6 mmol) in dry DCM (90 mL) was added DIEA and the suspension stirred at ambient temperature for 5 minutes. The mixture was cooled to 0° C. and POCl3 (12.3 mL, 134 mmol) was added over 5 minutes. The mixture was allowed to reach ambient temperature and the resulting thick slurry was treated with dry DCM (50 mL). The mixture was vigorously stirred at ambient temperature for 23 hours. The resulting light tan suspension was diluted with hexanes (90 mL) and collected by vacuum filtration. The collected solid was washed with Et2O and dried in vacuum to give the crude product salt. The salt was suspended in 5:20:75 MeOH/DIEA/EtOAc (200 mL) and stirred for 30 minutes at ambient temperature. The mixture was filtered through a SiO2 plug capped with a Celite layer eluting with 5% MeOH/EtOAc. The filtrate was concentrated and the residual solid dried in vacuum to provide the title compound (5.65 g, 54% yield) as a light cream colored solid. MS (apci) m/z=234.2 (M+H).