Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH2:14])=[N:10][CH:9]=2)=[CH:4][C:3]=1[F:15].Cl[CH:17]([CH:20]([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[CH:25]2)[CH3:21])[CH:18]=O.C(N(CC)CC)C>C(O)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:17]([CH:20]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)[CH3:21])=[CH:18][N:14]=3)[N:13]=2)=[CH:4][C:3]=1[F:15]
Reactant: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Reactant: CC(c1ccc2ncccc2c1)C(Cl)C=O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(c1ccc2ncccc2c1)c1cnc2ncc(-c3ccc(Br)c(F)c3)nn12
Temperature: 110 °C
Yield: 60 %

Procedure:
A mixture of 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (100.0 mg, 0.3716 mmol, prepared as described for Example 7, Steps 1-5) and 2-chloro-3-quinolin-6-ylbutanal (0.10 g, 0.44 mmol, prepared as described for Example 122, Steps 1-4) in isopropyl alcohol (3 mL) was heated at 110° C. for 48 h. The mixture was adjusted to pH 9 by adding triethylamine. The volatiles were removed under reduced pressure and the residue was purified by chromatography on silica gel with MeOH in methylene chloride (0-8%) to afford the desired product (0.10 g, 60%). LCMS: (M+H)=448/450.0.
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1.[Cl:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26](Cl)=[O:27])[CH:21]=[CH:22][C:23]=1[Cl:24]>>[ClH:17].[ClH:1].[Cl:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([N:8]2[CH2:9][CH2:10][N:5]([CH3:4])[CH2:6][CH:7]2[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:27])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: CN1CCNC(CN2CCCC2)C1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: CN1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C(CN2CCCC2)C1
Yield: 127.3 %

Procedure:
The procedure described in Example 17. but using 1.0 g of 1-methyl-3-(pyrrolidin-1-ylmethyl)piperazine trihydrochloride, 2.1 ml of tciethylamine and 0.8 g of 3,4-dichlorophenylacetyl chloride, to afford 1.01 g of the title compound, melting at 223°-227° C. (dec.).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[C:16]([OH:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O>>[Br:14][C:15]1[C:16]([OH:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cccc(Br)c1O
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3cccc(Br)c3O)CC2)nc[nH]1

Procedure:
6-[4-(3-Bromo-2-hydroxy-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3-bromo-2-hydroxybenzaldehyde (available from Aldrich). 1H NMR (400 MHz, CDCl3) δ 2.62-2.66 (m, 4H), 3.60-3.70 (m, 4H), 3.75 (s, 2H), 5.40 (s, 1H), 6.67-6.70 (m, 1H), 6.92-6.94 (m, 1H), 7.43-7.45 (m, 1H), 7.84 (s, 1H), 11.95 (br s, 1H). Mass spectrum (ES) MH+=365.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[Cl:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.ClCCl>C(OCC)(=O)C>[Cl:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1cnc2ccccc2c1Cl)c1ccccc1
Temperature: 40 °C
Yield: 25.5 %

Procedure:
Under a nitrogen atmosphere, a mixture of 3-amino-4-chloroquinoline (2.50 g, 1 eq), benzoyl chloride (3.0 g, 1.5 eq), and anhydrous dichloromethane (100 mL) was heated at 40° C. After 23 hours additional benzoyl chloride (3.0 g, 1.5 eq) was added and heating was continued for a total of 48 hours. The reaction mixture was diluted with ethyl acetate, washed sequentially with aqueous potassium carbonate (×2), water, and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The crude product was purified by column chromatography (230 g of silica gel eluted initially with a gradient of 20-50% ethyl acetate in hexanes and then with 4/3/3 dichloromethane/ethyl acetate/hexanes) to provide 1.01 g of N-(4-chloroquinolin-3-yl)benzamide as a white solid.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([CH2:11][CH:12]([F:28])[CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)=[CH:3]1>C(O)C>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([CH2:11][CH:12]([F:28])[CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]2)=[CH:3]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC(F)Cc2coc3ccccc23)CC1
Agent: Cl
Solvent: CCO
Product: NC1CCN(CC(F)Cc2coc3ccccc23)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A stream of hydrogen chloride gas is circulated through a solution of 3.64 g of the product obtained in Step A in 70 ml of ethanol. After 2 hours' stirring at 50° C., the reaction mixture is concentrated under reduced pressure. The residue is taken up in water and in 20% sodium hydroxide solution, extracted with dichloromethane, dried and then evaporated, enabling the expected product to be isolated.
Reaction SMILES: [C:1]1([CH:11]=[CH:12][CH:13]=[CH:14][C:15]([CH3:20])=[C:16]([F:19])[CH2:17][OH:18])[C:10]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:3][CH:2]=1.FO>ClCCl.[O-2].[O-2].[Mn+4]>[C:1]1([CH:11]=[CH:12][CH:13]=[CH:14][C:15]([CH3:20])=[C:16]([F:19])[CH:17]=[O:18])[C:10]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:3][CH:2]=1
Reactant: CC(C=CC=Cc1ccc2cccccc1-2)=C(F)CO
Agent: [Mn+4]
Agent: OF
Agent: [O-2]
Solvent: ClCCl
Product: CC(C=CC=Cc1ccc2cccccc1-2)=C(F)C=O

Procedure:
Alcohol 20 (obtained as described in Example 14) is oxidized with active manganese dioxide (5 g) in dichloromethane until the disappearance of starting material (monitored by thin layer chromatography on silica gel, dichloromethane solvent) affords the desired product, 7-(1-azulenyl)-2-fluoro-3-methyl- 2,4,6-heptatrienal, 21 , as a 2-cis/2-trans mixture as determined by NMR spectroscopy.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]([N:17]=[CH:18]N(C)C)=[S:16])=[O:7])([CH3:4])[CH3:3].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH3:33])=[O:25]>CN(C)C=O.ClCCl>[C:2]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[S:16][C:23]([C:24](=[O:25])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][CH3:33])=[CH:18][N:17]=1)=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: CN(C)C=NC(=S)NC[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: CCc1ccccc1C(=O)CBr
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1ccccc1C(=O)c1cnc(NC[C@@H]2CCCN2C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 65 h
Yield: 65.1 %

Procedure:
To a solution of 2-(S)-(3-dimethylaminomethylene-thioureidomethyl)-pyrrolidine-1-carboxylic acid 1,1-dimethylethyl ester (150 mg) in N,N-dimethylformamide (2 ml) was added 2-bromo-1-(2-ethylphenyl)-ethanone (109 mg). The mixture was stirred 65 h at room temperature, diluted with dichloromethane, washed twice with water, once with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (2:1 ethyl acetate/hexane eluant) to afford the product as yellow oil (129 mg, 65%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:17]=[C:16]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[C:15](=[O:25])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:26][C:27]([F:32])([F:31])[C:28]([O-:30])=[O:29].[CH:33]1([N:38]2[CH2:43][CH2:42][NH2+:41][CH2:40][C:39]2=[O:44])[CH2:37][CH2:36][CH2:35][CH2:34]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C.C(Cl)Cl>[F:26][C:27]([F:32])([F:31])[C:28]([O-:30])=[O:29].[CH:33]1([N:38]2[CH2:43][CH2:42][N:41]([C:4]([C:3]3[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=3[F:1])[CH2:11][C:12]3[CH:17]=[C:16]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[C:15](=[O:25])[NH:14][NH+:13]=3)=[O:6])[CH2:40][C:39]2=[O:44])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C1C[NH2+]CCN1C1CCCC1
Reactant: O=C(O)c1cc(Cc2cc(C(F)(F)C(F)(F)F)c(=O)[nH]n2)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1cc(Cc2cc(C(F)(F)C(F)(F)F)c(=O)[nH][nH+]2)ccc1F)N1CCN(C2CCCC2)C(=O)C1

Procedure:
OO7, 4-cyclopentyl-3-oxopiperazin-1-ium trifluoroacetate (1 eq.), TBTU (1 eq.) and N-methyl-morpholine (2.2 eq.) were stirred for 2 h in DMF. The product was purified by preparative HPLC (water/MeCN, 0.1% TFA as eluents) and desired pooled product fractions were lyophilized to afford a white powder. The powder was dissolved in DCM and washed with sat. aq. NaHCO3. The organic phase was dried (Na2SO4), filtered and concentrated to dryness to afford the product as colourless oil. 1H-NMR (300 MHz, DMSO-d6) δ: 13.52 (1H, s), 7.90 (1H, s), 7.46-7.22 (3H, m), 4.82-4.65 (1H, m), 4.15 (1H, s), 4.03 (2H, s), 3.80 (2H, s), 3.42-3.20 (3H, m), 1.80-1.40 (8H, m). MS (ES) C23H22F6N4O3 requires: 516, found: 517 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([O:22][CH2:23][CH3:24])=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14]CC2C=CC=CC=2)=[CH:10][CH:9]=1)[CH3:7])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[CH:5]([O:22][CH2:23][CH3:24])[CH:6]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(OCC)=C(C)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(OCC)C(C)c1ccc(O)cc1
Yield: 94 %

Procedure:
3-(4-Benzyloxyphenyl)-2-ethoxy-3-methylacrylic acid ethyl ester (1.58 g; 4.64 mmole) was hydrogenated at atmospheric pressure in ethyl acetate (20 ml) using Pd/C (wet) as catalyst. After filtration through celite, the solvent was evaporated in vacuo to give (1.1 g; yield 94%) of 3-(4-hydroxyphenyl)-2-ethoxybutanoic acid ethyl ester as a diastereomeric mixture.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[C:18](C(OCC)=O)=[C:17]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)[C:16]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:15]([CH2:38][CH2:39][C:40]([F:43])([F:42])[F:41])[N:14]=1)=O)(C)(C)C.C(N(CC)CC)C>OC(C(F)(F)F)=O.ClCCl.ClCCl>[CH2:36]([O:35][C:33]([C:16]1[C:15]([CH2:38][CH2:39][C:40]([F:41])([F:43])[F:42])=[N:14][C:13]2[C@H:9]3[N:8]([C:6](=[O:5])[C:18]=2[C:17]=1[C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)[CH2:12][CH2:11][CH2:10]3)=[O:34])[CH3:37]
Reactant: CCOC(=O)c1c(CCC(F)(F)F)nc([C@@H]2CCCN2C(=O)OC(C)(C)C)c(C(=O)OCC)c1-c1ccc(C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1c(CCC(F)(F)F)nc2c(c1-c1ccc(C(=O)O)cc1)C(=O)N1CCC[C@@H]21
Reaction time: 1.5 h
Yield: 40.7 %

Procedure:
To a stirred solution of 4-[2-[(2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl]-3,5-bis(ethoxycarbonyl)-6-(3,3,3-trifluoropropyl)-4-pyridinyl]benzoic acid (3.0 g, 4.93 mmol) dissolved in 30 mL of dichloromethane TFA (7 mL) was added. The reaction stirred for 1.5 h. and was then concentrated to yield a reddish brown oil. The crude mixture was dissolved in 35 mL of dichloromethane and triethylamine (10 mL) was added slowly. The reaction was allowed to stir overnight. The mixture was then concentrated and redissolved in 50 mL of ethyl acetate. The organics were washed with 1 M HCl, H2O and Brine. The organics were then dried over sodium sulfate, filtered and concentrated. The concentrated material was purified by column chromatography (dichloromethane/MeOH (20:1)) to yield 0.928 g (41%) of the desired product as an off white solid.
Reaction SMILES: C=C1CCCC1[O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:11]([O:13][CH3:14])=[O:12].N1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)C=CC=1.Cl>O>[C:26]1([CH2:25][C:9]2[C:8]([OH:7])=[C:17]([O:18][CH3:19])[CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])[CH2:27][CH2:28][CH2:29][CH:24]=1
Reactant: c1ccc2ncccc2c1
Reactant: C=C1CCCC1Oc1cc(C(=O)OC)ccc1OC
Agent: Cl
Solvent: O
Product: COC(=O)c1ccc(OC)c(O)c1CC1=CCCC1
Temperature: 190 °C
Reaction time: 1 h

Procedure:
12.7 g of methyl 3-(2-methylenecyclopentyloxy)-4-methoxybenzoate are treated with 50 ml of quinoline and the mixture is stirred at 190° C. for 1 h. After cooling, it is treated with water, adjusted to pH 3 using 2N HCl and extracted with ethyl acetate. The residue which remains after concentrating the solvent is chromatographed on a silica gel column using ethyl acetate/petroleum ether (4:6). The chromatographically pure fractions are concentrated and dried in a high vacuum. 10.2 g of the title compound are obtained as a yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:34]=[CH:33][C:32]([C:35](Cl)=[O:36])=[CH:31][CH:30]=1>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([NH:1][C:35]([C:32]3[CH:33]=[CH:34][C:29]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:30][CH:31]=3)=[O:36])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3ccc(-c4ccccc4)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and [1,1′-biphenyl]-4-carbonyl chloride: ESMS m/e: 560.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7]/[N:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21](/[CH:25]=[C:26](/[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)\[C:27]#[N:28])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[CH:20]=2)[C:26]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)([C:27]#[N:28])[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[NH:8]1)=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#C/C(=C\c1cccc(Cl)c1)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)C/N=C/c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1NC(c2cccc(Cl)c2)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1
Yield: 42.6 %

Procedure:
In a manner similar to the method described in Example 1c, {[1-(3-Chloro-phenyl)-meth-(E)-ylidene]-amino}-acetic acid tert-butyl ester prepared in Example 32a (2 g, 7.6 mmol) was reacted with (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (0.55 g, 2 mmol) prepared in Example 1b, AgF (1.3 g, 10 mmol), and triethylamine (1.9 g, 19 mmol) in dichloromethane (30 mL) at 50° C. for 20 h to give rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.45 g, 44%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:21](=[O:22])[NH:20][CH2:19][CH2:18][C:17]=2[C:16]=34)=[CH:5][CH:4]=1)=O.[CH3:23][NH:24][CH3:25].C([BH3-])#N.[Na+].Cl>CO.[Cl-].[Zn+2].[Cl-]>[CH3:23][N:24]([CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:21](=[O:22])[NH:20][CH2:19][CH2:18][C:17]=2[C:16]=34)=[CH:5][CH:4]=1)[CH3:25]
Reactant: CNC
Reactant: O=Cc1ccc(-c2[nH]c3cccc4c3c2CCNC4=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Product: CN(C)Cc1ccc(-c2[nH]c3cccc4c3c2CCNC4=O)cc1
Reaction time: 0.5 h

Procedure:
The aldehyde (310 mg, 1.07 mmol) in MeOH (40 mL) was treated with dimethyl amine (2M solution in MeOH, 6.41 mmol). The solution was cooled with an ice/water bath and treated dropwise with a solution of sodium cyanoborohydride (74 mg, 1.18 mmol) and zinc chloride (80 mg, 0.59 mmol) in MeOH (10 mL). The resulting solution was adjusted to pH=6-7 with 2M methanolic HCl. After stirring for 30 min., the reaction was quenched with conc. HCl (0.2 mL) and the methanol was removed by evaporation. The residue was diluted with water (30 mL). The solution adjusted to pH=10-11 with KOH (s) and extracted with CH2Cl2 (30 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The crude product was crystallized (CH2Cl2/MeOH/hexanes) to give 2-(4-(N,N-dimethylamino)methylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one, 245 mg (72%), as an off-white solid. mp 226-229° C. (dec.); 1H NMR (300 MHz, d6-DMSO) δ 2.18 (s, 6H), 3.06 (m, 2H), 3.40 (m, 2H), 3.44 (s, 2H), 7.21 (t, 1H, J=7.7 Hz), 7.43 (d of ABq, 2H, J=7.9 Hz), 7.56 (d, 1H, J=7.7 Hz), 7.61 (d of ABq, 2H, J=7.9 Hz), 7.69 (d, 1H, J=7.7 Hz), 8.05 (br t, 1H), 11.53 (br s, 1H); HRMS (FAB, MH+) Calcd for C20H22N3O: 320.1763; Found: 320.1753; Anal. (C20H21N3O.0.55H2O) C, H, N.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OC(C)(C)C)=O)[CH2:8][C@H:9]([O:10][S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C@H:5]2[O:4][CH2:3]1.[H][H]>[Pd].C(O)C>[CH3:18][C:17]1[CH:19]=[CH:20][C:14]([S:11]([O:10][C@H:9]2[CH2:8][NH:7][C@@H:6]3[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]23)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CN(C(=O)OC(C)(C)C)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)O[C@H]2CN[C@H]3[C@@H]2OC[C@@H]3O)cc1
Reaction time: 1.5 h

Procedure:
Preparation (3R,3aR,6S,6aS)-tert-Butyl 3-hydroxy-6-(tosyloxy)tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (35). Ethanol (20 mL) was added dropwise to a mixture of 10% palladium on charcoal (50 mg) and anti-(33) (578 mg, 1.33 mmol) under an atmosphere of argon. The argon was replaced by hydrogen then the suspension was stirred for 1.5 hours before filtering the mixture through celite in vacuo. The filter cake was washed with ethanol then the solvents removed in vacuo from the filtrate to obtain (3R,3aR,6S,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl 4-methylbenzenesulfonate which was used without further purification.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([OH:14])[CH2:9][CH2:10][CH2:11][C:12]#[CH:13].C1(NC2CCCCC2)CCCCC1.C(#N)C>[Cu]I.CCOCC>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[C:13]#[C:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:14]
Reactant: Brc1ncccn1
Reactant: C#CCCCCO
Agent: [Cu]I
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CCOCC
Solvent: CC#N
Product: OCCCCC#Cc1ncccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A mixture of 2-bromopyrimidine (3.96 g), 5-hexynol (2.44 g), dicyclohexylamine (4 g), BTPC (250 mg), copper (I) iodide (25 mg) and acetonitrile (40 ml) was stirred at ambient temperature under nitrogen for 1 h (temp. rose to ~45°). Ether (120 ml) was added, the mixture was filtered and the filtrate was evaporated in vacuo to an oil which was purified by FCC. Elution with ether followed by System C (17:3) gave the title compound as a pale yellow oil (3.64 g), t.l.c. (System C 17:3) Rf 0.34.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@@H:12]([CH3:15])[C@H:11]([OH:16])[CH2:10]2)[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][N:3]=1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21].CS(C)=O>O>[C:20]([NH:24][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@@H:12]([CH3:15])[C@H:11]([OH:16])[CH2:10]2)[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][N:3]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)N
Reactant: C[C@@H]1CC[C@@H](Nc2nc(Cl)ncc2C(N)=O)C[C@H]1O
Solvent: CS(C)=O
Solvent: O
Product: C[C@@H]1CC[C@@H](Nc2nc(NC(C)(C)C)ncc2C(N)=O)C[C@H]1O
Temperature: 68 °C
Reaction time: 60 h

Procedure:
A mixture of 2-chloro-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)pyrimidine-5-carboxamide (4 g), tert-butylamine (14 mL) and DMSO (20 mL) was heated to 68° C. and held for 60 hours. After cooling to room temperature, water (20× vol, 80 mL) was added over 2 hours. The slurry was agitated for 2 hours and the crude product was collected as the DMSO hemi-solvate of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide (Form H) by suction filtration.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH3:8][CH:9]([CH3:12])[CH2:10][SH:11].[NH2:13][C:14]1[N:22]=[C:21](Cl)[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Cl-].[Na+].O>[NH2:13][C:14]1[N:22]=[C:21]([S:11][CH2:10][CH:9]([CH3:12])[CH3:8])[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: CC(C)CS
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 100 °C
Yield: 31.5 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (300 mg, 7.5 mmol, 60% in mineral oil) were added 2-methylpropane-1-thiol (1 ml, 11 mmol) and 6-amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) in order. The mixture was stirred under heating at 100° C. for 5 hours. Brine was added thereto and the mixture was extracted with chloroform. The organic layer was dried on magnesium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (76 mg, yield 31%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:18])C=1.C(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)=[O:18]
Reactant: CSc1ccc(N)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CS(=O)c1ccc(N)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
20 g (143.66 mmol) of 4-methylthioaniline was placed in a flask and dissolved in 660 mL of CH2Cl2. The solution was cooled to 0° C. and 35.42 g (143.66 mmol) of m-chloroperbenzoic acid was added. The mixture was stirred for 3 h at room temperature and poured into CHCl3. It was then washed with saturated NaHCO3 solution, dried over MgSO4 and the solvent was removed, yielding a crude product that was purified by chromatography on silica gel, using MeOH/EtOAc/hexane mixtures of increasing polarity as eluent. The title compound of the example was obtained as a white solid (17.84 g, 80%).
Reaction SMILES: [OH-].[K+].C([O:6][CH2:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][O:12][CH:13]([CH3:15])[CH3:14])(=O)C>CO>[CH:13]([O:12][CH2:11][CH2:10][CH:9]([CH3:16])[CH2:8][CH2:7][OH:6])([CH3:15])[CH3:14]
Reactant: CC(=O)OCCC(C)CCOC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(CCO)CCOC(C)C

Procedure:
21 g (0.375 mol) of potassium hydroxide are added to 50.5 g (0.25 mol) of 1-acetoxy-5-isopropoxy-3-methylpentane, dissolved in 300 cc of methanol. The mixture is boiled at reflux for 1 hour, concentrated by evaporation to 20 cc at 30°C and 150 cc of water are added. The mixture is extracted with chloroform. The chloroform extract is washed with water, dried with sodium sulphate and evaporated. The residue is distilled at 20 mm Hg. Gas-chromatographically pure 5-isopropoxy-3-methyl-1-pentanol, having a B.P. of 118°-120° /20 mm Hg, is obtained. nD20 = 1.4371.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(N(CC)C(C)C)(C)C.CN(C)C=O.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)(=O)C>[N+:10]([C:3]1[CH:4]=[C:5]([CH2:8][OH:9])[CH:6]=[CH:7][C:2]=1[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([O-:12])=[O:11]
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1cc(CO)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(CO)ccc1Nc1ccccc1

Procedure:
(4-Fluoro-3-nitrophenyl)methanol (1.500 g, 0.008765 mol), N,N-diisopropylethylamine (3.054 mL, 0.01753 mol), N,N-dimethylformamide (3.688 mL, 0.04764 mol), and aniline (2.40 mL, 0.0263 mol) were placed into three separate microwave vials. Each was reacted at 150° C. for 30 minutes. The resultant gel was dissolved in ethyl acetate, washed once with 5% citric acid and once with brine, dried and concentrated. The residue was used directly in the next step.